Homeostasis: Active Regulation of the Internal Environment

9 Homeostasis: Active Regulation of the Internal Environment

Harsh Reality TV Introduced in 2004, the reality television show The Biggest Loser went on to become a huge prime-time hit. The premise of the show was simple enough--the contestant who lost the most weight during the season won--but the effort required from the contestants was immense. The biggest loser of them all in season 8 (2009) was Danny C. Through a punishing combination of near-starvation dieting and all-day exercise, Danny shed an incredible 239 pounds (108 kilograms), dropping from 430 pounds to a svelte 191 pounds in just 7 months. Other initially obese contestants similarly accomplished exceptional weight loss and delighted in revealing their new, slimmer silhouettes to their friends, families, and viewers. Recognizing an unusual opportunity, a group of scientists followed Danny and other

Biggest Loser contestants for 6 years following their weight loss: the longest-term study of its kind ever conducted (Fothergill et al., 2016). The results are discouraging. In the years after his appearance on the show, and despite exceptional ongoing efforts, Danny regained more than 100 pounds of the weight he had lost. In fact, all but one of the 14 contestants who were tracked in the study regained significant weight; some were even heavier after the show than they were before the contest started. The pattern of results confirms a common observation: it is very hard to keep the weight off after dieting. But what could explain the additional discovery that even after 6 long years of hard work, the metabolisms of these contestants still had not adjusted and instead strived to return them to their original obese state?

Millions of years of evolution have endowed our bodies with complex physiological mechanisms, and multiple backup systems, devoted to producing a stable internal environment, monitored and regulated by the brain at every stage. But in the context of modern society, some of these ancient systems are making trouble for us; obesity, for example, is reaching epidemic proportions and placing a severe burden on health care resources. The physiological and behavioral processes governing the internal environment, and their role when things go wrong, are our topic in this chapter.

9.1Homeostatic Systems Share Several Key Features

View Animation 9.2: Brain Explorer homeostasis The maintenance of a relatively constant internal physiological environment. motivation The psychological process that induces or sustains a particular behavior. thermoregulation The active process of maintaining a relatively constant internal temperature through behavioral and physiological adjustments. endotherm An animal whose body temperature is regulated chiefly by internal metabolic processes. ectotherm An animal whose body temperature is regulated by, and whose heat comes mainly from, the environment. negative feedback The process whereby a system monitors its own output and reduces its activity when a set point is reached. set point The point of reference in a feedback system. set zone The optimal range of a variable that a negative feedback system tries to maintain.

In the first part of the chapter, we use body temperature to explore the general principles of homeostasis. By the end of this section, you should be able to: 9.1.1 Define homeostasis and allostasis and their relationships to drive states. 9.1.2 Distinguish between endothermy and ectothermy, with examples, and discuss the pros and cons of each system. 9.1.3 Describe, with appropriate examples, how the engineering concepts of negative feedback and redundancy apply to homeostatic systems. 9.1.4 Discuss some of the ways in which animals use specialized behaviors to maintain a stable internal environment. The bodies of many animals exhibit some degree of homeostasis: a relatively stable, balanced internal environment that is optimized for cellular activities. Variables such as acidity, saltiness, water level, oxygenation, temperature, and energy availability are closely monitored and controlled by elaborate physiological systems. Deviations from optimum states can affect motivation, the psychological process that induces or sustains a particular behavior, and the effect can escalate rapidly as the deviation worsens from a minor distraction (like the urge to take a couple of sips if water is handy) to an overwhelmingly powerful need (like the raging thirst of someone lost in the desert). Because it is a relatively simple system, we'll start by using thermoregulation, the regulation of body temperature, to look at some important general concepts of homeostasis: negative feedback, redundancy, behavioral compensation, and the concept of allostasis. These topics will arise again when we talk about fluid balance, appetite, and body weight in the remainder of the chapter. We mammals are endotherms, meaning that we make our own heat inside our bodies, using metabolism and muscular activity (and if our muscles aren't making enough heat, we can shiver them to make more). Endothermy gives us clear advantages over ectotherms (animals that get their heat mostly from outside the body-- from the environment) by allowing us to roam more widely. Like endotherms, ectotherms such as lizards and snakes try to regulate their temperature within a range that is optimal for the functioning of their cells, but this means they need to stay near sources of warmth. Furthermore, the evolution of endothermy involved enhanced capacity for oxygen utilization, with the result that the muscles of mammals can work hard for longer periods of time: endothermic hares will always outrun ectothermic tortoises. (For more on the pros and cons of endothermy and ectothermy, see A STEP FURTHER 9.1, on the website.) So it's no surprise that we have dedicated systems for creating warmth and regulating our body temperature. The systems that govern body temperature operate according to several general principles common to almost all homeostatic systems. Negative feedback allows precise control The homeostatic mechanisms that regulate temperature, body fluids, and metabolism are primarily negative feedback systems, where deviation from a desired value, called the set point, triggers a compensatory action of the system. Restoring the desired value turns off the response (this is why it is called negative feedback). A simple analogy for this mechanism is a household thermostat (FIGURE 9.1): a temperature drop below the set point activates the thermostat, which turns on the heating system. The heat that is produced has a negative feedback effect on the thermostat, so it stops calling for heat. Most heating systems have at least a little bit of tolerance built in-- otherwise the system would be going on and off too frequently--so there is generally a set zone rather than a rigid set point.

Homeostasis: Active Regulation of the Internal Environment 293

A household thermostat uses negative feedback control. Such systems always include a sensor (a thermometer in this case) to monitor the controlled variable, and a response system (the heating system here) to change the monitored variable. Heat from the heating system provides negative feedback, inhibiting the thermostat from calling for more heat.

FIGURE 9.1 Negative Feedback

Just like a thermostat, your set zone for body temperature can be changed under certain circumstances. For example, your body temperature drops at night for much the same reason that people turn down their home thermostats at night: to conserve energy. Or your set zone may be temporarily elevated, producing a fever to help your body fight off an infection. But in either case there are narrow limits. Too hot, and proteins begin to lose their correct shape, link together, and malfunction (this modification of proteins is called denaturing or, if it is really hot, cooking), with lethal results if critical brain regions are compromised. If we are too cool, chemical reactions of the body occur too slowly; at very low body temperatures, ice crystals may disrupt cellular membranes, killing the cells. Watson/Breedlove The MRiendd'us Mndacahinnecy ensures critical needs are met Foundations of Brain and Behavior 4e Just as engineers equip critical equipment with several backup systems, our bodies MMt4en_0d9.t0o1 ha0v5/e2m8/u20ltiple mechanisms for monitoring our stores, conserving remaining supplies, obtaining new resources, and shedding excesses. Loss of function in one part of the system usually can be compensated for by the remaining parts. This redundancy attests to the importance of maintaining our inner environment, but it also complicates the lives of scientists who are trying to figure out exactly how the body normally regulates temperature, water balance, and food intake. It has long been known that the hypothalamus senses and controls body temperature, but lesion experiments eventually showed that different hypothalamic sites control two separate thermoregulatory systems. Lesions in the preoptic area (POA) of rats impair physiological responses to cold, such as shivering and constriction of the blood vessels (Morrison, 2016), but did not interfere with such behaviors as pressing levers to control heating lamps or cooling fans. Lesions in the lateral hypothalamus of rats abolished behavioral regulation of temperature but did not affect the physiological responses (Van Zoeren and Stricker, 1977). This is a clear example of homeostatic redundancy: two different systems for regulating the same variable.

Redundancy Engineers equip critical systems with multiple "fail-safe" redundancies--for example, skydivers generally carry a secondary parachute --so that a backup always protects the critical system (the skydiver, in this example). Multiple redundancy is a feature of many of the body's homeostatic systems, protecting the constant internal environment that is crucial for survival.

Animals use behavioral compensation to adjust to environmental changes

Organisms also use behavioral measures to help them acquire

more heat, water, or food, in order to achieve and maintain

homeostasis. In general, both ectotherms and endotherms

The iguana controls its body temperature by moving around

deploy three kinds of temperature-regulating behavior: (1) behaviors that change exposure of the body surface--for example, by huddling or extending limbs; (2) behaviors that

change external insulation, such as by using clothing or nests;

and (3) behaviors that change surroundings, by moving into

the sun, into the shade, or into a burrow. Because ectotherms generate little heat through metabo-

lism, behavioral methods of thermoregulation are especially important to them. In the laboratory, iguanas carefully regu-

late their temperature by moving toward or away from a heat

lamp, and when infected by bacteria, they even produce a fever through such behavioral means (FIGURE 9.2), which helps them fight off an infection. We endotherms instead use in-

ternal processes to generate a fever when fighting infections,

which boosts our immune system response. Unfortunately,

sometimes the body goes too far, as a fever above 104°F (40°C)

does more harm than good (see A STEP FURTHER 9.2, on

the website). FIGURE 9.3 summarizes the basic mammalian thermoregulatory system: receptors in the skin, body core,

Day 1 shows the normal daily cycle of body temperature.

On day 2, the iguanas were injected with bacteria, and they reacted by moving closer to the heat source to create a "behavioral fever" like the fever that endotherms use to help ght off infection.

and hypothalamus detect temperature and transmit that information to three neural regions (spinal cord, brainstem, and hypothalamus). If the body temperature moves outside the set zone, each of these neural regions can initiate physiological and behavioral responses to return it to the set zone.

FIGURE 9.2 Behavioral Thermoregulation in Bacteria-Challenged Iguanas (After M. J. Kluger, 1978. Amer. Sci. 66: 38.)

A wide array of sensors continuously monitors the many internal and external threats to our physiological stability. At any given moment, depending on what's happening in the

environment, simultaneous perturbations in multiple reg-

ulated systems cause varying degrees of physiological stress. Rather than defending

a single set point, many physiological systems must continually shift their respons-

es depending on the nature of the stressors and prior experience--for example, your

allostasis The varying behavioral and physiological adjustments that an individual makes in order to maintain optimal (rather than unchanging) functioning of a Watson/Breedlove The Mreingdu'lsaMtedacshyinsetem in the face of changing Foundeantivoinros nofmBernaitnalansdtreBsehsaovriso.r 4e

heart rate and blood pressure are continually shifting to accommodate your current or anticipated activity level--a dynamic process termed allostasis (McEwen and Wingfield, 2010; McEwen, 2016). Allostatic adjustments are a normal part of dealing with the demands of daily life, but the heavy physiological burden on chronically stressed individuals puts them at risk of pathology due to allostatic overload.

View Animation 9.4: Thermoregulation in Humans

Receptors Skin surface Body core Hypothalamus/POA

FIGURE 9.3 Basic Elements of Mammalian Thermoregulatory Systems

Neural regions Spinal cord Brainstem Hypothalamus/POA

Effectors Behavioral responses Shivering Heat-seeking/avoiding behaviors Physiological responses Constriction or dilation of blood vessels Sweating Respiration Thyroid hormone secretion

Homeostasis: Active Regulation of the Internal Environment 295 (A) 1. Define homeostasis, and discuss its relation to the psychological concept of motivation. Why do homeostatic systems tend to have a set zone instead of a set point? 2. Distinguish between endotherms and ectotherms, and give a few examples of each. 3. Using examples, define and describe negative feedback as it applies to homeostasis. 4. Many homeostatic systems feature redundancy. What is it and why is it important? 5. Although the concept of homeostasis primarily relates to the physical internal environment, behavior can play an important role too. How? 6. Define allostasis. How does allostasis relate to homeostasis? (B) 9.2The Body's Water Is Actively Balanced between Two Major Compartments

In the next section, we discuss the processes that maintain an optimal balance of water and salt in the body. By the end of this section, you should be able to: 9.2.1 Describe the compartmentalization of fluids in the body. 9.2.2 Briefly define diffusion and osmosis. 9.2.3 Describe the semipermeable membrane, and explain its role in the movement of water between compartments. 9.2.4 Define and compare osmotic thirst and hypovolemic thirst and the sensors that monitor each type of fluid loss. 9.2.5 Discuss the importance of salt homeostasis in each type of thirst. 9.2.6 Give an overview of physiological responses to thirst, and tell how the brain gauges when to stop drinking.

Behavioral Control of Body Temperature (A) A Galápagos marine iguana, upon emerging from the cold sea, raises its body temperature by hugging a warm rock and lying broadside to the sun. (B) Once its temperature is sufficiently high, the iguana reduces its surface contact with the rock and faces the sun to minimize its exposure. These behaviors control body temperature.

Our homeostatic mechanisms are continually challenged by obligatory losses: the unavoidable expenditures of bodily resources that must then be regained from the external environment. Many body functions use up resources. Water (and some salt molecules), for example, are lost when we produce urine to get rid of waste molecules. We even lose water in our breath. Restoring expended water (and food) can take up much of an animal's waking life. A precise balance of fluids and dissolved salts bathes the cells of the body and enables them to function. The composition of this fluid provides an echo of our evolutionary past. The first living organisms on Earth were single-celled inhabitants of the ancient oceans, and it was in these simple organisms that the fundamental processes of cellular life were established. When multicellular organisms evolved much later and began to exploit opportunities on land and in the air, they had no choice but to bring along with them the watery environment that their cells needed to survive. For this reason, most organisms evolved homeostatic systems that ensure that the composition of their body fluids closely resembles dilute seawater (Bourque, 2008) (FIGURE 9.4). Even relatively minor deviation from optimal water and salt balance can be lethal.

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The saltiness of the extracellular uid, resembling dilute seawater, is consistent across different species of animals. Despite

hundreds of millions of years of evolution, there are only a few exceptions.

FIGURE 9.4 Each Animal Contains a Tiny Sea (After C. W. Bourque, 2008. Nat. Rev. Neurosci. 9: 519.)

intracellular compartment The fluid of the body that is contained within cells. extracellular compartment The fluid of the body that exists outside the cells. diffusion The passive spread of solute molecules through a solvent until a uniform solute concentration is achieved. osmosis The passive movement of a solvent, usually water, through a semipermeable membrane until a uniform concentration of solute (often salt) is achieved on both sides of the membrane. osmotic pressure The tendency of a solvent to move across a membrane in order to equalize the concentration of solute on both sides of the membrane.

Scientists typically describe water balance by contrasting the inside versus the outside of our cells. Most of the water in the body is contained within our cells; this water is collectively referred to as the intracellular compartment. The fluid that is outside of our cells, called the extracellular compartment, is divided between the interstitial fluid (the fluid between cells) and blood plasma (the protein-rich fluid that carries red and white blood cells). Water is continually moving back and forth between these compartments, in and out of cells. To understand the forces driving the movement of water, we must understand diffusion and osmosis. In diffusion, molecules of a substance, like salt (a solute), that are dissolved in a quantity of another substance, such as water (a solvent), will passively spread through the solvent because of the random jiggling and movement of the molecules until they are more or less uniformly distributed throughout it (see Figure 2.3). If we divide a container of water with a membrane that is impermeable to water and salt and then put salt in the water on one side, the salt molecules will diffuse only within the water on that side. If instead the membrane impedes salt molecules only a little, then the salt will distribute itself evenly within the water on the initial side but will also--more slowly--invade and distribute itself across the other side. A membrane that is permeable to some molecules but not others is referred to as selectively permeable or semipermeable. As we saw in Chapter 2, selective permeability of cell membranes is what lets neurons create and transmit electrical potentials. Osmosis is the movement of water molecules that occurs so as to equalize the concentration of two solutions that are separated by a semipermeable membrane. This is the case we examine in FIGURE 9.5, where a semipermeable membrane that permits water to cross, but not salt, divides a tank into two sides. Adding extra salt to one side induces water molecules to move into the now-salty side until the concentrations of both solutions equalize. The physical force that pushes or pulls water across the membrane is called osmotic pressure.

FIGURE 9.5 Osmosis

Equal concentration of solute on both sides, so no net change.

Salt (NaCl) molecules cannot cross this membrane. If we add salt to one side...

...water molecules pass through semipermeable membrane, leading to equal concentration of solute on both sides. Concentration of solute is lower (on both sides) than it was before. ...water molecules on left cross membrane to approach equal solute concentration on both sides, despite the in uence of gravity.

Homeostasis: Active Regulation of the Internal Environment 297

Normally the concentration of salt (sodium chloride, or NaCl) in the extracellular fluid of mammals is about 0.9% (which means there's about 0.9 gram of NaCl for every 100 milliliters of water). A solution with this concentration of salt is called physiological saline or described as isotonic. Because water moves to produce uniform saltiness (see Figure 9.5), cells will lose water if placed in a saltier solution and will gain water in a less salty solution. If excessive, this movement of water will damage or kill the cell. The extracellular fluid serves as a buffer, a reservoir of isotonic fluid that provides and accepts water molecules, so cells can maintain proper internal conditions and prevent such damage. The nervous system uses two cues to ensure that the extracellular compartment has about the right amount of water and solute, as we'll see next. Osmotic thirst occurs when the extracellular fluid becomes too salty The brain contains a dedicated network that carefully monitors the quantity and concentration of the fluid in our bodies and triggers thirst to stimulate the intake of more water when needed (Zimmerman et al., 2017). Most of the time, we feel thirsty because of the obligatory water losses we mentioned earlier--through respiration, urination, and so on--in which more water is lost than salt. In this case, not only is the volume of the extracellular fluid decreased, but also the solute concentration of the extracellular fluid is increased. As a result of the increase in extracellular saltiness, water is pulled out of cells through osmosis and we experience osmotic thirst (FIGURE 9.6A). Another thing that can make the extracellular fluid more concentrated is eating a lot of salty food. Once again, water will be drawn out of cells through osmosis. This loss of intracellular water triggers osmotic thirst, and we want to drink water in order to return the extracellular fluid to a comfortable isotonic state. Specialized osmosensory neurons--neurons that specifically monitor the concentration of the extracellular fluid--are found in numerous regions of the hypothalamus, including the preoptic area, the anterior hypothalamus, and the supraoptic nucleus. Osmosensory neurons are also found in the organum vasculosum of the lamina terminalis (OVLT), one of a set of specialized brain structures, called the

osmotic thirst A desire to ingest fluids that is stimulated by high concentration of solute (like salt) in the extracellular compartment. osmosensory neuron A specialized neuron that monitors the concentration of the extracellular fluid by measuring the movement of water into and out of the intracellular compartment.

(A) Osmotic thirst Osmosensory neurons in the brain detect the increased saltiness of the extracellular uid. Extracellular compartment Intracellular compartment

(B) Hypovolemic thirst Baroreceptors in major blood vessels detect any pressure drop from uid loss.

FIGURE 9.6 Two Kinds of Thirst

In osmotic thirst a change in the balance of water to salt in the extracellular uid (from gaining salt or losing water) pulls water out of the intracellular compartment.

Hypovolemic thirst results from loss of uids that contain both water and solutes, such as through hemorrhage, intense sweating, or diarrhea.

circumventricular organs, that monitor the fluid balance of the body (FIGURE 9.7). Outputs from the circumventricular organs project to multiple cortical regions, including the insula and anterior cingulate cortex, leading to the conscious perception of thirst (Farrell et al., 2011; McKinley et al., 2019). One of the brain's primary thirst responses is increased release of the posterior pituitary hormone vasopressin (also called arginine vasopressin [AVP] or antidiuretic hormone [ADH]; diuresis refers to the production of urine), which acts on the kidneys to slow the production of urine by increasing the reabsorption of water. Because osmotic forces are continually driving water into and out of cells, it is not enough to just control the intake of pure water; we must also regulate the intake and excretion of salt (NaCl). We cannot maintain water in the extracellular compartment without solutes; if the extracellular compartment contained pure water, osmotic pressure would drive it into the cells until they ruptured and died. In fact, the amount of water that we can retain is determined primarily by the number of Na+ ions we possess. That's why thirst is quenched more effectively by very slightly salty drinks (like sports drinks) than by pure water. But saltier water, like seawater, has the reverse effect. Seawater is hypertonic (saltier than our body fluids), so just like eating salty food, drinking seawater causes ever-worsening osmotic thirst. Lacking the specialized salt-excreting organs that marine animals have evolved, we simply can't get rid of excess salt fast enough to survive on seawater. Some Na+ loss is inevitable, as during urination or sweating. When water is scarce, the body tries to conserve Na+ in order to retain water. One way this is accomplished is through the release of the steroid hormone aldosterone from the adrenal glands. Aldosterone directly stimulates the kidneys to conserve Na+, and it also contributes to the salt appetite that powerfully drives animals to find additional salt in their environments (de Kloet and Joëls, 2017). Hypovolemic thirst is triggered by a loss of fluid volume A second signal that triggers thirst involves not salt balance or osmosis, but rather a decrease in the overall volume of the extracellular fluid, called hypovolemia (literally "low volume"). Normal everyday obligatory losses cause moderate decreases in extracellular fluid volume (in addition to increased saltiness), but more sudden and dramatic losses of fluid from the body--due to hemorrhage, vomiting, sustained diarrhea--may trigger thirst that is primarily hypovolemic in nature. In either case, blood vessels that would normally be full and slightly stretched no longer contain their full capacity. The loss of

FIGURE 9.7 Circumventricular Organs

circumventricular organ Any of multiple distinct sites that lie in the wall of a cerebral ventricle and monitor the composition of the cerebrospinal fluid. vasopressin Also called arginine vasopressin (AVP) or antidiuretic hormone (ADH). A peptide hormone from the posterior pituitary that promotes water conservation and increases blood pressure. aldosterone A mineralocorticoid hormone, secreted by the adrenal cortex, that promotes the conservation of sodium by the kidneys.

Organum vasculosum of the lamina terminalis (OVLT)

As shown in this sagittal view of the rat brain, the circumventricular organs lie in the walls of the ventricular system (blue). Thanks to a diminished blood-brain barrier, neurons of the circumventricular organs can monitor the concentration and composition of body uids.

Homeostasis: Active Regulation of the Internal Environment 299

body fluids, and resultant decrease in extracellular volume and blood pressure, cause the individual to experience hypovolemic thirst (FIGURE 9.6B)--sometimes very powerfully, if the hemorrhage or other volume loss is severe enough. Note that a decrease in fluid volume from blood loss (or from severe diarrhea or vomiting) does not necessarily change the concentration of the extracellular fluid, because salts and other ions are lost along with the water (see Figure 9.6B). The initial drop in extracellular volume is detected by pressure receptors, called baroreceptors, which are located in major blood vessels and in the heart. Reacting to the signal from the baroreceptors, the brain activates a variety of responses, such as thirst (to replace the lost water) and salt hunger (to replace the solutes that have been lost along with the water). Replacing the water without also replacing the salts would result in hypotonic (less salty than normal) extracellular fluid. The sympathetic nervous system also stimulates muscles in the artery walls to constrict, reducing the size of the vessels and partly compensating for the reduced volume. Finally, several different organs respond by altering hormonal release. The heart decreases its secretion of atrial natriuretic peptide (ANP), which normally reduces blood pressure, inhibits drinking, and promotes the excretion of water and salt at the kidneys. The brain's posterior pituitary gland releases more vasopressin, and the kidneys trigger the production of angiotensin II (AII) from a precursor circulating in the bloodstream. Angiotensin II has several water-conserving actions. By directly constricting blood vessels, AII increases blood pressure, ensuring that the brain and vital organs continue to receive essential materials for as long as possible. AII further stimulates the release of vasopressin and of aldosterone (discussed above) and acts directly on the brain, at the POA and at the circumventricular organs, to stimulate thirst and drinking behavior (Daniels and Marshall, 2012; Augustine et al., 2018) (FIGURE 9.8). We don't stop drinking just because the throat and mouth are wet

hypovolemic thirst A desire to ingest fluids that is stimulated by a reduction in volume of the extracellular fluid. baroreceptor A pressure receptor in the heart or a major artery that detects a change in blood pressure. atrial natriuretic peptide (ANP) A hormone, secreted by the heart, that normally reduces blood pressure, inhibits drinking, and promotes the excretion of water and salt at the kidneys. angiotensin II (AII) A hormone produced in the blood by the action of renin and that may play a role in the control of thirst. vagus nerve Cranial nerve X, which transmits information between the brain and the viscera. Anterior cingulate cortex

Although plausible, the most obvious explanation of why we stop drinking--that we have dampened our previously dry throat and mouth--is insufficient. Classic research showed that thirsty animals allowed to drink water, but not consume water-- because the water is diverted out of the esophagus before reaching the stomach--remain thirsty and continue drinking. However, researchers also know that a drink of water is more thirst quenching if taken by mouth than if infused directly into the stomach (N. E. Miller et al., 1957). So, provided that water actually reaches the stomach, oral sensations must play some role in reducing thirst. Further, although we stop drinking before most water has left the gastrointestinal tract and entered the extracellular compartment, gut neurons monitor the saltiness of the fluid in the stomach and intestine and communicate this information to the brain via the vagus nerve (Zimmerman et al., 2019). There, drinking behavior is governed by neurons within the subfornical organ--one of the circumventricular organs--and drinking is stopped in anticipation of correcting the extracellular volume and/or the concentration of solutes (Zimmerman et al., 2016; Augustine et al., 2018). Thus, experience may teach us how to gauge accurately whether we've ingested enough to counteract our thirst. Normally, all the signals--blood volume, solute concentration, moisture in the mouth, estimates of the amount of water we've ingested that's "on the way"--are in agreement, but the cessation of one signal alone will not stop thirst; in this way, animals ensure against dehydration.

Left insula Temporal cortex Right These fMRI images show cortical regions selectively activated in thirsty subjects in green. Blue shows regions activated after drinking water, and red shows regions that are active in both states. Regions showing activation that is speci c to strong thirst include the anterior cingulate (top) and the left insula (bottom), along with temporal regions.

FIGURE 9.8 Feeling Thirsty Patterns of brain activity in thirsty participants before and after drinking water.

From M. J. Farrell et al., 2011. Am. J. Physiol.-Regul., Integr. and Comp Physiol. 301: R623

If solute concentration is high... Osmotic thirst

Thirst is a homeostatic signal that intrudes forcefully into consciousness, with associated strong activation of certain brain regions, particularly in the limbic system (Denton et al., 1999). The two types of thirst (osmotic and hypovolemic), the two fluid compartments (extracellular and intracellular), and the multiple redundant methods to conserve water make for a fairly complicated system that is not yet fully understood. The current conceptualization of this system is depicted in FIGURE 9.9. Our need to compensate for obligatory losses is also crucial to understanding energy regulation, as we'll see in the next section.

Supraoptic nucleus, paraventricular nucleus Vasopressin release Water conservation

1. After so many millions of years of evolution, why do we still have body fluids with composition resembling dilute seawater? 2. Briefly describe diffusion and osmosis, and define osmotic pressure. How do these relate to the composition of fluids in the intracellular versus extracellular compartments? 3. What is the normal concentration of salt in extracellular fluid? What happens to cells if the saltiness of the extracellular fluid increases or decreases? 4. Distinguish between hypovolemic and osmotic thirst, and identify the physiological sensors that detect each condition. 5. Why do we sometimes get hungry for salt? 9.3Our Bodies Regulate Energy Balance and Nutrient Intake to Serve Current Needs and Prepare for Future Demands

FIGURE 9.9 An Overview of Fluid Regulation

We now turn to the topic of energy homeostasis. By the end of this section, you should be able to: 9.3.1 Define basal metabolism, and discuss its role in dieting and weight loss. 9.3.2 Discuss the importance of circulating glucose and bodily mechanisms of energy storage. 9.3.3 Summarize the relationship between insulin secretion and energy utilization by cells.

Watson/Breedlove The Mnuintrdi'esnMtsac hiCnehemicals required for the Founedfafteiocntisvoef fBurnaicntiaonndinBge,hagvrioowr 4the, and mainte- nance of the body. MMg4elu_0c9o.0s9e 0A3/n0i5m/p2o0rtant sugar molecule used by the body and brain for energy. glycogen A complex carbohydrate made by the combining of glucose molecules for a short-term store of energy. insulin A pancreatic hormone that lowers blood glucose, promotes energy storage, and facilitates glucose utilization by cells. glucagon A pancreatic hormone that converts glycogen to glucose and thus increases blood glucose.

Hunger for the food that we need to build, maintain, and fuel our bodies is a compelling drive, and the delicious flavors of foods provide powerful reward signals. Most of us are "foodies" to some extent, consuming "food porn," trying new recipes, and watching reality TV shows in which chefs try to outcook each other. The regulation of eating and of body energy, compared with regulation of drinking, involves even more redundancy and a more complex set of homeostatic mechanisms. The added complexity is due to the fact that the brain must monitor and regulate a wide range of nutrients (chemicals required for the effective functioning, growth, and maintenance of the body), including more than 20 amino acids (of which 9 essential amino acids cannot be synthesized by the body) and a variety of vitamins and minerals, as well as carbohydrates (sugars and starches) for energy. No animal can afford to run out of energy or nutrients, so we need systems to anticipate future needs and keep a reserve on hand (but not too much!). (For more information about the complexity and variation in the nutrient needs of different species, see A STEP FURTHER 9.3, on the website.)

The brain uses only glucose for energy, but it can do so without the aid of insulin. The body can make use of either fatty acids or glucose for energy, but it requires insulin in order to use glucose.

Homeostasis: Active Regulation of the Internal Environment 301 No insulin required

Energy is shuttled back and forth between long-term storage (as glycogen or fat) or readily usable glucose, by hormones that are regulated by the brain.

Fat (energy store) Fatty acids (ready energy)

FIGURE 9.10 The Role of Insulin in Energy Utilization

The principal fuel for the cells of the body is glucose, a simple sugar that is ob-

lipid A large molecule (frequently a fat)

tained through the breakdown of more-complex molecules. We need a steady supply of circulating glucose between meals, strictly maintained within an optimal range, and

that consists of fatty acids and glycerol. Lipids are insoluble in water.

may also experience elevated demand for fuel at other times--for example, during intense physical activity--so several mechanisms have evolved for short- and long-term

adipose tissue Commonly called fat tissue. Tissue made up of fat cells.

storage of excess fuel. For shorter-term storage, glucose can be converted into a more complex molecule called glycogen and stored as reserve fuel in several locations, notably the liver and skeletal muscles. This process, called glycogenesis, is promoted by the hormone insulin, which is synthesized and released by the pancreas. When blood glucose levels drop too low, a second pancreatic hormone, glucagon, converts glycogen back into glucose (a process called glycogenolysis; FIGURE 9.10). For longer-term storage,

ketone An organic molecule, derived from the breakdown of fat, that can be used by cells as an energy source. basal metabolism The use of energy for processes such as heat production, maintenance of membrane potentials, and all the other basic life-sustaining functions

molecules of lipid (fat) from dietary sources or created from surplus sugars and other of the body.

nutrients are stored in adipose tissue (commonly called fat tissue). Under conditions of

pWroaltosonng/eBdrefeodolodvedeprivation, body fat can be converted into glucose--a process called

gTluhceoMneinodg'esnMesaicsh--inae nd a secondary form of Foundations of Brain and Behavior 4e fuel, called ketones, which can similarly bMeMut4ieli_z0e9d.10by t0h3/e0b5o/d20y and brain. Only about 10-20% of the energy in food is used for active behavioral processes. The majority of food energy is spent on basal metabolism: the basic physiological processes of life, like heat production (the price we pay for endothermy), cellular activity, and maintenance of membrane potentials. Metab-

450 calories/day Body weight Basal metabolism

After 7 days on a rich 3,500-calorie diet, six obese participants reduced their daily calories by 87%, to 450 calories per day. However, basal metabolism also declined by 15%; so after 3 weeks on the

new diet, body weight had declined by only 6%.

An all-too-familiar consequence of this metabolic flexibility is that the body tends to resist either losing or gaining weight

following dietary changes (FIGURE 9.11). FIGURE 9.11 Why Losing Weight Is So Difficult (After G. A. Bray, 1969. Lancet 2: 397.)

FIGURE 9.12 Metabolic Adaptation in the Biggest Losers (After E. Fothergill et al., 2016. Obesity 24: 1612.)

To the frustration of dieters everywhere, many studies show that a calorie-reduced diet prompts the body to reduce its basal metabolic rate, which in turn slows the loss of weight (C. K. Martin et al., 2007). Along with the other Biggest Loser contestants, Danny C., whom we met at the outset of the chapter, has learned the hard way that our brains and bodies vigorously defend our energy balance and body weight, even if we are obese. Due to a dramatic decrease in his basal metabolism following weight loss--a process called metabolic adaptation--Danny now needs to consume 800 fewer calories per day than the typical man, just to maintain his current 295-pound body weight. And to make matters worse, this metabolic adaptation is annoyingly persistent; even after 6 long years, the metabolisms of the other contestants also remained very low (FIGURE 9.12) as their brains continued to try to regain the lost weight (Fothergill et al., 2016). A major goal for researchers is thus to discover a way to reset the body's set point (or set zone) for energy storage. An additional topic under debate is whether the concept of a set point, borrowed from engineering, really fits very well with observations from studying obesity, where body weight seems to drift steadily upward (Müller et al., 2018). Some researchers now think that body composition instead reflects a "settling point," where a complex set of physiological, behavioral, and social factors combine to determine body weight and resist radical losses or gains (Speakman et al., 2011). Theories about how to best lose weight through dieting are endlessly popular topics in the mass media. Although it is counterintuitive, some evidence suggests that diets low in carbohydrates, and correspondingly high in fats and proteins, can help people lose weight and also may increase serum levels of "good" cholesterol while decreasing serum fats (G. D. Foster et al., 2003; Samaha et al., 2003). However, long-term studies will be required to establish the overall safety of low-carbohydrate diets. The only certain way to lose weight is to decrease the number of calories taken in and/or increase the number of calories spent in physical activity, and for the weight loss to be permanent, these changes in diet and activity must be permanent too. As an added bonus, research with monkeys suggests that long-term restriction of caloric intake can slow the aging process and reduce the prevalence of disease (Colman et al., 2014; Mattson and Arumugam, 2018). And while the effects of caloric restriction on human aging remain to be established, researchers have reported that restricted food intake may have some beneficial effects on cognitive performance in elderly participants, at least over the short term (Witte et al., 2009; Prehn et al., 2017).

Weight change (lb.) Change in calories burned per day

(A) Weight 50 0 -50 -100 -150 -200 -250 Season 8: 2009

Other contestants Danny C. Six years later: 2015 Danny lost 239 lbs. to win The Biggest Loser in 2009, but in the following six years he regained more than 100 lbs. All but one of the other contestants similarly regained weight, and four ended up weighing more than before the contest.

(B) Metabolism 200 0 -200 -400 -600 -800 -1,000 Season 8: 2009

Six years later: 2015 The contestants' dramatic weight loss prompted large compensatory decreases in metabolism that persisted even six years after their weight loss. Danny now burns 800 fewer calories per day than would be average for a man of his size.

Homeostasis: Active Regulation of the Internal Environment 303

Insulin is essential for obtaining, storing, and using food energy In addition to converting surplus glucose into glycogen, as we discussed earlier, insulin has another critical function: your body needs insulin to make any use of the circulating glucose (brain cells are an important exception; they can use glucose without the aid of insulin). That's because glucose transporters--the membrane-spanning proteins that most cells use to import glucose from the blood--need insulin in order to function properly. The disease diabetes mellitus results from a lack of insulin production (in the type 1, or juvenile-onset, variety of the disease) or from greatly reduced tissue sensitivity to insulin (type 2, or adult-onset, diabetes, which is often associated with obesity). Although the brain can still make use of glucose from the diet, the rest of the body cannot and is forced to use energy from fatty acids while glucose builds up in the blood, resulting in gradual severe damage to many tissues. Insulin release around mealtimes is so important that it is triggered by several different mechanisms at different points in time. First comes the cephalic phase of insulin release, triggered by sights, smells, and tastes that we have learned to associate with food (cephalic means "of the head"). Then, during the digestive phase, food entering the digestive tract prompts an additional release of insulin. We now know that the digestive tract contains the same sort of sweet taste receptors as are found on the tongue, and it uses them to help regulate insulin release (Kokrashvili et al., 2009). Finally, during the absorptive phase, as digested food is absorbed into the bloodstream, specialized liver cells called glucodetectors detect the increase in circulating glucose and signal the pancreas to release still more insulin. The liver communicates with the pancreas via the nervous system. Information from glucodetectors in the liver travels via the vagus nerve to the nucleus of the solitary tract (NST) in the brainstem and is relayed to the hypothalamus (Maniscalco and Rinaman, 2018). This system informs the brain of circulating glucose levels and contributes to hunger, as we'll discuss shortly. Given the crucial role of insulin in mobilizing and distributing food energy, and its fluctuations in association with feeding, it might seem an obvious candidate for signaling the brain to start or stop eating. Lowering an animal's blood insulin level does cause it to become hungry and eat a large meal, and injecting some insulin causes the animal to eat much less. But injecting a larger dose of insulin doesn't produce fully satiated animals; instead, they become hungry again and eat a large meal! The reason for this surprising result is that the high insulin levels direct much of the blood glucose into storage, which means that there is less glucose in circulation. The brain learns of this condition, called hypoglycemia, directly via glucodetectors, leading to a hunger response. And while it is certainly important, glucose can't be the sole appetite signal either, because people with untreated diabetes have very high levels of circulating glucose yet are constantly hungry. Somehow the brain integrates insulin and glucose

diabetes mellitus A condition, characterized by excessive glucose in the blood and urine and by reduced glucose utilization by body cells, that is caused by the failure of insulin to induce glucose absorption. glucodetector A specialized type of liver cell that detects and informs the nervous system about levels of circulating glucose. Not Too Sweet People with type 1 diabetes mellitus must receive insulin in order to utilize glucose. Taking insulin requires careful monitoring of blood glucose and, as shown here, selfadministration via (A) daily injections or (B) drug pumps to infuse insulin throughout the day. Until the 1920s, when insulin was discovered as a result of experiments on dogs, this form of diabetes was a dreaded killer of children. (C) In an especially dramatic moment in science, three of the Canadian discoverers of insulin--Frederick Banting (right), Charles Best (left), and James Collip (not pictured)--went through a hospital ward full of dying diabetic children, injecting them with the newly purified hormone. By the time the last child had been injected, the first was already waking up from a diabetic coma. The discovery saved millions of lives and garnered a Nobel Prize in 1923. (C)

Library and Archives Canada © istock.com/MarkHatfield © Dmitry Lobanov/Shutterstock

levels with other sources of information to decide whether to initiate eating. As we'll see next, this has become a central theme in research on appetite control--that the brain integrates many different signals rather than relying exclusively on any single signal to trigger hunger. 1. Provide a review of how glucose is used, stored, and retrieved from storage. Be sure to identify the roles of pancreatic hormones in each step. 2. What is basal metabolism? How is it affected by homeostatic processes, and how does the homeostatic regulation of metabolism frustrate efforts to lose weight? 3. Define the types of diabetes mellitus, and discuss their causes. What are some of the ways that insulin release is normally controlled? 4. Discuss the evidence about whether blood levels of insulin and glucose directly control hunger.

ventromedial hypothalamus (VMH) A hypothalamic region involved in eating and sexual behaviors. lateral hypothalamus (LH) A hypothalamic region involved in the control of appetite and other functions.

9.4The Hypothalamus Coordinates Multiple Systems That Control Hunger There has been rapid progress in understanding the multiply redundant hypothalamic mechanisms for regulating appetite. After studying this section, you should be able to: 9.4.1 Summarize the historical evidence that hunger signals converge on the hypothalamus. 9.4.2 Identify and briefly describe the actions of major hormonal appetite signals. 9.4.3 Provide an overview of the hypothalamic appetite controller, including the organization of its neurons, and the signals it receives from the body. 9.4.4 Discuss some additional, redundant appetite signals. 9.4.5 Define the gut microbiome, and discuss some of the ways it may interact with the nervous system. Although no single brain region has exclusive control of appetite, decades of research in the twentieth century established that the hypothalamus is critically important for regulating metabolic rate, food intake, and body weight. In this classic research, scientists found that lesions in the hypothalamus of rats could induce either chronic hunger and massive weight gain, or chronic satiety (feeling full) and severe weight loss, depending on the location of the lesion.

Lesion studies showed that the hypothalamus is crucial for appetite

Early researchers made discrete bilateral lesions in the hypothalamus--in either the ventromedial hypothalamus (VMH) or the lateral hypothalamus (LH)--of rats (FIGURE 9.13). After recovery, VMH-lesioned rats ate to excess

and became obese (Hetherington and Ranson, 1940), leading researchers to suggest that the VMH is the satiety center of the brain (because the rats didn't show evidence of satiety once the VMH was gone). Rats with LH lesions,

conversely, ceased eating and rapidly lost weight, suggesting that the LH acts as a hunger center (because rats who lost their LH stopped acting hungry) (Anand and Brobeck, 1951). So, an early model of feeding behavior featured the

Homeostasis: Active Regulation of the Internal Environment 305

VMH and LH acting in opposition to control appetite. It soon became clear that this dual-center model of appetite was too simple. For one thing, although the VMH was identified as a satiety center, its destruction did not create out-of-control feeding machines. Instead, VMH-lesioned animals exhibited a period of rapid weight gain but then stabilized at a new, higher level. When obese VMH-lesioned animals were forced to either gain or lose weight through dietary

manipulation, they returned to their new "normal" weight as soon as they were allowed to eat freely again. So, because VMH-lesioned rats experienced satiety, the VMH cannot be the sole satiety controller. Similarly, although they initially stopped eating, LH-lesioned rats that were kept alive with a feeding tube soon resumed eating and drinking, and their body weight eventually stabilized at a new, lower level. As with the VMH-lesioned animals, LH- lesioned animals that were later forced to

gain weight would swiftly return to their new, lower set point for body weight after they returned to eating at will (see Figure 9.13) (Keesey, 1980). Researchers thus realized that the hypothalamic system controlling feeding must involve multiple components that coordinate to establish a set point for metabolic fuels, monitor energy balance in the body, and trigger behavioral responses to meet the established energy goals, with a collective effect on body weight.

Hypothesis The hypothalamus contains discrete systems for controlling hunger and satiety.

Test Place small lesions in target areas within the hypothalamus.

VMH-lesioned animals stabilize at a new, higher body weight. Normal rats defend a stable body weight. LH-lesioned rats stabilize at a new, lower body weight.

Result Animals with lesions of the lateral hypothalamus (LH) decrease their food intake and rapidly lose weight, but they eventually stabilize at a new, lower weight. Following recovery, LH-lesioned animals forced to gain or lose weight return to the new lower weight when allowed to feed freely. Animals with lesions of the ventromedial hypothalamus (VMH) increase their food intake and rapidly gain weight, but they eventually stabilize at a new, higher weight. Following recovery, VMH-lesioned animals forced to gain or lose weight return to their new higher weight when allowed to feed freely.

Conclusion The LH and VMH appear to play a role in appetite and body weight control, but because LH- and VMH-lesioned animals eventually show hunger and satiety, these two hypothalamic centers alone cannot constitute the entire appetite control system.

FIGURE 9.13 Lesion Studies Revealed That the Hypothalamus Is Involved in Appetite (After R. E. Keesey and P. C. Boyle, 1973. J. Comp. Physiol. Psychol. 84: 38 and D. Sclafani et al., 1976. Physiol. Behav. 16: 631.)

Following glucose ingestion, changes in activity in the hypothalamus are evident in this midsagittal fMRI image.

By demonstrating that the hypothalamus contains distinct components of an appetite control network, the early work on hunger and satiety provided a framework for subsequent research. For example, fMRI studies show that elevations in circulating glucose after a period of fasting produce large changes in the activity of the human hypothalamus (FIGURE 9.14), probably acting via hypothalamic glucodetector neurons that directly monitor blood levels of glucose (Parton et al., 2007). Today it is clear that the hypothalamic control of feeding is quite complicated and, as we will see shortly, exhibits considerable redundancy as a safety measure.

From Y. Liu et al., 2000. Nature 405: 1058

Hormones from the body drive a hypothalamic appetite controller

A spate of discoveries has sharpened our understanding of the hypothalamic control

of appetite. This evidence indicates that a circuit within the arcuate nucleus of the

hypothalamus is the key element in a highly specialized appetite network integrat-

ing peptide hormone signals from several sites in the body. One important source of

FIGURE 9.14 Sweet Spot

information about energy stores is the pancreas; we have already discussed how the pancreatic hormone insulin signals the state of glucose circulating in the blood. Other

information about energy balance--especially short-term and long-term reserves--

comes in the form of hormonal secretions from elsewhere in the body, particularly the

You may be surprised to learn that the fat cells that make up adipose tissue are

endocrine; in fact, they release a hormone called leptin (from the Greek leptos, "thin")

arcuate nucleus An arc-shaped hypothalamic nucleus implicated in appetite Watscoonn/tBrorel.edlove The Mind's Machine Founldeaptitoinnsof ABrpaienpatniddeBhehoarvmioorn4ee released by fat cells. MM4geh_r0e9l.1in4 A03p/e05p/ti2d0e gut hormone believed to act on the hypothalamic appetite system to increase hunger.

into the bloodstream (Y. Zhang et al., 1994). Multiple types of leptin receptors (named LepRa through LepRf ) are found in locations throughout the brain, including the cortex and several nuclei of the hypothalamic appetite network that we will discuss shortly (Wada et al., 2014). Mutations that result in defective leptin receptors cause morbid obesity in lab animals (Roh et al., 2018; Zabeau et al., 2019) and in humans (Niazi et al., 2018). Likewise, mice that fail to produce leptin because of a genetic modification rapidly become obese (FIGURE 9.15). Experiments with leptin signaling therefore tell us that the brain monitors circulating leptin levels as an indicator of the body's lon-

PYY3-36 A peptide gut hormone believed to act on the hypothalamic

ger-term energy reserves in the form of fat. Defective leptin production or impaired leptin sensitivity causes a false underreporting of body fat and leads to overeating,

Shorter-term energy balance--the presence

or absence of food in the gut--is reported by

numerous hormones from the digestive organs.

One of these--ghrelin, synthesized and re-

leased into the bloodstream by endocrine cells

of the stomach--reaches high concentrations

during fasting and powerfully stimulates appe-

tite (Wren et al., 2000, 2001), dropping sharply

after a meal is eaten (Nakazato et al., 2001). Ex-

perimental manipulations of ghrelin activity in

the brains of hamsters alter their foraging and

feeding behaviors, illustrating the importance

of ghrelin for stimulating food intake (M. A.

Conversely, several intestinal hormones are

candidate satiety signals. For example, the ac-

This mouse has the same two copies of the

tions of the awkwardly named intestinal pep-

This mouse has two copies of the obese gene, impairing the production of leptin by fat cells, and it weighs 67 grams.

obese gene, but following treatment with leptin its weight is much closer to normal (around 30 grams). Few cases of human obesity are due to leptin de ciency, so such treatment is not generally effective in people.

tide PYY3-36 may be the converse of ghrelin's actions, with PYY3-36 spiking to higher levels on ingestion of a meal and providing an ap- petite-suppressing signal (Karra et al., 2009).

Injections of ghrelin cause increased appetite

FIGURE 9.15 Inherited Obesity Can Be Overcome

and feeding in rats or humans, and injections

Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e

Homeostasis: Active Regulation of the Internal Environment 307

of PYY3-36 into the bloodstream or directly into the arcuate nucleus curb appetite (Chelikani et al., 2005; Baynes et al., 2006). Furthermore, ghrelin is chronically slightly ele- vated in obese people, and PYY3-36 is chronically lowered--possibly causing continual hunger (English et al., 2002). Like PYY3-36, the intestinal hormone glucagon-like peptide 1 (GLP-1) shows a rapid increase in secretion during a meal, especially if the meal is high in fats and carbohydrates. The release of GLP-1 is initially governed by a rapid autonomic neural mechanism, and then by the presence of nutrients in the intestinal tract (E. W. L. Sun et al., 2019). Receptors for GLP-1 are found in several brain regions implicated in food intake (Knudsen et al., 2016; Burmeister et al., 2017), mediating reductions in appetite and feeding, along with changes in the system that signals the rewarding aspects of food (Sekar et al., 2017; Yang et al., 2017). In addition, GLP-1 activity directly blocks the effects of ghrelin on metabolism and appetite (Abtahi et al., 2019). The discoveries of PYY3-36, ghrelin, and GLP-1 have provided important clues about the appetite control mystery, and these hormones converge on an appetite controller in the arcuate nucleus, so next we'll have a look at how that system seems to work. A simplified (yes, really) view of the organization of the appetite control circuitry in the hypothalamus is illustrated in FIGURE 9.16. Within the arcuate nucleus, the system relies on two types of neurons with opposite effects. POMC neurons act as satiety

glucagon-like peptide 1 (GLP-1) A peptide gut hormone believed to act on the hypothalamic appetite system to suppress appetite. POMC neuron A neuron, involved in the hypothalamic appetite control system, that produces both pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. View Activity 9.1: An Appetite Controller in the Hypothalamus

Neural inputs: Visceral and somatosensory information travels via the vagus nerve and spinal nerves.

Lateral hypothalamus (orexigenic) Second-order neurons

Paraventricular nucleus (anorexigenic) Arcuate nucleus NPY neuron (hunger)

Nucleus of the solitary tract Neural inputs from gut

Hormonal inputs: peptide hormones from the gut--or in the case of leptin, from body fat cells--are carried to the brain, where they help regulate appetite.

FIGURE 9.16 An Appetite Controller in the Hypothalamus The brain integrates many peripheral signals to determine appetite.

Leptin provides information about current energy stores, decreasing feeding behavior by inhibiting NYP neurons and stimulating POMC neurons.

Ghrelin, PYY3-36, and GLP-1 are thought to exert ongoing minute-to-minute control on appetite, and they have opposing effects on NPY neurons: ghrelin stimulates eating, and PYY3-36 appears to inhibit appetite.

NPY neuron A neuron in the hypothalamic appetite control system, that produces both neuropeptide Y and agouti-related peptide. orexigenic neurons Neurons of the hypothalamic appetite system that promote feeding behavior. anorexigenic neurons Neurons of the hypothalamic appetite system that inhibit feeding behavior. paraventricular nucleus (PVN) A nucleus of the hypothalamus involved in the release of peptide hormones and in the control of feeding and other behaviors. nucleus of the solitary tract (NST) A complicated brainstem nucleus that receives visceral and taste information via several cranial nerves. cholecystokinin (CCK) A peptide hormone that is released by the gut after ingestion of food that is high in protein and/or fat. orexin Also called hypocretin. A neuropeptide produced in the hypothalamus that is involved in switching between sleep states, in narcolepsy, and in the control of appetite.

neurons when activated, inhibiting appetite and increasing metabolism. However, neighboring NPY neurons act as hunger neurons when they are activated, stimulating appetite directly and also inhibiting the POMC neurons (thereby blocking satiety signals) and reducing metabolism. (In case you are wondering, these neurons get their names from the signaling compounds they produce: pro-opiomelanocortin in the case of POMC neurons, and neuropeptide Y for NPY neurons. POMC neurons also produce CART, short for cocaine- and amphetamine-regulated transcript, and NPY neurons also produce AgRP, short for agouti-related peptide. (These sorts of details are why graduate school takes so long.) So how do the peripheral hormone signals interact with the arcuate-based appetite controller? As we've discussed, leptin levels (and to a lesser extent, insulin levels) in the blood convey information about the body's longer-term energy reserves, stored in fat cells. Leptin affects both types of arcuate appetite neurons, but in opposite ways. High circulating levels of leptin activate the POMC satiety neurons and simultaneously inhibit the NPY hunger neurons--so in both ways leptin is working to suppress hunger, and selective deletion of the leptin receptors on NPY neurons causes mice to rapidly become obese (Xu et al., 2018). In contrast to leptin, the trio of gut hormones that we discussed earlier--ghrelin, PYY3-36, and GLP-1--provide shorter-term, hour-to-hour hunger signals from the gut. Ghrelin and PYY3-36 act primarily on the appetite-stimulating NPY neurons of the arcuate nucleus. In this model, ghrelin stimulates these cells, leading to a corresponding increase in appetite, while PYY3-36 works in opposition, inhibiting the same cells to reduce appetite. Short-term effects on appetite exerted via the NPY neurons therefore reflect a balance between ghrelin and PYY3-36 activity. In contrast, GLP-1 acts on the appetite-reducing POMC cells of the arcuate nucleus, resulting in a reduction in appetite and food intake (Sekar et al., 2017), directly opposing the appetite-enhancing actions of the NPY system. The net result of all this is a constant balancing act between the appetite-stimulating effects of the NPY system and the appetite-suppressing effects of the POMC system. Two nearby hypothalamic sites appear to be primary targets of projections from the arcuate appetite controller. Orexigenic neurons (from the Greek orexis, "appetite," and genein, "to produce"), located principally in the lateral hypothalamus, coordinate increased appetite and food intake signals. In contrast, anorexigenic neurons of the paraventricular nucleus (PVN) coordinate signals that decrease appetite and feeding (Garfield et al., 2015; Krashes et al., 2016) (refer to Figure 9.16B for help in understanding this circuit). Other systems also play a role in hunger and satiety Appetite signals from the hypothalamus converge on the nucleus of the solitary tract (NST) in the brainstem (see Figure 9.16B). The NST can be viewed as part of a common pathway for feeding behavior, receiving appetite signals from a variety of sources in addition to the hypothalamus. Thus, the sensation of hunger is affected by a wide variety of peripheral sensory inputs, such as oral stimulation and the feeling of stomach distension, transmitted via spinal and cranial nerves. Information about nutrient levels is conveyed directly from the body to the NST via the vagus nerve (Maniscalco and Rinaman, 2018). For example, various peptides released by the gut after feeding, including cholecystokinin (CCK) and GLP-1, act directly on receptors of the vagus nerve to alter appetite (Alhadeff et al., 2017; Huston et al., 2019). In keeping with the concept of multiple redundancy that we discussed earlier in the chapter, a variety of additional signals and brain locations also participate in feeding behavior, either directly or through indirect effects on other processes. The peptide orexin, produced by neurons in the lateral hypothalamus, appears to participate in the subsequent control of feeding behavior. Direct injection of orexin into the hypothalamus of rats increases feeding. And it probably won't surprise you to learn that the brain's reward system is intimately involved with feeding. Activity of a circuit

Homeostasis: Active Regulation of the Internal Environment 309

including the amygdala and the dopamine-mediated reward system of the nucleus accumbens (see Chapter 3) is hypothesized to mediate pleasurable aspects of feeding (Volkow and Wise, 2005). The endocannabinoid system (see Chapter 3) likewise has a potent effect in appetite and feeding. Endocannabinoids, such as anandamide, are endogenous substances that act much like the active ingredient in cannabis (Cannabis sativa) and, like cannabis, can potently stimulate hunger. Acting both in the brain and in the periphery, endocannabinoids might stimulate feeding by affecting the mesolimbic dopamine reward system. However, injection of anandamide into the hypothalamus also stimulates eating (C. D. Chapman et al., 2012), confirming that endocannabinoids act directly on hypothalamic appetite mechanisms, while inhibiting satiety signals from the gut (Di Marzo and Matias, 2005). Cannabinoid drugs may be useful for stimulating appetite and weight gain in people who are having trouble maintaining their body weight because of cancer or other diseases (Horn et al., 2019; J. Wang et al., 2019). Hypothalamic feeding control must be strongly influenced by inputs from higher brain centers, but little is known about these mechanisms. During development, for example, our feeding patterns are increasingly influenced by social factors such as parental and peer group pressures. Understanding the nature of cortical influences on feeding mechanisms is a major challenge for the future. The list of participants in appetite regulation is long and growing longer, revealing overlapping and complex controls with a high degree of redundancy, as befits a behavioral function of such critical importance to health and survival. There is also growing evidence that gut bacteria regulate body weight, as we'll see in Signs & Symptoms next.

endocannabinoid An endogenous ligand of cannabinoid receptors, thus a cannabis analog that is produced by the brain. gut microbiota The microorganisms that normally inhabit the digestive system. microbiome The collective term for a population of microorganisms. enterotype Each individual's personal composition of the gut microbiota. fecal transplantation A medical procedure in which gut microbiota, via fecal matter, are transplanted from a donor to a host.

SIGNS & SYMPTOMS­­ Friends with Benefits Most people know that the gut is normally inhabited by helpful bacteria, but the extent of that occupation may surprise you. You probably contain in the range of 2.5-5 pounds of gut microbes: trillions of individual organisms belonging to dozens (perhaps hundreds) of different species of bacteria, fungi, and viruses, making up more than half the contents of your large intestine (Guarner and Malagelada, 2003). Put another way, you have more gut microbes than body cells, and they weigh more than your brain. This huge population, known as the gut microbiota or, collectively, as the microbiome, normally provide a variety of beneficial actions in return for their comfortable lodgings. Each of us possesses a distinct microbial enterotype--a personal combination of different species of microbiota--that researchers increasingly believe to be in extensive two-way communication with our brain via the vagus nerve and chemical signals (Bonaz et al., 2018; Cussotto et al., 2018). Your enterotype reflects the history of your gut, so substantial changes in your diet, or the use of antibiotics to treat infections, can change the composition and health of the microbiome, with varying consequences for health (David et al., 2014; Wilson et al., 2020). Preliminary evidence has tentatively linked the microbiome enterotype to such diverse domains as mood, stress, social behavior, and cognitive functioning (Sylvia and Demas, 2018; Tetel

et al., 2018) and also various neurological conditions, including autism, schizophrenia, bipolar disorder, and Parkinson's disease (Fung et al., 2017; Tremlett et al., 2017). But one of the areas where an effect of changes in the gut microbiota may be most evident is obesity. Feeding antibiotics to young mice, even at relatively low doses, changes gut microbiota and circulating hormones, leading to weight gain (I. Cho et al., 2012). Similarly, two studies looking at almost 40,000 babies have found that human infants given antibiotics in their first 6 months were statistically more likely to be overweight at age 7 (Ajslev et al., 2011; Trasande et al., 2013). It remains to be seen how much adult obesity is accounted for by long-lasting changes to our enterotypes, but it is at least possible that early exposure to antibiotics--or even chlorinated drinking water (because the whole point of adding chlorine is to kill bacteria)--is making some of us fat (L. M. Cox and Blaser, 2015). What can we do about it? Scientists hope to turn our new knowledge of the connection between the gut and brain into novel treatments, such as drugs based on metabolites secreted by specific gut bacteria (Suez and Elinav, 2017). Researchers have also been investigating the possible benefits of a nasty-sounding procedure: fecal transplantation. Yes, it is just what it sounds like: feces are collected from carefully screened donors, processed to create a liquid (Continued )

SIGNS & SYMPTOMS­(continued)­­ suspension, and then passed through a catheter into the colon of the recipient (FIGURE 9.17), where the donor's healthy enterotype establishes itself. Transplantation is an effective treatment for certain dangerous gut infections and may be effective in various diseases, including inflammatory bowel disease and type 2 diabetes (F. Yu et al., 2019; Zou et al., 2020). Initial findings suggest that fecal transplants improve metabolic function and other digestive processes in obese people (Vrieze et al., 2012; Z. Zhang et al., 2019). Although research on the topic is in its infancy, we can hope that our tiny passengers can someday be coaxed to pay their way by supplying benefits like weight loss and better brain health. Each new discovery brings us closer to developing safe and effective treatments for obesity and eating disorders, as we discuss next.

FIGURE 9.17 Fecal Transplantation

A transplant of feces from a healthy donor into the colon establishes a new population of gut microbiota and may aid in diverse problems, including severe infection, neurological conditions, and obesity.

1. Review the early work implicating the LH and VMH in appetite control. Why did researchers abandon the view that the LH and VMH were the sole controllers of appetite and satiety?

2. Sketch or briefly describe the major components of the hypothalamic appetite

Foundations of Brain and Be3h.avDioers4ceribe how the hypothalamic appetite controller functions during hunger, in

MM4e_09.17 09/01/204. What is leptin? Discuss its origins in the body and its effects on feeding behavior.

5. What are some of the gut hormones that may be involved in appetite control, and what are they thought to do?

6. Briefly describe some of the additional (redundant) mechanisms of appetite control that supplement the hypothalamic appetite system. What is the basis of the increased appetite frequently experienced after use of cannabis?

7. Describe the makeup of the gut microbiome. What are some ways that the microbiome affects the brain and behavior?

Homeostasis: Active Regulation of the Internal Environment 311 9.5Obesity and Eating Disorders Are Difficult to Treat

Problems with appetite, energy balance, and body weight are all too common. After reading this section, you will be able to: 9.5.1 Define overweight and obesity, with reference to BMI. 9.5.2 Describe and compare the various pharmacological and surgical approaches to treating obesity. 9.5.3 Discuss the symptoms, possible causes, and treatment of the major eating disorders: anorexia nervosa, bulimia, and binge eating disorder. Unfortunately, effective treatments to aid weight loss have been elusive. In our modern world, with its plentiful calories and sedentary lifestyles, the multiple redundant systems for appetite and energy management that evolved in our distant ancestors work all too well in preventing weight loss. Obesity has certainly reached epidemic proportions: a majority of the adults in the United States are overweight as defined by body mass index (BMI) (TABLE 9.1)--about two-thirds--and about one in three qualify as obese (FIGURE 9.18) (Flegal et al., 2002). To date, no country has ever succeeded in reducing obesity to any significant degree (M. Ng et al., 2014), and it seems likely that future health care systems will be burdened by obesity-related disorders such as cardiovascular disease and diabetes. To make matters worse, parental obesity may program metabolic disadvantages in offspring via epigenetic transmission (S. F. Ng et al., 2010). As in adults, overweight and obesity in children (2-19 years old) has steadily increased in recent decades; more than 30% of children in the USA are now overweight or obese (E. A. O'Connor et al., 2017), in many cases leading to lifelong impacts on metabolic and behavioral aspects of energy homeostasis, and elevated risk of many associated diseases. In Lewis Carroll's Alice's Adventures in Wonderland, Alice quaffs the contents of a small bottle in order to shrink. The quest for a real-life

TABLE 9.1 Body Mass Index (BMI)

Starvation Underweight Ideal weight Overweight

weight (kg) height × height (m × m) or weight (lb) height × height (in. × in.)

epigenetic transmission The passage from one individual to another of changes in the expression of targeted genes, without altering the sequence of nucleotides in the gene.

The prevalence of obesity changed little before 1980. At about this time, medical recommendations to avoid dietary fats became widespread. Researchers now believe that the subsequent replacement of 50 fat calories with carbohydrates, especially sugar, is a leading cause of obesity.

In the span of just 35 years, the prevalence of obesity in the USA has tripled.

0 196 1 2 97 1 4 98 1 0 99 2 4 00 2 0 00 2 2 00 2 4 00 2 6 00 2 8 01 2 0 01 2 2 014 0- 71- 76- 88- 99- 01- 03- 05- 07- 09- 11- 13- 196 19 19 19 19 20 20 20 20 20 20 20

FIGURE 9.18 An Epidemic of Obesity (After Fryar et al., 2016. Natl. Ctr. Hlth. Stat. July 2016. www.cdc. gov/nchs/data/hestat/obesity_adult_13_14/­obesity_ adult_13_14.htm.)

shrinking potion--but one that makes you thin rather than short--is the subject of intense scientific activity, and several major strategies or targets are emerging: 1. Appetite control Hopes are high that drugs designed to reset the hypothalamic appetite controller will be safe and potent obesity treatments. Alteration of leptin levels has not proven to be very effective (DePaoli, 2014). Drugs that directly interfere with endocannabinoid activity, which is normally regulated by leptin in the hypothalamus, effectively produce"anti-munchies"--the reverse of the hunger experienced by cannabis users (Thornton-Jones et al., 2006). However, significant mood problems (an"anti-high"?) also occur, so the search continues for drugs that can selectively modify the signaling systems in the arcuate appetite controller. Treatments that mimic other signaling hormones are promising, especially those that exploit the shorter-term satiety-signaling peptides from the gut. Simply spraying a PYY3-36 solution into the mouths of lab mice is apparently not aversive, yet it powerfully suppresses their appetite (Hurtado et al., 2013). The prescription anti-obesity drug Saxenda (liraglutide) suppresses appetite by mimicking the gut peptide hormone GLP-1 (glucagon-like peptide), which we discussed earlier (Halford et al., 2010). 2. Increased metabolism An alternative approach to treating obesity is to raise the body's metabolic rate and thus expend extra calories in the form of heat. For example, scientists are trying to design drugs that will mimic some of the metabolism-elevating actions of thyroid hormones without producing harmful side effects (Grover et al., 2003). Another promising approach involves inducing fat tissue to start burning stored energy faster than normal (Kajimura and Saito, 2014). 3. Inhibition of fat tissue A third way to treat obesity involves blocking the formation of new fat tissue. For example, in order for fat tissue to grow, it must be able to recruit and develop new blood vessels. Drugs that block this process inhibit weight gain in mice and may have similar anti-obesity benefits in humans (Tam et al., 2009). 4. Reduced absorption The anti-obesity medication orlistat (trade name Xenical) works by interfering with the digestion of fat. However, this approach has generally produced only modest weight loss, and it often causes intestinal discomfort. 5. Reduced reward A different perspective on treating obesity focuses on the rewarding properties of food. Not only is food delicious, but"comfort foods"also directly reduce circulating stress hormones, thereby providing another reward. Drugs that affect the brain's reward circuitry (see Chapter 4), reducing the rewarding properties of food, may promote weight loss (Volkow and Wise, 2005). 6. Anti-obesity surgery Because fat tissue tends to regrow after liposuction (the surgical removal of fat tissue), some people are turning to a different strategy: bariatric surgeries that bypass part of the intestinal tract or stomach, or install a gut liner, in order to reduce the absorptive capacity of the digestive system (FIGURE 9.19). Alterations in appetite hormones such as ghrelin reportedly also accompany such surgeries (D. E. Cummings, 2006). These surgeries can bring about substantial and lasting weight loss, which may also reverse comorbid conditions like type 2 diabetes and hypertension. 7. Lifestyle changes Follow-up research with the Biggest Loser contestants has confirmed what many of us already suspected: increased physical activity can help keep the pounds off after dieting. However, the required change may need to be very substantial, and sustained. Compared with the contestants who regained all of their former weight, the few who maintained their new lower weight 6 years after the end of the contest had to increase their physical activity level by an average of 160% (Kerns et al., 2017) relative to their pre-contest activity levels. At least in this group, exercise played a significantly greater role than dietary changes, but the relationship between weight loss and lasting decreases in metabolic rate remains mysterious (Hall, 2018).

Homeostasis: Active Regulation of the Internal Environment 313

(A) Sleeve gastrectomy By reducing the stomach to a narrow tube, its ability to absorb nutrients is reduced, and secretion of the appetite hormone ghrelin is reduced.

(B) Gastrointestinal bypass In Roux-en-Y bypass, a reduced stomach is reconnected so as to bypass the initial stretch of small intestine. New stomach Food Digestive juice Bypassed portion of small intestines

(C) Gut liner A less invasive option is a surgically implanted intestinal liner that can act as a barrier to prevent absorption of nutrients. Stomach Liner

FIGURE 9.19 Surgical Options for Obesity

Eating disorders can be life-threatening Sometimes people shun food, despite having no apparent aversion to it. These people are usually young, become obsessed with their body weight, and become extremely thin--generally by eating very little and sometimes also by vomiting, taking laxatives, overexercising, or drinking large amounts of water to suppress appetite. This condition, which is more common in adolescent and adult women than in men, is called anorexia nervosa. The name of the disorder indicates (1) that the afflicted people have no appetite (anorexia) and (2) that the disorder originates in the nervous system (nervosa). People with anorexia nervosa tend to think about food a good deal, and evidence suggests that they respond even more than healthy people to the presentation of food (Brooks et al., 2012). So, in a physiological sense their hunger may be normal or even exaggerated, but this hunger is somehow absent from their conscious perceptions and they refuse to eat. The idea that anorexia nervosa is primarily a nervous system disorder stems from this mismatch between physiology and cognition, as well as from the distorted body image of the people with anorexia (they may consider themselves fat when others see them as emaciated). There may also be abnormalities in the functioning of the dopamine-based reward system that signals pleasurable aspects of eating, persisting even after recovery (Kaye et al., 2009). Anorexia nervosa is notoriously difficult to treat, because it appears to involve an unfortunate combination of genetic, endocrine, personality, cognitive, and environmental variables. One approach that is successful in some cases is a family-based treatment (sometimes termed Maudsley therapy after the hospital where it was introduced) that de-emphasizes the identification of causal factors and instead focuses on intensive, parent-led "refeeding" of the anorexic person (Le Grange, 2005; Kass et al., 2013). Bulimia (or bulimia nervosa, from the Greek boulimia, "great hunger") is a related disWoradtesor.nL/Bikreeepdleoovpele with anorexia nervosa, people with bulimia may believe themselves TtohebMe ifnadt'tseMr tahchainnethey are, but they periodically gorge themselves, usually with "junk Ffoouondd,a"tiaonnsdoftBhreanineanitdhBeerhvavoimor 4itethe food or take laxatives to avoid weight gain. Also like MpeMop4ele_0w9.i1t9h an05o/r2e0x/ia20nervosa, people with bulimia may be obsessed with food and body weight, but not all of them become emaciated. And as in anorexia nervosa, bulimia can be deadly if the person's lack of nutrient reserves damages various organ systems and/or

anorexia nervosa A syndrome in which individuals severely deprive themselves of food. bulimia Also called bulimia nervosa. A syndrome in which individuals periodically gorge themselves, usually with "junk food," and then either vomit or take laxatives to avoid weight gain.

leaves the body unable to battle otherwise mild diseases. Prompt interventions, such as cognitive behavioral therapy that focuses on overcoming distorted views of food and eating, can relieve bulimia and lessen the risk of relapse and serious health impacts (De Jong et al., 2018). In binge eating, people spontaneously gorge themselves with far more food than is required to satisfy hunger, often to the point of illness. Such people are often obese, and the causes of the bingeing are not fully understood. In susceptible people, the strong pleasure associated with food activates opiate and dopaminergic reward mechanisms to such an extent that bingeing resembles drug addiction. Indeed, "binge eating disorder" is now a psychiatric diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; American Psychiatric Association, 2013). Despite the epidemic of obesity in our society, or perhaps because of it, our present culture emphasizes that women, especially young women, must be thin to be attractive. This cultural pressure is widely perceived as one of the causes of eating disorders. In earlier times, however, when plump women were considered the most beautiful, some women still fasted severely, showing all the hallmarks of anorexia nervosa. The origins of these disorders remain elusive, and to date, the available therapies help only a minority of people with eating disorders.

© Kunsthistorisches Museum, Vienna © Fred Duval/FilmMagic/Getty Images

Changing Ideals of Female Beauty Actress Keira Knightley (A) exemplifies modern society's emphasis on thinness as an aspect of beauty, while Helena Fourment as Aphrodite (B), which Flemish painter Peter Paul Rubens painted of his wife circa 1630, illustrates the very different fashion of her era. This treatment of the female body as an object, subject to fluctuating cultural norms and whims of fashion, may play a role in the development of eating disorders such as anorexia nervosa and bulimia.

1. What proportion of adults in the United States are overweight or obese? How might homeostasis be part of the problem? 2. If you were designing drugs to combat obesity, what specific parts of the hypothalamic appetite controller might you target? Why? 3. Compare and contrast anorexia nervosa and bulimia. Are people with anorexia interested in food at all? Briefly discuss possible methods of treating anorexia. 4. Drawing on concepts covered in this chapter, discuss the likely contributions of cultural versus biological factors in various eating disorders. 5. Discuss nonpharmacological methods of weight reduction. Is surgery a good option?

Watson/BreedloveSee Video 9.5: The Mind's Machine Anorexia Foundations of Brain and Behavior 4e MM4e_UN.09.04 03/05/20 binge eating The rapid intake of large quantities of food, often poor in nutritional value and high in calories.

Recommended Reading Agras, W. S., and Robinson, A. (Eds.). (2018). Oxford Handbook of Eating Disorders (2nd ed.). New York, NY: Oxford University Press. Anderson, S. C., Cryan, J. F., and Dinan, T. (2019). The Psychobiotic Revolution: Mood, Food, and the New Science of the Gut-Brain Connection. Washington, DC: National Geographic. Brownell, K. D., and Walsh, B. T. (2017). Eating Disorders and Obesity (3rd ed.). New York, NY: Guilford Press. DeSalle, R., and Perkins, S. L. (2015). Welcome to the Microbiome: Getting to Know the Trillions of Bacteria and Other Microbes In, On, and Around You. New Haven, CT: Yale University Press. Logue, A. W. (2014). The Psychology of Eating and Drinking (4th ed.). New York, NY: Routledge. Lustig, R. H. (2018). The Hacking of the American Mind: The Science behind the Corporate Takeover of Our Bodies and Brains. New York, NY: Avery. McNab, B. K. (2012). Extreme Measures: The Ecological Energetics of Birds and Mammals. Chicago, IL: University of Chicago Press. Schulkin, J. (Ed.). (2012). Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, UK: Cambridge University Press.

You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.

1 Homeostatic systems, such as the processes regulating thermoregulation (body temperature), work to maintain a constant internal environment. Like other homeostatic systems, thermoregulation employs negative feedback control: the resulting heat inhibits the system from calling for more. Review Figure 9.1, Animations 9.2-9.4 3 Our cells function properly only when the concentration of salt in the intracellular compartment of the body is within a critical range. The extracellular compartment is a source of replacement water for osmosis and a buffer between the intracellular compartment and the outside world. Review Figures 9.5 and 9.6 5 Specialized osmosensory neurons detect the concentration of extracellular fluid. Baroreceptors in the major blood vessels monitor blood pressure and volume. Review Figure 9.7

42 40 38 36 34 32 30 28 Temperature gradient (°C)

Supraoptic nucleus, paraventricular nucleus Vasopressin release Water conservation

2 Homeostatic systems rely on specialized behaviors to help regulate physiological parameters. For example, most species have specialized behaviors to help warm or cool the body. Review Figure 9.2 4 Thirst is a powerful motivator, triggered either by hypovolemic thirst (decreased volume of the extracellular fluid) or by osmotic thirst (increased extracellular saltiness). Because of the importance of solute concentration, we must regulate salt intake in order to regulate water balance effectively. Review Figure 9.6 6 Hypovolemic and osmotic thirsts are triggered by different mechanisms and differ in their immediate effects, but both forms of thirst ultimately trigger a complex shared thirst network. Review Figures 9.8 and 9.9

7 Our digestive system breaks down food and uses most of it for energy. Insulin helps most body cells to use glucose for fuel (the brain can use glucose directly) and promotes the storage of excess food energy. Another pancreatic hormone, glucagon, helps liberate glucose from storage. Review Figure 9.10 9 Early evidence implicated the hypothalamus in the control of appetite, but the existence of multiple redundant control signals from the gut and brain have complicated efforts to fully describe the appetite controller. Review Figures 9.13 and 9.14

Fat (energy store) Fatty acids (ready energy)

300 Recovered VMH-lesioned rat 200 Normal rat

10 Caloric intake 0 4 8 12 16 20 24 28 32 Days

8 In endotherms, most food energy is used for basal metabolism. Metabolism readily shifts to compensate for changes in the availability of food. To the dismay of dieters, the body responds to caloric restriction by reducing metabolism, thus limiting weight loss. Review Figure 9.11

10 An appetite controller located in the arcuate nucleus of the hypothalamus responds to levels of several peptide gut hormones. When activated, arcuate POMC neurons act to decrease appetite, and arcuate NPY neurons act to stimulate appetite. Leptin and insulin provide important hormonal signals about longer-term energy storage. Ghrelin, GLP-1, and PYY3-36 provide more-acute signals from the gut. Ghrelin stimulates, and PYY3-36 and GLP-1 inhibit, the arcuate appetite control system. Review Figure 9.16, Activity 9.1

11 Obesity is a pervasive and worsening public health problem that is difficult to treat through diet, drugs, or surgery. The only long-lasting medical intervention for obesity is bariatric surgery, but several drug strategies based on a new understanding of appetite control offer promise. Review Figure 9.18 and 9.19, Video 9.5

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