Energy Balance

What is the currently-accepted hypothesis for how the brain monitors energy and food intake?

-"Metabolic" or "energostatic" hypothesis: food intake is responsive to the final common events in metabolism, which lead to the phosphorylation of ATP. -Thus, in order to maintain a constant supply of metabolic fuels for intracellular oxidation, the body monitors metabolic fuel oxidation AND changes in food intake, energy expenditure, and body fat storage. -The brain does NOT care where energy comes from, and will induce cravings for glucose or fatty acids depending on whether the metabolism of one or the other is blocked.

What characterizes positive and negative energy balance?

-"Positive" energy balance: there is an abundance of glucose and excess is stored. -"Negative" energy balance: when the body runs out of glucose, and needs to break down fuel stores (i.e., glycogen and triglycerides).

Hyperinsulenemia

-A condition in which the body produces too much insulin, resulting in increased glucose uptake. -The consequent physiological side effects include inhibited lipolysis and low blood pressure. -Additionally, hyperinsulinemia also leads to obesity because sufferers of the condition are always hungry.

Adipokine

-A hormone that was once heralded as the "satiety hormone." -Adipokine has limited use as a treatment for obesity. -However, the hormone may play a greater role in orchestrating sexual and feeding behaviors.

alpha-MSH

-A melanocortin that inhibits food intake, often after being produced by the POMC circuit. -alpha-MSH levels increase after overfeeding. -There are melanocortin receptors in both the hypothalamus and the hindbrain, which are involved in feeding.

Due to need to conserve energy in the long-term, how have animals' bodies adapted?

-A need for energy explains why there are fewer mechanisms to STOP eating (i.e., satiety signals) than mechanisms to PROMOTE eating (i.e., hunger signals). -"Satiety peptides" fail to keep many individuals lean, even though they may be used in the management of obesity and diabetes.

Tumor necrosis factor (TNF)

-A pro-inflammatory cytokine involved in cachexia, which is characterized by a dramatic reduction in food intake and wasting body mass. -TNF is thought to reduce food intake when administered centrally or peripherally.

Hunger

-A strong motivation to seek out and ingest food. -This is considered a psychological state experienced by individuals as satiety from a previous meal wanes.

What were the results of the "liver" experiment, and what do they suggest?

-After the brain was treated with ketones and insulin, animals experienced feeding behavior. This suggested ketones had no effect on the insulin pathway. -However, after the liver was treated with fructose and insulin, feeding behavior (characteristic of the insulin pathway) stopped. -This suggests the liver plays a role in insulin-induced feeding, perhaps by monitoring glycogen stores and communicating this information to the CNS.

5-thio-D-glucose (5TG)

-Another antimetabolic glucose analogue. -Along with 2DG, stimulates glucoprivic hunger.

What do the differential responses of the liver and brain to epinephrine suggest about their roles in feeding behavior?

-As part of the brain-mediated pathway (i.e., the brain receives glucose), epinephrine levels decrease. This is the pathway by which feeding behavior is inhibited. -By contrast, the liver can reduce feeding behavior but has no effect on epinephrine levels. Thus, it can only regulate eating BEHAVIOR.

How does insulin secretion correlate with body weight?

-Aside from changing in response to meals, insulin secretion is affected by the amount of stored fat. Thus, obese people have relatively high circulating insulin levels. -Moreover, infusion of insulin directly into the cerebral ventricles decreases food intake and causes animals to maintain their body mass at lower levels than before. -As such, it has been suggested that insulin serves as an indicator of fat stores.

How do cells make sure the brain receives ample energy during fasting state?

-During fasting, cells in the periphery switch from metabolizing glucose for ATP production to metabolizing free fatty acids from lipids stored in adipose tissue. -This occurs not only during fasting, but when a person is not consuming carbohydrates.

How are fatty acids produced in the body?

-During lipolysis, triglycerides stored in adipose tissue are broken down into free fatty acids and glycerol. -This provides oxidizable fuels for peripheral tissues, especially when glucose is scarce and the brain demands glucose.

Why might the cephalic phase of insulin release be associated with hunger?

-During the cephalic phase, sensory stimuli associated with food intake leads to neurally-triggered insulin release. -Shortly thereafter, insulin causes the reduction of metabolic fuel levels in the blood. -This may be why elevated insulin levels are associated with increased hunger.

In general, what occurs during the postabsorptive phase of digestion?

-During this stage, excess energy from the postprandial phase is stored. -At the same time as glucagon secretion falls, insulin secretion rises. Insulin is solely responsible for energy storage in vertebrates.

What was the problem with the Amgen deal?******

-Early on, researchers discovered that leptin could make obese ob/ob mice (which are unable to produce leptin) thin. -Thus, Amgen bought the rights to develop leptin for $20 million, in hopes of using it to cure obesity. -However, obese people have high levels of leptin but are insensitive to it. -Thus, leptin treatments were largely unsuccessful in reversing human obesity, except in those with congenital leptin deficiency. -Yet leptin could still act as a short-term satiety system (?).

Instead of acting as the "satiety center," what role could VMH play in food metabolism instead?

-Evidence has disproved the notion that the VMH is a center for satiety. -Instead, the VMH be part of a complex circuit that regulates feeding via the autonomic NS, which affects both energy metabolism and certain motivated behaviors.

In general, what occurs during the postprandial phase of digestion?

-Food is broken down into glucose, free fatty acids, and amino acids, which enter the bloodstream almost immediately. This results in an energy surplus. -Glucose is then used to power the brain and muscles, first and foremost.

What effect does ghrelin have on the two feeding pathways?

-Ghrelin exerts the opposite effect as insulin and leptin on feeding behavior. -Afferent information about satiety from the liver and gut peptides (i.e., CCK) travel via the vagus nerve and sympathetic fibers of the nucleus of the solitary tract. -The integration of this information is associated with the termination of a meal.

Where and when is ghrelin produced?

-Ghrelin is thought to be produced by cells in the stomach (but probably not the brain). -Ghrelin levels rise before meals and fall after meals.

Where are ghrelin receptors expressed in the brain? Where does the region project to?

-Ghrelin receptors are expressed in a group of neurons adjacent to the third ventricle, between the dorsal/central/periventricular/arcuate hypothalamic nuclei. -These neurons project axons to key hypothalamic circuits, including those producing POMC, CRH, and NPY/AgRP.

How was ghrelin first discovered?

-Ghrelin was discovered as a molecule that could stimulate growth hormone (GH) secretion from the anterior pituitary, but was not related to GHRH from the hypothalamus. -The molecule appeared to act through G-protein receptors. -Then, receptors for ghrelin were discovered in rat stomachs.

What starts the process of energy mobilization during a fast? How?

-Glucagon, which is released from pancreatic alpha-cells, starts by inhibiting insulin secretion. -By inhibiting insulin secretion, glucagon starts the process of energy mobilization by inducing the following processes: 1. Glycogenolysis, and 2. Lipolysis.

What is the importance of glucose in the body?

-Glucose acts as a central bodily nutrient, since all cells in the body can use it. -However, insulin is required for glucose to enter cells. -Glucose can be oxidized and converted into ATP, given by the following formula: glucose + O2 = CO2 + H2O + ATP.

How do leptin/insulin/ghrelin act on the hypothalamus during the first step of the feeding INHIBITORY circuit?

-HIGH leptin and insulin/LOW ghrelin levels stimulate the production of two neurotransmitters: POMC and CART. -Both POMC and CART inhibit food intake by acting on the periventricular circuit and/or LHA. -The pathway also inhibits NPY/AgRP release.

What percentage of new diabetes cases are type 2?

-In 2005, type 2 diabetes accounted for 45% of new cases among adolescents. -Nowadays, approximately 60% of new cases of diabetes among children and adolescents are thought to be type 2.

How does gastric bypass surgery affect satiety?

-Individuals who have undergone gastric bypass surgery do not show an anticipatory ghrelin elevation, which those who eat at consistent times do. -This may be due to a reduction in meal size and altered satiety. -For instance, those who have undergone the procedure tend to eat 5-7 small meals throughout the day, which may remove the anticipatory ghrelin response. -As a result, the symptoms of type 2 diabetes resolve almost immediately after gastric bypass surgery.

Where are insulin receptors found in the brain, and why is this thought to be the case?

-Insulin receptors are most prevalent in the arcuate nuclei. -Although insulin is not required for glucose to enter brain cells, insulin receptors monitor metabolic fuel levels (i.e., glucose). -From there, insulin- and leptin-receptive neurons in the arcuate nuclei integrate this information to affect energy balance (see other card for pathway).

How do leptin/insulin/ghrelin act on the hypothalamus during the first step of the feeding STIMULATORY circuit?

-LOW leptin and insulin/HIGH ghrelin levels stimulate the production of two neurotransmitters by the arcuate nuclei: NPY and AgRP. -Both NPY and AgRP stimulate food intake by acting on the periventricular nuclei (PVN) and/or LHA. -The pathway also inhibits POMC/CART release.

Besides food intake, what other biological conditions could leptin mediate?

-Leptin is thought to orchestrate short-term changes in behavioral priorities. -For instance, leptin increases sexual motivation in lab animals. This might be because leptin signals the reproductive system that there are sufficient calories stored up to support reproduction. -Leptin also reverses nutritional amenorrhea in women with anorexia nervosa.

What is the role of leptin in the body? What evidence suggests this?

-Leptin levels are proportional to the total amount of fat in the body. -At some point, researchers believed leptin to be a satiety hormone that curtails food intake when body fat levels fall. -However, when fat is being used for energy, leptin levels fall faster than levels of fat being metabolized. This suggests leptin acts as a "starvation" signal, triggering food intake when levels drop.

How was leptin discovered?

-Leptin was discovered at Rockefeller by Jeffrey Friedman, in 1993. -Leptin was only found in fat cells, but was used to communicate with the brain. -Found that circulating leptin levels were proportional to fat stores.

How do VMH lesions affect insulin secretion, and what does this mean?

-Lesions to the VMH (which was once thought to be the "satiety center") increase insulin levels substantially. -Animals also became obese without overeating. Thus, overeating is caused by obesity in this case, not vice versa.

What evidence suggests the VMH might control the autonomic NS, rather than being the "satiety center"?

-Lesions to the VMH suppress sympathetic NS activity and stimulate parasympathetic NS activity. This results in increased fat storage and inhibited lipolysis. -However, by storing too much energy as fat, the animal experiences a shortage of energy needed to maintain daily processes. -As such, animals with VMH lesions experience voracious appetites in order to maintain a steady delivery of metabolic fuel from the intestines. -Once the animal becomes obese and may develop insulin resistance, they can no longer respond by taking up more glucose, meaning food intake and body weight stabilize at a new "set point."

Are there glucose sensors in the brain?

-Metabolic fuel detectors are located in the brain, liver, muscles, and fat cells. -However, there is evidence that some CNS cells can also sense changes in glucose oxidation, even though the brain receives a relatively constant supply of glucose.

Where are receptors for NPY and AgRP located?

-Most receptors are located in both the hypothalamus and hindbrain. -Receptors are also found elsewhere.

How might the ability to mobilize energy stores affect weight gain in some individuals?

-Obese people may not be able to mobilize their preexisting fat stores normally, so are driven to eat more frequently to meet their normal energy demands. -This problem might manifest as not being able to mobilize fat stores or monitor blood glucose levels.

What experimental setup was used to determine how metabolic inhibitors affect food intake in rats?

-Researchers set out to determine whether other parts of the body, besides the hypothalamus, could regulate food consumption. -As such, researchers removed the hypothalamuses of rats, rendering them decerebrate. -Then, researchers introduced metabolic inhibitors and studied subsequent food intake in the rats.

How does meal time regularity affect ghrelin levels?

-Several studies suggest individuals on fixed meal schedules produce significant anticipatory increases in circulatory ghrelin. -For instance, rats given daily food provisions during a 4-hour window displayed an increase in plasma ghrelin levels. This response is similar in humans.

What were weight outcomes for the "Biggest Losers"?

-Six years after their weight loss, virtually all participants gained back ~70% of their lost weight or more. -Moreover, those who had lost the most weight displayed the slowest metabolic rates.

In general, what brain areas are feeding behaviors associated with?

-The actions related to feeding and foraging behavior are mediated via descending pathways. -These go through hindbrain motor areas.

How did researchers set out to find which organ controlled insulin-induced feeding behavior, between the liver and brain?

-The liver can "ingest" fructose. However, because fructose is too large to cross the blood-brain barrier, the brain cannot. -By contrast, the brain can use ketone bodies for fuel, but the liver cannot. -Researchers determined which organ was responsible for insulin-induced feeding behavior by injecting either the brain with ketone bodies or the liver with fructose. -Then, researchers injected cells ACROSS THE BODY with insulin, so as to lower blood glucose levels and induce feeding behavior. -This is because, normally, an animal would not eat once some organ (either the brain or liver) had already been "fed" and sensed there was an adequate fuel supply.

What organ gets priority for glucose during energy mobilization? Why?

-The metabolic system is designed to provide sufficient energy to the brain via the bloodstream, first and foremost. -This is because the brain cannot process fatty acids for fuel, whereas other cells in the body can. -As such, during long-term food deprivation, the body is starved of glucose to feed the brain (see other card). -However, when glucose is scarce, the brain can use ketone bodies in its place.

Ketosis

-The production of toxic levels of ketone bodies. -This often occurs during prolonged fasting, when muscles are used for energy. -The most dangerous effect of ketosis is elevated blood pH, which can impair neural function.

"Dual-center" hypothesis

-The theory that two separate brain centers controlled hunger and satiety. -This hypothesis pegged the LHA and VMH as important components of the systems involved in regulating glucose ("glucostat" hypothesis) and triglycerides ("lipostat" hypothesis). -After being used for two decades, the hypothesis has been replaced by evidence that multiple integrated neural circuits (encompassing areas of the hind-, mid-, and forebrain) receive direct metabolic input from the periphery.

What role do the arcuate nuclei of the hypothalamus play in food intake?

-Two pathways in the arcuate nuclei of the hypothalamus (see other card) send signals primarily to the PVN. -However, they also send information to other nuclei of the hypothalamus, which then directly modulate feeding behavior. -These pathways are modulated by peripheral hormonal signals that cross the blood-brain barrier (i.e., leptin, insulin, ghrelin, and PYY).

What characterizes type 1 diabetes?

-Type 1 diabetes is an autoimmune disorder in which pancreatic beta-cells are destroyed by the immune system, causing insulin deficiency. -The disease typically has rapid onset. -Because type 1 diabetes is common in children and young adults, it was once coined "childhood diabetes."

What characterizes type 2 diabetes?

-Type 2 diabetes occurs when some tissues develop insensitivity to insulin. -The disease usually develops slowly in adults. -Because type 2 diabetes is usually diagnosed after the age of 40, it was once coined "adult onset diabetes." However, an increasing number of young, obese individuals are developing type 2 diabetes, rendering the term misleading.

What evidence supports the "energostatic" hypothesis of energy regulation?

-Various "nutrient sensing" substrates and enzymes (i.e., AMPK and mTOR) affect ATP concentrations by mediating previous metabolic steps in the formation of ATP. -Specifically, AMPK and mTOR are sensitive to intracellular fuel availability and mediate the effects of food intake-related hormones (i.e., leptin) and neuropeptides (i.e., alpha-MSH).

Why does type 2 diabetes often lead to weight gain?

-When cells that are crucial for daily activity become insensitive to insulin, an intracellular energy deficit results (and triggers increased insulin secretion). This is because glucose fails to enter cells without insulin binding. -Moreover, adipose tissues usually become insensitive to insulin after muscle and liver cells, causing insulin to deposit fuel as fat. -The combination of an intracellular energy deficit and increased lipogenesis causes many to have greater appetites and gain weight.

How does type 2 diabetes affect insulin secretion throughout its progression?

-When cells that are crucial for daily activity become insensitive to insulin, an intracellular energy deficit results and triggers increased insulin secretion. -Over time, however, untreated diabetes may cause the pancreas to stop producing insulin, thereby necessitating the use of exogenous insulin.

What did the "metabolic inhibitors" experiment show? What is the significance?***

-When decerebrate rats were treated with 2DG in the HINDBRAIN (?), their food intake increased, even though the metabolic inhibitor induces severe hyperglycemia. -When decerebrate rats were treated with MP alone, their food intake increased to approximately the same extent. -However, when given a combination of treatments, food intake increased substantially (more than either drug alone). -This suggests that the hypothalamus isn't required for the control of feeding, but that metabolic signals can act on OTHER brain regions to control feeding.

What evidence contradicts the two main hypotheses for how the brain monitors energy and food intake?

1. "Glucostatic" hypothesis: diabetics have high circulating glucose levels, but still get hungry without the action of insulin. 2. "Lipostatic" hypothesis: even though we haven't lost any weight since our last meals, we still start to feel hungry four hours later.

What were two original two hypotheses for how the brain monitors energy and food intake?

1. "Glucostatic" hypothesis: suggests the brain monitors circulating glucose levels. When glucose falls below a certain level, we become hungry; then, after we eat and blood glucose levels return to normal, we are no longer hungry. 2. "Lipostatic" hypothesis: suggests the brain monitors the storage of triglycerides. When fat stores fall below a certain level, we become hungry; then, after we eat and replace the missing body fat, we are no longer hungry.

What two brain regions were implicated in the "dual-center" hypothesis? Why?

1. "Hunger center": located in the lateral hypothalamus area (LHA). This is because bilateral destruction of this brain region led to complete anorexia (i.e., loss of appetite) and subsequent of aphagia (i.e., loss of feeding behavior) in rats. 2. "Satiety center": located in the ventromedial hypothalamus (VMH). This is because lesions in this brain region cause hyperphagia and enormous, rapid weight gain.

What are two types of metabolic inhibitors?**** (slide 13)

1. 2-deoxy-D-glucose (2DG): blocks glucose metabolism. Induces hunger by causing glucoprivation (i.e., a fall in blood glucose levels). 2. Mercaptoacetate (MP) (????): blocks fatty acid metabolism. Induces hunger by causing lipoprivation (i.e., rendering cells unable to metabolize fatty acids).

What are some common occasions when the body must mobilize, rather than store, energy? (3)

1. After strenuous activity, 2. After a prolonged fast, and 3. Every morning before the first meal of the day (in order to break the nighttime fast, or eat "breakfast").

What are the benefits of storing body adipose tissue? (2)

1. Allows animals to engage in courtship, gestation, and other reproductive behaviors that conflict with food acquisition. 2. Allows animals to survive harsh environmental conditions (i.e., winter, drought, and famine).

Why is it difficult to study the physiological basis of feeding behavior? (3)

1. An animal might choose to eat or not based on some factor unrelated to a true appetite regulator, such as illness or aversion. 2. There are redundant systems for regulating appetite (i.e., many neuropeptides and mechanisms for initiating or suppressing feeding). 3. A substance could have direct OR indirect effects on feeding behavior.

What evidence disproves the theory that the LHA is the "hunger center"? (2)

1. Bilateral lesions of the LHA were shown to interfere with ALL motivated behaviors, not just feeding. 2. Lesions to the dopaminergic tracts passing through the LHA (from the midbrain to the striatum), but NOT to hypothalamic tissue, produce similar behavioral effects as lesions to the LHA itself.

In what ways could insulin influence food intake INDIRECTLY? (3)

1. By facilitating the use and storage of ingested carbohydrates. 2. Via feedback mechanisms involving other hormones and the autonomic NS. 3. The oxidation of metabolic fuels could generate a signal that controls food intake. Thus, the storage and mobilization of fat could change the rate of oxidation.

How do POMC and CART act on the brain to INHIBIT feeding behavior?

1. CART: increased secretion in the PVN decreases food intake. 2. POMC: produces alpha-MSH, which acts on the melanocortin type 4 receptor to inhibit appetite.

What evidence suggests the caudal brainstem controls food intake? (4)

1. Cells in the caudal brainstem express genes for leptin, ghrelin, NPY/AgRP, and POMC receptors. 2. Treatment with metabolic inhibitors that affect food intake increase the activity of neurons in the area postrema and nuclei of the solitary tract (of the brainstem), as well as in forebrain regions (i.e., PVN). 3. Normally, 2DG or 5TG infusion stimulates hunger due to glucoprivation. However, rats no longer experience increased food intake with 2DG after receiving damage to the area postrema and medial nucleus of the solitary tract. 4. Infusions of 5TG into the brainstem, but not hypothalamus, caused rats to increase their food intake and blood glucose levels.

What are the two stages of insulin release during digestion?

1. Cephalic phase: sensory stimuli associated with food (i.e., smelling food) leads to neurally-triggered insulin release from pancreatic beta-cells. 2. Gastrointestinal (GI) phase: after a meal, the absorption of nutrients from the gut triggers insulin release. This is associated with the primary storage uptake of excess nutrients.

What are some examples of primary sensory signals? (3)

1. Changes in glucose metabolism generate signals for insulin secretion. 2. Changes in the availability of free fatty acids. 3. Changes in ATP levels.

Besides the most common, what are some other ways of raising blood sugar levels (more specific to emergencies)? (2)

1. Corticosterone or cortisol release during vigorous exercise can induce gluconeogenesis. 2. During stress, epinephrine from the adrenal medulla can stimulate glycogenolysis.

Under what circumstances does glycogenolysis occur, and where? (2)

1. During a typical fast, by breaking down glycogen in the liver. 2. During extreme physical work, by breaking down glycogen in the muscles.

What hormones signal the body to break down different fuel sources during "negative energy balance"? (3)*****

1. Epinephrine: stimulates the breakdown of glycogen AND triglycerides into glucose and fatty acids. 2. Glucagon (produced by pancreatic alpha-cells): stimulates the breakdown of glycogen. 3. Glucocorticoids: stimulate the breakdown of glycogen.

What two pathways originate in the arcuate nuclei of the hypothalamus?

1. Feeding STIMULATORY circuit, and 2. Feeding INHIBITORY circuit.

During a fast, what are some methods of mobilizing energy? (2)

1. First, glycogenolysis breaks down glycogen in the liver, releasing glucose into the bloodstream. 2. Next, lipolysis breaks down triglycerides stored in adipose tissue into free fatty acids and glycerol. This provides oxidizable fuels for peripheral tissues.

What are the most common pathways by which the body raises blood sugar levels without eating? (3)

1. Glucagon release, which triggers glycogenolysis and lipolysis. 2. Gluconeogenesis: the process by which amino acids are converted to glucose in the liver. 3. Sympathetic NS stimulation of fat breakdown, which may signal the release of stored glycogen.

How are ketone bodies produced in the body? (2)

1. Gluconeogenesis, which occurs in the liver, converts amino acids into glucose as part of an "emergency system" for raising blood glucose. This results in the formation of ketone bodies as a side reaction. 2. Ketone bodies are also generated from the incomplete oxidation of free fatty acids.

What are some main sources of fuel in the human body? Which bodily cells can use them? (3)

1. Glucose: all cells in the body can use it, with the aid of insulin. 2. Fatty acids: all cells EXCEPT brain cells can use fatty acids, and the heart uses fatty acids principally for fuel. 3. Ketone bodies: can be used by the brain when glucose levels are scarce.

How are different types of metabolic fuels stored in the body? (2)********

1. Glucose: converted to glycogen and stored in the insulin and muscle. Insulin is required for storage (???? Slide #7). 2. Fatty acids: may combine with glycerol to form triglycerides, which are primarily stored in the tissues. Insulin is not required for storage. Can also be stored on their own (?).

What does the feedback cycle consist of for the feeding INHIBITORY circuit?

1. HIGH leptin and insulin/LOW ghrelin levels are secreted, proportionally to the amount of fat stored in the body. 2a. This causes food intake to decrease. 2b. Meanwhile, fuel stores are broken down.

What evidence suggests insulin influences food intake DIRECTLY? (3)

1. Hunger ensues when insulin levels drop at the end of the postabsorptive phase. 2. Infusion of insulin directly into the cerebral ventricles decreases food intake and causes animals to maintain their body mass at lower levels than before. 3. Rats with destroyed pancreatic beta-cells often develop long-term hyperphagia (i.e., elevated appetite), suggesting insulin affects satiety.

What conditions characterize diabetes? (4)

1. Hyperphagia (i.e., elevated appetite), 2. Hyperglycemia: extremely high levels of glucose in the blood, 3. Increased thirst and urination, and 4 Excretion of some glucose in the urine.

What are some examples of hormones or states that play an appetitive role in food intake, for rodents?

1. In Syrian hamsters, food deprivation increases food hoarding but not food intake. 2. In Syrian and Siberian hamsters, leptin diminishes food deprivation-induced food hoarding. 3. NPY causes rats to eat only if they don't already have food in their mouths.

Besides eating patterns alone, what factors could account for and perpetuate obesity? (2)

1. In obese individuals, consumption of certain calorically-dense foods derail hormonal homeostatic mechanisms, leading to cravings, hunger, and overeating. 2. Genome-wide association studies have revealed more than 32 candidate obesity genes, most of which are expressed or act in the brain.

What fuel sources does insulin cause to be STORED during the postabsorptive phase of digestion? (3)

1. In the liver, insulin stimulates the conversion of glucose to glycogen, which is then stored in the liver and muscles. 2. Insulin facilitates the transport of glucose into muscle and fat cells, as well as the transport of amino acids into muscle cells. 3. In peripheral cells, insulin is crucial for glucose oxidation and lipogenesis, which both result in the storage of fat in adipose tissue.

Besides the "liver" experiment, what other evidence suggests the liver acts as a peripheral fuel detector? (3)

1. Infusion of 2DG directly into the hepatic portal vein increases food intake (since 2DG inhibits glucose metabolism). 2. When low-dose nutrients are infused directly into the hepatic portal vein, food intake decreases. However, nutrients at low doses have no effect on feeding behavior when injected into general circulation. 3. When the vagus nerve was severed, 2DG-induced hunger was abolished. However, there was no effect on MP-induced hunger (which inhibits fat, rather than glucose, metabolism).

What does the feedback cycle consist of for the feeding STIMULATORY circuit (including negative feedback)?

1. LOW leptin and insulin/HIGH ghrelin levels are secreted, proportionally to the amount of fat stored in the body. 2a. This causes food intake to increase. 2b. Consequently, fuel stores are built up. 3. Full food stores then release insulin and leptin (in proportion to body fat), which inhibit the pathway (as part of negative feedback) and stimulate the feeding INHIBITORY circuit.

What role does the BRAIN play in epinephrine-mediated feeding behavior? (3)

1. Large doses of insulin induce glucose uptake and glycogen formation. 2. Once bodily fuel is pushed into storage and blood glucose levels drop, animals feel hunger. Moreover, their epinephrine levels rise (leading to breakdown of glycogen and triglycerides). 3. However, when the brain is supplied with glucose, it inhibits food intake and reduces epinephrine levels.

What role does the LIVER play in epinephrine-mediated feeding behavior?

1. Large doses of insulin induce glucose uptake and glycogen formation. 2. Once bodily fuel is pushed into storage and blood glucose levels drop, animals feel hunger. Moreover, their epinephrine levels rise (leading to breakdown of glycogen and triglycerides). 3. When the liver is treated with fructose, food intake is inhibited because the liver sends signals to the CNS via the vagus nerve. However, epinephrine levels do not decrease.

What two systems does leptin act on to signal fat storage levels?

1. Leptin signals the PNS and CNS that fat stores are reduced or increasing, thereby inhibiting or encouraging food intake. 2. Signals the reproductive system that there are sufficient calories stored to support reproduction.

What hormones trigger lipolysis in adipose tissue after prolonged fasting or very demanding exercise? (4)

1. Low levels of insulin, 2. Sympathetic release of norepinephrine, 3. Increased levels of glucagon and growth hormone, and 4. Corticosterone and cortisol release, which can induce lipolysis.

How do NPY and AgRP act on the brain to STIMULATE feeding behavior?

1. NPY: signals the PVN directly to evoke feeding behavior. 2. AgRP: promotes feeding indirectly by blocking the melanocortin type 4 receptor, which is an inhibitory appetite receptor (normally acted upon by alpha-MSH).

What types of congenital problems could arise with leptin? (2)

1. No leptin: found in obese ob/ob mice. 2. No leptin receptors: found in the Zucker fatty (fa/fa) rat. This was discovered in 1995 and led to gene therapies for leptin insensitivity.

What might explain the weight outcomes of the "Biggest Losers"? (2)

1. Once the losers' weight dipped far below a bodily "set point," their bodies slowed down metabolic rates until their original weights were restored. 2. The losers started the show with normal-range leptin levels, but left with virtually no detectable leptin. This might have rendered the losers ravenously hungry.

What hormones affect energy conservation INDIRECTLY, and in what way? (2)

1. Orexin: indirectly increases food intake by increasing general arousal. For example, animals treated with orexin tend to sleep less. 2. CCK: decreases food intake by making animals feel too nauseated to eat.

What are two ways to organize the endocrine signals regulating food intake?

1. Organizing by different TYPES OF HORMONAL signals (i.e., preparatory and primary sensory signals). 2. Organizing by the ORIGIN of signals in either the PNS or CNS.

What are some examples of GI tract hormones, and what are their effects on food intake? (4)

1. Pancreatic polypeptide (PP): INCREASES food intake. 2. Peptide YY (PYY): INCREASES food intake. 3. Glucagon-like peptide 1 (GLP-1): INCREASES food intake. 4. Ghrelin: DECREASES food intake.

How are endocrine signals regulating food intake organized by their ORIGIN? (2)

1. Peripheral: originate outside the nervous system. 2. Central: originate inside the nervous system.

What characterizes the two stages of energy utilization during the well-fed state?

1. Postprandial phase: occurs immediately after the ingestion of food, where an influx of metabolic fuels enters the bloodstream almost immediately. 2. Postabsorptive phase: when excess energy is stored within the body.

How are the endocrine signals regulating food intake organized by HORMONAL signals? (3)

1. Preparatory factors: cause changes in certain hormone levels (i.e., ghrelin or NPY) before a meal. 2. Primary sensory signals: biochemical changes that occur when fuels are metabolized to generate cellular activity. 3. Secondary mediators/modulators: the neuropeptides and hormones that influence food intake. These are controlled by primary sensory signals, and may have direct or indirect effects on food intake.

What fuel sources does insulin prevent from being BROKEN DOWN during the postabsorptive phase of digestion? (2)

1. Prevents the breakdown of glycogen (i.e., glycogenolysis) and liver cells. 2. Prevents the breakdown of triglycerides (i.e., lipolysis) in adipose tissue.

How can an individual acquire ketosis? (3)

1. Prolonged fasting, whereby muscles are broken down for energy. 2. Diabetes: individuals with uncontrolled blood sugar levels can enter ketosis when there is insufficient insulin for glucose uptake by cells. 3. Those on long-term, carbohydrate-free diets (due to the incomplete oxidation of free fatty acids during lipolysis).

How does the brain integrate gastrointestinal satiety signals to control all aspects of energy homeostasis?

1. Satiety signals converge in the dorsal hindbrain. 2a. The dorsal hindbrain sends information about satiation to the hypothalamus and other brain areas, which integrate information about other food-related conditions (see other card). 2b. The dorsal hindbrain sends information to the ventral hindbrain. 3. After receiving signals from the dorsal hindbrain, the ventral hindbrain relays them to the autonomic NS to influence blood glucose. The ventral hindbrain also relays signals to areas that influence motor control over feeding behavior. 4. After being integrated, information from part (2a) converges and moves back to the ventral hindbrain and the pituitary. This influences all aspects of energy homeostasis.

In accordance with the "energostatic" hypothesis, how are signals about food intake relayed to the brain, by order of pathway? (4)

1. Sensory neurons the stomach and liver detect signals generated by the oxidation of metabolic fuels. 2. Signals from these organs are sent through the vagus nerve to the area postrema and the nucleus of the solitary tract. 3. From these brain stem areas, signals are sent to the pontine parabrachial nucleus. 4a. Signals travel to the forebrain, including certain areas of the hypothalamus. 4b. Reciprocal input also travels to the hypothalamus from the sensory and higher cortical centers.

What is the way by which leptin acts on the brain to mediate food intake? (2)

1. Since leptin is a large peptide, it cannot cross the blood-brain barrier. Therefore, leptin must be actively transported into the brain. 2. Leptin signals to the arcuate nuclei of the hypothalamus (which has the highest concentration of leptin receptors) that fat stores are either increasing or decreasing.

In humans, what environmental factors contribute to caloric intake and body mass? (5)

1. Specific social situations (i.e., attending a movie in the theater). 2. Time of day. 3. Convenience (i.e., passing by a snack machine). 4. Habit. 5. Stress (i.e., food cravings while studying).

Specifically, how does ghrelin affect NPY-related brain regions? (2)

1. Stimulates activity of NPY neurons in the arcuate nuclei. 2. Mimics the effects of NPY in the PNV.

How does the sympathetic NS precipitate energy release during bodily emergencies?

1. Sympathetic nerves surrounding fat cells may induce lipolysis. 2. Sympathetic nerves in the liver may signal the organ to release stored glycogen.

How does ghrelin affect food intake in rats? (3)

1. Systemic injections of ghrelin stimulated food intake in rats. 2. Injections also increased body mass. 3. Blood concentrations of ghrelin peaked around the time of meal onset.

What intrinsic factors control food intake? (5)

1. The amount of fat stored in adipose tissue. 2. The amount of glycogen stored in the liver. 3. The biochemical qualities of the food being ingested. 4. The perceived pleasantness of the food. 5. Neural and endocrine signals from the gut.

Where are metabolic fuel detectors located throughout the body?

1. The brain, 2. In the periphery (i.e., liver), providing either a NEURAL or HORMONAL link to the brain.

In what ways does ghrelin exert the opposite physiological effect as leptin?

1. The hormones exert opposite effects on hypothalamic neurons that produce alpha-MSH, NPY, and AgRP. 2. High leptin concentrations are permissive of reproductive function, whereas ghrelin is inhibitory at EVERY level of the hypothalamic-pituitary-gonadal axis.

What aspects of food intake are controlled by hormones?

1. The number of calories consumed, 2. The size of meals, 3. Motivation to obtain food (both appetitive and consummative).

How might responsiveness to the phases of insulin release affect weight gain in some individuals? (2)

1. There is evidence that some are overly-responsive to the cephalic phase of insulin release, and therefore become obese because they experience greater hunger during meals. 2. Some may experience hyperresponsiveness to the GI phase of insulin release.

What accounts for most animals' need for energy?

Animals must maintain a relatively constant body temperature of 37°C, meaning they require a persistent influx of energy.

Besides the hypothalamus, what other brain regions influence food intake?

Areas of the midbrain and brainstem are known to carry many of the same neuropeptides that influence food intake in the hypothalamus.

What are different ways of classifying peptides involved in feeding behavior? (2)

Peptides that serve as neuromodulators in the arcuate nuclei (but act as hormones elsewhere in the body) can be classified as: 1. Anabolic effectors: increase appetite and food intake, while suppressing energy metabolism. 2. Catabolic effectors: increase appetite and food intake, while suppressing energy metabolism.

How do animals behave when given lesions to the dopaminergic tracts passing through the LHA?

The animals appear extremely sick and lack motivation.

What suggests leptin affects fuel oxidation?

The effects of leptin are blocked by treatments that influence either: 1. Metabolic fuel oxidation, or 2. AMPK, a nutrient-sensing enzyme.