The Gut-Brain Connection

The brain, in particular the hypothalamus, plays highly critical roles in the regulation of energy metabolism, nutrient partitioning, and the control of feeding behaviors. The gastrointestinal tract is intimately connected to the actions of the hypothalamic-pituitary axis via the release of peptides that exert responses within the brain as well as through neuroendocrine and sensory inputs from the gut. The primary centers in the brain involved in the control of appetite are the hypothalamic-pituitary axis and the brain stem.

The consumption of food initiates a cascade of neuronal and hormonal responses within and by the gastrointestinal system that impact responses in the central nervous system. The brain initiates responses to feeding even before the ingestion of food. The very sight and smell of food stimulates exocrine and endocrine secretions in the gut as well as increasing gut motility. Ingestion of food stimulates mechanoreceptors leading to distension and propulsion to accommodate the food. As the food is propelled through the gut regions of the intestines secrete various hormones that circulate to the brain and impact hypothalamic responses as discussed in the sections later. The mechanoreceptor responses are transmitted via afferent nerve signals along the vagus nerve to the dorsal vagal complex in the medulla and terminating in the nucleus of the solitary tract (NTS, for the Latin term nucleus tractus solitarii). Projections from the NTS enter the visceral sensory complex of the thalamus which mediates the perception of gastrointestinal fullness and satiety. Several hormones released from the gut in response to food intake exert anorexigenic (appetite-suppressing) responses in the brain, particularly in the hypothalamus. These hormones include glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), pancreatic polypeptide (PP), and oxyntomodulin (OXM or OXY). A single orexigenic (appetite-stimulating) hormone, ghrelin, is known to be released by cells of the gut.

Gastrointestinal Hormones and Peptides

There are more than 30 peptides currently identified as being expressed within the digestive tract, making the gut the largest endocrine organ in the body. The regulatory peptides synthesized by the gut include hormones, peptide neurotransmitters, and growth factors. Indeed, several hormones and neurotransmitters first identified in the central nervous system and other endocrine organs have subsequently been found in endocrine cells and/or neurons of the gut (Table 44-1).

Glucagon-Like Peptide-1

The glucagon gene encodes a precursor protein identified as preproglucagon (Figure 44-1). Depending on the tissue of expression, coupled with the presence of specific proteases called prohormone convertases, preproglucagon can be processed into several different biological peptides in addition to glucagon. The glucagon-like peptide-1 (GLP-1), derived from the proglucagon protein, is a gut hormone that is referred to as an incretin.

The primary physiological responses to GLP-1 are glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric acid secretion, and gastric emptying. The latter effect will lead to increased satiety with reduced food intake along with a reduced desire for food. The action of GLP-1 at the level of insulin and glucagon secretion results in significant reduction in circulating levels of glucose following nutrient intake. This activity has significance in the context of diabetes. The glucose-lowering activity of GLP-1 is highly transient as the half-life of this hormone in the circulation is less than 2 minutes. Removal of bioactive GLP-1 is a consequence of N-terminal proteolysis catalyzed by dipeptidyl peptidase IV (DPP4). DPP4 is also known as the lymphocyte surface antigen CD26 and has numerous activities unrelated to incretin inactivation.

All of the effects of GLP-1 are mediated following activation of the GLP-1 receptor (GLP-1R). The GLP-1R is a G protein-coupled receptor (GPCR) coupled to G_s-protein activation, increased cAMP production, and activation of protein kinase A (PKA). In addition the GLP-1R is coupled to the activation of PI3K which in turn activates PKB/Akt. The other major responses to the actions of GLP-1 include pancreatic β-cell proliferation and expansion concomitant with a reduction of β-cell apoptosis. In addition, GLP-1 activity results in increased expression of the glucose transporter 2 (GLUT2) and glucokinase genes in pancreatic β-cells.

Oxyntomodulin

Oxyntomodulin (OXM) is so called given that is was originally discovered from work examining the inhibition of the activity of oxyntic glands (gastric acid secreting) of the stomach. OXM is a 37-amino acid peptide derived from the proglucagon peptide and contains the entire 29 amino acids of glucagon. Synthesis and release of OXM occurs in the enteroendocrine L cells of the distal gut. These are the same cell populations that secrete GLP-1 and PYY. The secretion of OXM occurs within 5 to 10 minutes following ingestion of food and peaks within 30 minutes. The amount of OXM that is released is directly proportional to caloric intake. In addition to stimulated release in response to food intake, OXM exhibits diurnal variation in its concentration in the blood with highest levels detected in the evening and lowest levels in the morning. Like GLP-1, OXM has demonstrated incretin activity.

A distinct OXM receptor has not been identified but the protein can bind to the GLP-1R and the glucagon receptor. Indeed, evidence indicates that the incretin and anorexigenic effects of OXM are exerted via the GLP-1R as these activities of OXM are abolished in the GLP-1R knock-out mouse. OXM exerts a protective effect on pancreatic β-cells similar to that exerted by GLP-1. Although the affinity of OXM for the GLP-1R is at least 50-fold less than that of GLP-1 itself, the ability of OXM to exert inhibition of food intake is equal to that of GLP-1.

When OXM is administered into the brain the response is suppression of the effects of circulating ghrelin. These results suggest that part of the appetite suppressing effects of OXM are mediated by reduced ghrelin as well as increased hypothalamic release of anorexigenic peptides. Of potential significance to the treatment of obesity is that when OXM is administered intravenously to human subjects there is an observed reduction (19.3%) in food intake at mealtime. Additionally significant is the fact that this reduction in desire for food intake persists over the course of 12 hours. When OXM is administered subcutaneously to overweight and obese subjects over a period of 4 weeks there is a significant reduction in body weight. Although these results prove promising for the potential for OXM in the treatment of obesity it is important to note that OXM is a target for inactivation by DPP4 just as is GLP-1.

Glucose-Dependent Insulinotropic Peptide

GIP is derived from a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. GIP is synthesized by enteroendocrine K cells whose locations are primarily in the duodenum and proximal jejunum. Like GLP-1, GIP is a gut hormone possessing potent glucose-dependent insulin secretion (an incretin) activity. In addition, GIP has significant effects on fat metabolism exerted at the level of adipocytes. These actions include stimulation of lipoprotein lipase (LPL) activity leading to increased uptake and incorporation of fatty acids by adipocytes. Whereas GIP exerts positive effects on pancreatic β-cell proliferation and survival similar to that shown for GLP-1, the hormone does not affect glucagon secretion nor gastric emptying. Like GLP-1, GIP is inactivated through the action of DPP4.

The GIP receptor (GIPR) is a G_s-protein coupled GPCR found on pancreatic β-cells. Stimulation of the GIPR elevates intracellular cAMP levels and also results in increased uptake of Ca²⁺ into pancreatic β-cells. Responses to GIP have been shown to be defective in T2D patients.

Cholecystokinin

Cholecystokinin (CCK) is derived via posttranslational modification of the procholecystokinin peptide. CCK was the first gut hormone to be identified as having an effect on appetite. There are several bioactive forms of CCK that are designated based upon the number of amino acids in the peptide. The 4 major forms are CCK-8, CCK-22, CCK-33, and CCK-58. The predominant form that is found in human plasma is the CCK-33 form. CCK is secreted from intestinal enteroendocrine I cells predominantly in the duodenum and jejunum. The level of CCK in the blood rises within 15 minutes of food ingestion and reaches a peak by 25 minutes. The most potent substances initiating a release of CCK from the I cells are fats and proteins. Conversely, duodenal bile acids are potent suppressors of the secretion of CCK.

CCK exerts its biological actions by binding to 2 specific GPCRs identified as CCK-1 and CCK-2. The CCK receptors are also identified as CCK_A and CCK whose designations referred to their location of prominent expression with CCK_A referring to the alimentary tract (the gut) and CCK_B referring to the brain. However, both receptors are found widely expressed in the CNS as well as the periphery.

Upon binding its receptors in the gut CCK induces contractions of the gallbladder and release of pancreatic enzymes and also inhibits gastric emptying. Within the brain, specifically the median eminence and ventromedial nucleus of the hypothalamus (VMH), CCK actions elicit behavioral responses and satiation. Central administration of CCK results in reduced food intake. Of significance to appetite control, this effect is enhanced with coadministration of leptin. The synergistic effects of CCK and leptin may be due to the fact that their receptors are colocalized to the same sensory vagal afferent neurons.

Ghrelin

Ghrelin was first discovered based upon its ability to interact with the growth hormone secretagogue (GHS) receptor and stimulate the release of growth hormone. Indeed, ghrelin was found to be the endogenous ligand for the GHS receptor. The name ghrelin is derived from growth-hormone release. The specific receptor to which ghrelin binds and activates is identified as GHSR type 1a (GHSR1a).

The ghrelin gene encodes the ghrelin preproprotein that can undergo differential processing to yield mature ghrelin peptide or obestatin. Ghrelin is produced and secreted by the X/A-like enteroendocrine cells of the stomach oxyntic (acid-secreting) glands. Because the X/A-like cells express ghrelin they are also sometimes referred to as ghrelin cells or Gr cells. X/A-like cells express the receptor for gastrin (see Table 44-1) and, therefore, it is believed that gastrin may directly stimulate ghrelin release. Smaller amounts of ghrelin are released from the small intestine and the colon. A low level of ghrelin is also produced in pancreatic ε-cells.

Due to alternative splicing and posttranslational cleavage, the 117-amino acid preproghrelin protein can be processed into ghrelin (28 amino acids corresponding to amino acids 24-51 of the preproprotein), obestatin (23 amino acids corresponding to amino acids 76-98 of the preproprotein) and des-acyl ghrelin (27 amino acids). Bioactive ghrelin is acylated on the serine at position 3 with n-octanoic acid. The attachment of octanoic acid to Ser3 of ghrelin is accomplished by the acyltransferase identified as ghrelin O-acyltransferase (GOAT; also referred to as membrane-bound O-acyltransferase domain-containing 4, MBOAT4). The nonacylated form of ghrelin may act as an antagonist of the acylated hormone. The des-acyl ghrelin protein is also acylated on Ser3 which is required for its activity as for full-length ghrelin.

The major effect of ghrelin is exerted within the hypothalamus at the level of the arcuate nucleus (ARC) where it stimulates the release of neuropeptide Y (NPY) and agouti-related protein (AgRP). As discussed below, the actions of NPY and AgRP enhance appetite and thus, food intake. Within the hypothalamus, ghrelin action results in activation of AMPK leading to reduced intracellular levels of long-chain fatty acids. The reduction in fatty acid levels appears to be the molecular signal leading to increased expression of NPY and AgRP. However, it is important to note that the signaling events triggered by ghrelin binding to GHSR1a are complex.

The secretion of ghrelin is the inverse of that of insulin. The primary mechanisms that are coupled to production of ghrelin are fasting, hypoglycemia, and leptin. Conversely, inhibition of ghrelin production is exerted by food intake, hyperglycemia, and obesity. The action of ghrelin at the level of increasing the release of NPY is the exact opposite to that of leptin which inhibits NPY release. Additional effects of ghrelin include inhibition of the expression of proinflammatory cytokines, modulation of exocrine and endocrine functions of the pancreas, regulation of gastric acid secretion and gastric motility, and the modulation of sleep patterns, memory and anxiety-like behavioral responses.

Obestatin

Whereas ghrelin actions result in increased appetite and food intake, obestatin action suppresses food intake. The name obestatin is derived from a contraction of obese and statin (to suppress). Release of obestatin suppresses food intake and gastric emptying activity. Like ghrelin, which is posttranslationally modified, obestatin is also modified but its modification is an amidation. The mechanism(s) by which obestatin exerts its effects is unclear since a definitive receptor has not yet been identified for this gut peptide.

Pancreatic Polypeptide

Pancreatic polypeptide (PP) was the first member of the PP-fold family (PP, PYY, and NPY) to be isolated and characterized. PP is produced and secreted by type F cells within the periphery of pancreatic islets. The stimulus for the release of PP is the ingestion of food and the level of release is proportional to the caloric intake. Increased circulating levels of PP can be detected in the blood for up to 6 hours following ingestion of food. Humoral signals that are involved in food intake-mediated secretion of PP include ghrelin, CCK, motilin, and secretin. Additionally, adrenergic stimulation secondary to either hypoglycemia or exercise results in increased release of PP. The actions of PP include delaying gastric emptying, inhibition of gallbladder contraction, and attenuation of pancreatic exocrine secretions. These gut actions of PP are associated with the mechanism referred to as the ileal brake which is manifest with the slowing of the passage of nutrients through the gut.

The PP-fold proteins bind to a family of receptors that were originally characterized as NPY receptors (see later). There are 4 NPY receptors in humans designated as Y1, Y2, Y4, and Y5. PP induces an anorexigenic response within the brain stem (area postremus, AP) and vagus. These responses are mediated via activation of the Y4 receptor which binds PP with highest affinity. In addition to its expression in the AP, the Y4 receptor is also expressed in regions of the hypothalamus including the ARC. Therefore, additional anorexigenic responses to PP can be induced within the hypothalamus.

PP plays an important role in the regulation of satiety. In obese individuals there is a reduced level of PP secretion in response to food intake, whereas, in anorexia nervosa there is increased PP release following consumption of food. PP may also play a role in the pathogenesis of Prader-Willi syndrome (PWS). This disorder is characterized by short stature, reduced intellect, and hyperphagia. In patients with PWS there is a reduced secretion of PP in response to food intake as well as a reduced basal level of circulating PP.

Protein Tyrosine Tyrosine

Protein tyrosine tyrosine (PYY) is another member of the PP-fold family. PYY is produced and secreted by intestinal enteroendocrine L cells of the ileum and colon. Additional gut hormones that are secreted along with PYY include GLP-1 and OXM. Secreted forms of PYY include PYY_1-36 and PYY_3-36 with PYY_3-36 being generated via the actions of DPP4. Within the central nervous system PYY is detectable in the hypothalamus, medulla, pons, and spinal cord.

The release of PYY results in reduced gut motility, delayed gastric emptying, and inhibition of gallbladder contraction. All of these actions are, like that of PP, associated with the ileal brake. CCK and gastrin are thought to mediate the rapid release of PYY in response to eating. The amount of PYY released in response to the ingestion of food is proportional to the caloric intake. PYY has a critical role in satiety. Within the CNS, PYY exerts its effects on satiety via actions in the hypothalamus, specifically the ARC. Given the role of PYY in appetite suppression it is thought that disturbances in PYY release in response to food intake may play a role in the development of obesity. Indeed, in obese humans there is a blunted PYY response following food intake compared to lean humans. Current therapeutic interventions designed to combat obesity involve studies of the efficacy of PYY at suppressing appetite.

Hypothalamic Control of Feeding Behavior

The location and organization of the hypothalamus is discussed in Chapter 49. The primary nuclei of the hypothalamus that are involved in feeding behaviors and satiety include the arcuate nucleus of the hypothalamus (ARC, also abbreviated as ARH), the dorsomedial hypothalamic nucleus (DMH or DMN), and the ventromedial hypothalamic nucleus (VMH or VMN) all of which are located in the tuberal medial area. The ARC is involved in control of feeding behavior as well as secretion of various pituitary releasing hormones, the DMH is involved in stimulating gastrointestinal activity, and the VMH is involved in satiety. Early experiments involving lesions in the hypothalamus demonstrated that the lateral hypothalamic area (LHA) is responsible for transmitting orexigenic signals and loss of this region results in starvation. The medial hypothalamic nuclei (VMH and to a lesser extent the DMH) are responsible for the sensations of satiety and lesions in these regions of the hypothalamus result in hyperphagia and obesity.

Appetite is a complex process that results from the integration of multiple signals at the hypothalamus. The hypothalamus receives neural inputs, hormonal signals such as leptin, CCK, and ghrelin, and nutrient signals such as glucose, free fatty acids, amino acids, and volatile fatty acids. Each of these elicits effects that are processed by a specific set of neurotransmitters primarily acting within the ARC (Figure 44-2). Within the ARC the orexigenic neurons express NPY and AgRP and the anorexigenic neurons express proopiomelanocortin, POMC-derived melanocortins (principally α-MSH) and cocaine and amphetamine-regulated transcript (CART). These so-called first-order neurons then act on second-order neurons. The orexigenic second-order neurons express either MCH or the orexins. The anorexigenic second-order neurons express corticotropin-releasing hormone, CRH. The net effect of the concerted action of these neuropeptide is alterations in feeding behaviors and food intake. In addition, satiety signals from the liver and gastrointestinal tract signal through the vagus nerve to the nucleus of the solitary tract (NTS, for the Latin term nucleus tractus solitarii). The NTS is a cluster of specialized cells within the medulla responsible for sensations of taste and visceral sensations of stretch. Activation of the NTS via the vagal nerve causes meal termination, and in combination with the hypothalamus, integrates the various signals to determine the feeding response. The activities of these neuronal pathways are also influenced by numerous factors such as nutrients, fasting, and disease to modify appetite and hence exert impacts on growth and reproduction.

Neuropeptide Y

Neuropeptide tyrosine (NPY) is a hypothalamic neuroendocrine protein that is a member of the PP family of hormones. Each of these peptide hormones contains 36 amino acids including numerous tyrosines (hence the Y nomenclature). Each of the PP family of proteins binds to a family of receptors that were originally characterized as NPY receptors designated as Y1, Y2, Y4, and Y5. Receptors Y1, Y2, and Y5 preferentially bind NPY and PYY, whereas, Y4 exhibits highest affinity for PP. The Y2 receptor is involved in anorexigenic responses whereas the Y1 and Y5 receptors have been shown to induce orexigenic responses. The Y2 receptors are referred to as inhibitory receptors with respect to the activity of NPY and they are abundantly expressed on NPY neurons in the ARC of the hypothalamus.

NPY is expressed throughout the brain with highest levels found in the ARC of the hypothalamus. NPY is one of the most potent orexigenic factors produced by the human body. Within the ARC there are 2 neuronal populations that exert opposing actions on the desire for food intake. Neurons that coexpress NPY and another neuropeptide called AgRP stimulate food intake, whereas, neurons that coexpress POMC and cocaine and amphetamine-regulated transcript (CART) suppress the desire for food intake. The Y1 and Y5 receptors mediate the bulk of the effects of NPY on the hypothalamic-pituitary-thyroid axis. Within the ventromedial nucleus (VMN) of the hypothalamus, binding of NPY to the Y1 receptor results in inhibition of neuronal function (via hyperpolarization) thereby interfering with the satiety role of the VMN. The majority of hypothalamic Y2 receptors are found on NPY-containing neurons. Conversely, Y2 receptor activation in the ARC results in inhibition of the actions of NPY which accounts for the anorexigenic actions associated with PP activation of Y2 receptors. Of significance to dieting and weight loss is the fact that when people lose excess weight the level of NPY increases which likely is a contributing factor to the inability of most people to keep the weight off.

NPY exerts differential orexigenic effects on food choice. NPY action causes a strong preference for carbohydrate-rich foods. NPY activity leads to reduced fatty acid oxidation while simultaneously promoting carbohydrate oxidation and fatty acid synthesis. The synthesis and release of NPY is also responsive to the particular fuel source being metabolized in the brain. Reduced hypothalamic glucose oxidation results in increased NPY release whereas fatty acid metabolism exerts no appreciable effect on NPY synthesis.

Agouti-Related Peptide

As the name implies, AgRP is a protein with sequence homology to the agouti protein which controls coat color in rodents. AgRP is expressed primarily in the ARC and is found to colocalize with neurons that also produce NPY. Although expression of AgRP is restricted to the ARC, AgRP fibers project to several brain areas as well as to multiple areas within the hypothalamus, including the paraventricular nucleus (PVN or PVH) and the perifornical lateral hypothalamus (PFLH). In addition, all of these AgRP nerve terminals contain NPY. The PVN is a region of the hypothalamus that integrates neuropeptide signals from numerous regions of the brain and hypothalamus as well as the brain stem. The PFLH is a subdomain of the lateral hypothalamic area (LHA) that is involved in arousal and food-seeking behaviors.

AgRP together with NPY represent a distinct set of ARC-expressed orexigenic peptides. AgRP is classically referred to as a member of the central melanocortin system, which in addition to AgRP comprises α-MSH (see later) and 2 melanocortin receptors identified as melanocortin receptor 3 (MC3R) and melanocortin receptor 4 (MC4R). Whereas, α-MSH is an agonist of both MC3R and MC4R, AgRP serves to antagonize the actions of α-MSH at these same receptors with highest antagonist activity on MC4R. In addition to antagonizing the effect of α-MSH at the MC3R and MC4R, AgRP suppresses the basal activity of the MC4R, thus defining AgRP as an inverse agonist.

The close functional relationship between AgRP and NPY is demonstrated by the fact that the expression of these 2 peptides is similarly modulated under identical physiological conditions such as negative energy balance or increased energy demand that occurs during food deprivation. During periods of fasting both AgRP and NPY levels rise, primarily as a result of a drop in the level of the peripheral hormones leptin (see Chapter 45) and insulin (see Chapter 46) and a rise in ghrelin. The expression of both AgRP and NPY is suppressed under conditions of positive energy balance.

Central injection of AgRP has a potent stimulatory effect on food intake which can also be seen using a MC4R antagonist. These results confirm the function of AgRP as an antagonist of α-MSH. Chronic administration of AgRP results in increased daily food intake while simultaneously decreasing oxygen consumption and the capacity of brown adipose tissue to expend energy.

There exists an antagonism between the actions of AgRP (and NPY) and the melanocortins in controlling eating and body weight. Changes in endogenous AgRP levels are opposite to those seen with the melanocortin peptides. AgRP neurons interact with POMC neurons in the ARC through the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Both AgRP and NPY axons, that colocalize GABA, project onto POMC-expressing cells in the ARC. AgRP activity stimulates the release of GABA resulting in inhibition of the activity of the POMC neurons.

Leptin binds to its receptor presents on AgRP and NPY neurons and inhibits their firing resulting in reduced GABA release onto POMC neurons. This leptin-induced reduction in GABA action at POMC neurons is a disinhibition and is, in part, the mechanism by which leptin decreases feeding behaviors. Conversely, ghrelin binding its receptor activates AgRP and NPY neurons, resulting in an increase in GABA release with resultant inhibition of POMC neurons.

Melanin-Concentrating Hormone

Melanin-concentrating hormone (MCH) was originally identified as a 19-amino acid cyclic peptide that induced the lightening of the skin in fish. Subsequently the peptide was as overexpressed in response to fasting and also elevated in genetically obese mice (ob/ob mice). In humans MCH is expressed exclusively in the lateral hypothalamus and zona incerta (region of gray matter cells in the subthalamus below the thalamus). In humans there are 2 GPCRs that bind MCH identified as MCH1R and MCH2R. MCH1R couples to the activation of both G_q and G_i type G proteins.

Involvement of MCH in the regulation of feeding behaviors and energy homeostasis has been shown in mice where either the MCH or the MCH1R genes have been knocked out. Loss of MCH leads to hypophagia and lean body mass indicating that MCH is an important orexigenic hormone. In contrast, central administration of MCH results in increased food intake. Loss of the MCH1R gene induces hyperphagia and hyperactivity. When MCH1R antagonists are administered, there is a decrease in MCH-induced food intake. MCH1R antagonists have been shown to modulate leptin secretion and insulin release which suggests that the weight loss associated with systemic antagonist administration is due to both central and peripheral effects.

The synthesis and release of MCH is also responsive to the fuel source being metabolized in the brain. When fatty acid metabolism occurs there is no appreciable effect on MCH synthesis, however, inhibition of fatty acid oxidation results in increased MCH synthesis and release. In contrast, modulation of glucose oxidation has no effects on MCH expression.

Orexins

The orexins were identified as substances that bound to orphan GPCRs and induced an orexigenic response. The orexins constitute 2 neuroendocrine peptides derived from the same gene. These peptides are designated as orexin A and orexin B. The orexins are also referred to as the hypocretins. Orexin A corresponds to hypocretin 1 (HCRT-1) and orexin B corresponds to hypocretin 2 (HCRT-2).

The orexin preproprotein is 131 amino acids in length with the 33-amino acid orexin A peptide encoded by amino acids 33 to 65 and the 28-amino acid orexin B peptide encoded by amino acids 69 to 96. Both orexin A and orexin B peptides are C-terminally amidated. The N-terminal glutamine residue of orexin A is cyclized into a pyroglutamyl residue and the peptide contains 2 intrachain disulfide bonds. There are 2 orexin receptors identified as OX₁R and OX₂R. OX₁R exhibits an order of magnitude higher affinity for orexin A compared to orexin B whereas OX₂R has been shown to bind both peptides with equal affinity. The orexin receptors are typical GPCRs with OX₁R coupling to the G_q proteins and OX₂R coupling to both the G_q and G_i proteins.

The cell bodies of orexin expressing neurons are found in the lateral and posterior hypothalamic areas with axonal projections throughout the brain. Expression of the orexin receptors is also widely distributed throughout the central nervous system. Central injection of orexin peptides increases food consumption and wakefulness and suppresses REM sleep. The latter observations demonstrate that orexins play a causative role in the regulation of sleep-wake cycles. Indeed, loss of orexin function results in a condition in animals that mimics the sleep disorder in humans known as narcolepsy. In human narcolepsy patients there is a significant reduction in the amount of detectable orexin A and orexin B as well as an 80% to 100% reduction in the number of neurons that contain detectable prepro-orexin mRNA.

Galanin

Galanin (GAL) is a 29-amino acid peptide whose name is derived from the fact that it contains an N-terminal glycine residue and a C-terminal alanine. GAL is expressed in the gut and the brain with wide distribution throughout the hypothalamus including the PVN, the PFLH, and ARC. The expression of GAL in the hypothalamus is directly correlated to its role in energy homeostasis and the control of feeding behaviors. In addition to regulating feeding, GAL serves as a growth and prolactin-releasing factor to the lactotroph, especially in states of high estrogen exposure, is involved in learning and memory through effects in the hippocampus, and is involved in pain and seizures. Additionally, GAL exerts affective responses such as in mood disorders and anxiety. GAL exerts these myriad effects via binding to 3 distinct GPCRs identified as GALR1, GALR2, and GALR3.

Central administration of GAL elicits a strong orexigenic response with a preference for fat over protein and carbohydrates. The feeding behavior responses to GAL exposure are primarily due to binding GALR1 in the hypothalamus. GAL-induced feeding is greatly attenuated when fat is removed from the diet. The primary function of GAL when an animal is consuming a high-fat diet is to restore carbohydrate balance, through behavioral and metabolic actions, under conditions where carbohydrate intake and metabolism are suppressed.

Insulin suppresses GAL expression whereas leptin produces little or no change in basal GAL expression in the ARC and only a small suppression of GAL expression in the PVN. The differential responsiveness of GAL neurons to leptin is likely due to the low concentration of leptin receptors on GAL neurons. Administration of inhibitors of fatty acid oxidation suppresses GAL expression. Conversely, administration of inhibitors of glucose oxidation does not alter GAL expression. The ability of GAL to exert its stimulation of feeding responses may be due to its interactions with other peptide systems. The opioids are believed to have some role in mediating GAL-induced feeding, since the opioid receptor agonist naloxone attenuates the GAL feeding response. GAL may also induce feeding via an inhibition of the anorexigenic melanocortin system.

Melanocortins

The POMC-derived melanocortin peptides include α-MSH, β-MSH, γ-MSH, ACTH^1-24, and ACTH^1-13–NH₂ (desacetyl-α-MSH). The POMC-derived melanocortins belong to a family of peptides referred to as the melanocortin system (see Figure 49-3). This system includes the POMC-derived melanocortins which exhibit agonist activities, the antagonist peptide AgRP, the melanocortin receptors (MCR), and the melanocortin receptor accessory proteins (MRAPs). The MCR family of receptors consists of 5 identified members termed MC1R through MC5R.

The melanocortin system has been shown to be critical in the regulation of food intake and energy expenditure. Central administration of α-MSH, β-MSH, or ACTH^1-24 inhibits the intake of food. The actions of MSH peptides in feeding behavior are exerted primarily via peptide binding to the MC4R and to a lesser extent to the MC3R. Genetic mutations in humans that disrupt the expression and processing (this includes the proteases that process the POMC precursor) of POMC peptides and MCRs are associated with changes in energy balance and can lead to obesity and T2D. Mutations have been identified in prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), as well as in the α-MSH degrading enzyme prolylcarboxypeptidase (PRCP) that are associated with energy imbalance and a propensity for obesity. In genome-wide screens for polymorphisms in genes associated with an increased risk of developing T2D the MC4R gene was identified (see Chapter 47). Indeed, mutations in the MC4R gene are the most frequent causes of severe obesity in humans.

Humans with a lack of POMC expression are unable to survive without glucocorticoid supplementation from birth. Individuals that survive have red hair, dramatically increased desire for food intake, and high propensity for obesity. Another POMC mutation that has been identified in humans resulting in obesity is a point mutation in the cleavage site between β-MSH and β-endorphin. The consequences of this mutation suggest that β-MSH may be a significant endogenous anorectic agonist that activates the MC4R.

Cocaine- and Amphetamine-Regulated Transcript

The cocaine- and amphetamine-regulated transcript (CART) peptides are neuroendocrine peptides involved in feeding behavior, drug reward systems, stress, cardiovascular functions, and bone remodeling. Expression of the CART gene is essentially confined to hypothalamic neuroendocrine neurons and limbic system circuits involved in reward processes. CART peptides are found in areas of the brain involved in the control of feeding behaviors including regions of the hypothalamus such as the VMN, lateral hypothalamus (LH), PVN, NTS, ARC, and the nucleus accumbens.

The human CART gene is transcribed into 2 alternatively spliced mRNAs that encode proCART peptides of different lengths identified as proCART1-89 and proCART1-102. However, only the proCART1-89 peptide is found in humans. The processing of proCART1-89 yields CART peptides identified as CART 42-89 and CART 49-89. A definitive CART receptor has as yet not been isolated, however, evidence suggests the CART receptor is a GPCR that activates the G_i/o class of G proteins.

Central administration of CART peptides results in decreased food intake indicating the peptides are anorexigenic. Within the ARC of the hypothalamus CART-peptide containing neurons are surrounded by NPY expressing nerve terminals. The distribution of CART and NPY in the ARC suggests that these 2 neuropeptides may exhibit cross-talk in the regulation of feeding behavior. Food deprivation leads to decreases in the level of CART mRNA in the ARC. Conversely, when leptin is administered, the level of CART mRNA in the ARC increases.

Several human studies have also indicated that CART peptides function in appetite control. Missense mutations in the CART gene are associated with obesity and a single nucleotide polymorphism (SNP) was identified in the CART gene in several morbidly obese individuals. In addition, a polymorphism that resides approximately 156 kb upstream of the CART gene may be associated with obesity.

Galanin-Like Peptide

Galanin-like peptide (GALP) is a 60-amino acid peptide that is structurally related to galanin. Amino acids 9 to 21 of GALP are identical to the first 13 amino acids of GAL. The structural and sequence similarities between GALP and GAL explain the fact that GALP functions by binding with high affinity to GAL receptors. However, there are differences in affinities of the 2 peptides for the different GAL receptors. GAL binds all 3 receptor subtypes (GALR1, GALR2, and GALR3) with similar affinities, whereas, GALP binds with highest affinity to GALR3 followed by GALR2 with GALR1 binding with least affinity. Expression of GALP is almost exclusively found in the hypothalamic ARC, and GALP neurons project to the PVN but not the lateral hypothalamus.

Central injection of GALP induces an anorexigenic response. The leptin receptor is expressed on most GALP neurons and expression of GALP in the ARC is induced by leptin. In contrast, GALP expression in the ARC is significantly reduced in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Food deprivation results in reduced circulating levels of leptin and this in turn reduces the rapid entry of circulating GALP into the brain. Fasting results in a decrease in both the level of GALP mRNA as well as the number of GALP expressing neurons. Leptin administration will restore GALP expression in fasted animals as well as in leptin-deficient (ob/ob) mice.

Corticotropin-Releasing Factor and Related Peptides

Corticotropin-releasing factor (CRF, also known as corticotropin-releasing hormone, CRH) belongs to an interacting family of proteins that includes CRF, at least 2 different CRF receptor subtypes (CRF1 and CRF2), a CRF-binding protein (CRF-BP), and the urocortins which are endogenous CRF receptor ligands. There are 3 known urocortins identified as urocortin 1, 2, and 3 (Ucn1, Ucn2, Ucn3). CRF is a 41-amino acid peptide that is found widely expressed in the brain. CRF-expressing neurons are abundant in the hypothalamic PVN where they control the pituitary-adrenal axis regulating the release of ACTH and glucocorticoids.

CRF binds to 2 GPCRs identified as CRF1 and CRF2. In addition to binding to 2 receptors, CRF also binds to CRF-BP, which is expressed in association with CRF-expressing neurons in many brain areas including the hypothalamus. CRF-BP acts as an inhibitor of CRF action, thereby, modulating its biological actions.

Hypothalamic expression of CRF is negatively regulated by the circulating level of corticosterone such that CRF mRNA and protein levels are highest when corticosterone levels are declining. Other glucocorticoids also negatively regulate CRF expression. Diabetes leads to increased CRF expression in the PVN and this effect can be further enhanced by the administration of insulin. Expression of CRF is also stimulated in states of positive energy balance and is reduced in states of negative energy balance, such as food deprivation. Circulating nutrients also affect the level of CRF expression. When glucose levels rise, CRF levels decline with the opposite occurring when glucose levels fall. In contrast to the changes in CRF levels in response to serum glucose changes, excess fat consumption does not appear to alter CRF expression.

Central administration of CRF induces anorexigenic responses. The CRF-mediated suppression of feeding occurs along with a stimulation sympathetic nervous system activity and resting oxygen consumption which results in increased fat mobilization and oxidation and raises blood glucose while inhibiting insulin secretion. The role of CRF as an anorexigenic hormone may involve the NPY, melanocortin and CART systems, acting in a downstream fashion. The CRF neurons in the hypothalamus colocalize with both the NPY Y5 receptor and the MC4R. In addition, CRF expression in the PVN is stimulated by central administration of a melanocortin agonist but is inhibited by an MC4R antagonist. Leptin is also involved in the effects of CRF as demonstrated by the fact that the anorexigenic actions of leptin are attenuated in the presence of CRF antagonists.

REVIEW QUESTIONS

  1. You are performing laser ablation experiments on laboratory animals to ascertain the effects, on feeding behaviors, of damage to certain regions of the brain. In one series of experiments it is found that loss of the targeted brain region causes the animals eat nearly continuously, no matter the time of day, nor the composition of the chow. The ablation was centered on the hypothalamus and these results strongly indicate the damage affected which of the following regions of this structure?

      A. lateral hypothalamic area (LHA)

      B. nucleus of the solitary tract (NTS, NST)

      C. paraventricular nucleus of the hypothalamus (PVN, PVH)

      D. suprachiasmatic nucleus (SCN)

      E. ventromedial hypothalamus (VMH, VMN)

Answer E: The hypothalamus is involved in control of feeding behavior as well as the secretion of various pituitary releasing hormones. Specific nuclei within the hypothalamus exert different effects on appetite and the desire for food. The ventromedial hypothalamic nucleus (VMH), and to a lesser extent the dorsomedial hypothalamic nucleus (DMH) is involved in the sensation of satiety and lesions in these regions of the hypothalamus result in hyperphagia (excessive hunger) and obesity.

  2. You are assessing the effects of injecting synthetic peptides into laboratory mice. You discover that injecting one of the peptides induces hyperphagia. Which of the following hormones is most likely being mimicked by the actions of the synthetic peptide?

      A. cholecystokinin, CCK

      B. cocaine- and amphetamine-regulated transcript, CART

      C. ghrelin

      D. α-melanocyte stimulating hormone, α-MSH

      E. peptide tyrosine tyrosine, PYY

Answer C: Ghrelin is produced and secreted by the X/A-like enteroendocrine cells of the stomach oxyntic (acid-secreting) glands. The major effect of ghrelin is exerted within the central nervous system at the level of the arcuate nucleus where it stimulates the release of neuropeptide Y (NPY) and agouti-related protein (AgRP). The actions of NPY and AgRP enhance appetite and thus, food intake.

  3. Fatty acid metabolism within the brain is not a significant pathway for the generation of ATP. However, this does not mean that fatty acid metabolism is not a useful pathway in brain. Which of the following would be expected to be found at elevated levels in brain tissues following the metabolism of free fatty acids?

      A. acetate

      B. alanine

      C. ceramide

      D. citrate

      E. sphingosine

Answer C: Although β-oxidation of fatty acids represents a minor, if at all, source of the ATP pool in neurons, it is an important metabolic pathway determining the ultimate fate of fatty acids that enter the brain. As a result of fatty acid oxidation, a number of aqueous byproducts are detected in the brain such as fatty acyl-CoAs, fatty acyl-carnitines, ketone bodies, and various amino acids. Central metabolism of palmitate diverts its carbon atoms into the amino acids glutamate, glutamine, aspartate, asparagine, and GABA. In addition, numerous organic acids including citrate, malate, β-hydroxybutyrate, and acetyl-CoA result from palmitate oxidation. By far, citrate represents the largest by-product of fatty acid oxidation in the brain.

  4. You are examining feeding behavior in laboratory animals in response to the addition of a test organic molecule to their chow. Following consumption of the compound you discover that the animals loose interest in food. Additional experiments demonstrate that central metabolism of palmitic acid is reduced in these animals. Given these observations you believe that the test compound is most likely inhibiting which of the following hypothalamic enzymes?

      A. acetyl-CoA carboxylase

      B. carnitine palmitoyltransferase I

      C. fatty acid synthase

      D. malonyl-CoA decarboxylase

      E. medium-chain acyl-CoA dehydrogenase

Answer B: Fatty acids, specifically long-chain fatty acids via the formation of long-chain fatty acyl-CoAs, exert anorexigenic effects via the hypothalamus. Mitochondrial CPT-1 activity is involved in the central effects of fatty acids. Inhibition of hypothalamic CPT-1 leads to an increase in cytosolic long-chain acyl-CoA content and results in anorexigenic effects.

  5. You are testing the effects of central administration of inhibitors of fatty acid oxidation on hypothalamic activity. Which of the following neuropeptides would you expect to see expressed at elevated levels in response to the actions of the inhibitor?

      A. agouti-related peptide, AgRP

      B. cocaine- and amphetamine-regulated transcript, CART

      C. galanin

      D. melanin-concentrating hormone, MCH

      E. neuropeptide Y, NPY

Answer D: Melanin-concentrating hormone (MCH) expression is responsive to differences in fuel source availability in the brain. Pharmacological inhibition or activation of glucose metabolism exerts no effect on the expression of MCH, however, inhibition of fatty acid oxidation results in increased expression and release of the hormone.

  6. The pancreatic polypeptide (PP) family of proteins binds to a family of receptors that were originally characterized as NPY receptors. There are 4 NPY receptors in humans and they are designated as Y1, Y2, Y4, and Y5. Which of the following hormone-receptor combinations is involved in exerting anorexigenic responses?

      A. NPY + Y1

      B. NPY + Y4

      C. PP + Y4

      D. PYY + Y2

      E. PYY + Y4

Answer D: Receptors Y1, Y2, and Y5 preferentially bind NPY and PYY, whereas, Y4 exhibits highest affinity for PP. The Y2 receptor is involved in anorexigenic responses, whereas the Y1 and Y5 receptors have been shown to induce orexigenic responses. The Y2 receptors are thus, referred to as inhibitory receptors with respect to the activity of NPY and they are abundantly expressed on NPY neurons in the ARC of the hypothalamus.

  7. Which of the following gut hormones is known to bind to one of the cholecystokinin receptors resulting in activation of the oxyntic glands of the stomach?

      A. cholecystokinin, CCK

      B. gastrin

      C. ghrelin

      D. GLP-I

      E. protein tyrosine tyrosine, PYY

Answer C: Gastrin is produced in enteroendocrine G cells of the gastric antrum and duodenum and exists in 2 forms, little gastrin (17 amino acids) and big gastrin (34 amino acids). Gastrin is responsible for inducing gastric acid production and pepsin secretion. Both forms of gastrin bind to the CCK2 (CCK_B) receptor on stomach and gut parietal cells with an affinity equal to that of CCK. Activation of the CCK_B receptor by gastrin triggers the production of gastric acid.

  8. Laser ablation experiments are being performed in laboratory animals to ascertain the effects, on feeding behaviors, of damage to certain regions of the brain. In one series of experiments it is found that loss of the targeted brain region causes the animals to avoid food, no matter the time of day, nor how long they have gone without eating. The ablation was centered on the hypothalamus and these results strongly indicate the damage affected in which of the following regions of this structure?

      A. lateral hypothalamic area (LHA)

      B. nucleus of the solitary tract (NTS, NST)

      C. paraventricular nucleus of the hypothalamus (PVN, PVH)

      D. suprachiasmatic nucleus (SCN)

      E. ventromedial hypothalamus (VMH, VMN)

Answer A: The hypothalamus is involved in control of feeding behavior as well as the secretion of various pituitary releasing hormones. Specific nuclei within the hypothalamus exert different effects on appetite and the desire for food. The lateral hypothalamic area (LHA) is responsible for transmitting orexigenic signals (desire for food intake) and loss of this region results in starvation.

  9. A patient is diagnosed with problems in emptying the gallbladder. On a blood checkup, one hormone/peptide that is known to stimulate gallbladder contraction is inappropriately low. Which of the following hormones is most likely deficient leading to the observed symptoms?

      A. cholecystokinin, CCK

      B. gastrin

      C. GLP-1

      D. pancreatic polypeptide

      E. peptide tyrosine tyrosine, PYY

Answer A: Cholecystokinin (CCK) is secreted from intestinal enteroendocrine I cells predominantly in the duodenum and jejunum. The level of CCK in the blood rises within 15 minutes of food ingestion and reaches a peak by 25 minutes. Upon binding its receptors in the gut, CCK induces contractions of the gallbladder and release of pancreatic enzymes and also inhibits gastric emptying.

10. Blocking the actions of which of the following hormones would be expected to lead to the greatest level of appetite suppression?

      A. adiponectin

      B. ghrelin

      C. GLP-1

      D. obestatin

      E. peptide tyrosine tyrosine, PYY

Answer B: Ghrelin is produced and secreted by the X/A-like enteroendocrine cells of the stomach oxyntic (acid-secreting) glands. The major effect of ghrelin is exerted within the central nervous system at the level of the arcuate nucleus where it stimulates the release of neuropeptide Y (NPY) and agouti-related protein (AgRP). The actions of NPY and AgRP enhance appetite and thus, food intake.

11. Several gut-derived factors control feeding behaviors elicited by the brain. Most of these factors exert their effects by reducing the desire for food intake. The synthesis of one of these factors is stimulated by fat intake and inhibited by leptin release from adipose tissue. In addition, vagal efferents are not required for release but the activity of another gut factor is involved in its release. Which one of the following factors fits each of these statements?

      A. apolipoprotein A-IV, apoA-IV

      B. cholecystokinin, CCK

      C. ghrelin

      D. GLP-1

      E. peptide tyrosine tyrosine, PYY

Answer A: Apolipoprotein A-IV (apoA-IV) is synthesized exclusively in the small intestine and the hypothalamus. Intestinal synthesis of apoA-IV increases in response to ingestion and absorption of fat and it is subsequently incorporated into chylomicrons and delivered to the circulation via the lymphatic system. Systemic apoA-IV exerts effects in the CNS involving the sensation of satiety.

12. The gut peptide ghrelin is posttranslationally modified before it is fully active. Which of the following represents the type of modification that is necessary for its biological action?

      A. acetylation

      B. acylation

      C. methylation

      D. phosphorylation

      E. prenylation

Answer B: Bioactive ghrelin is acylated on the serine at position 3 with n-octanoic acid. The attachment of octanoic acid to Ser3 of ghrelin is accomplished by the acyltransferase identified as ghrelin O-acyltransferase (GOAT; also referred to as membrane-bound O-acyltransferase domain-containing 4, MBOAT4).

13. You are investigating the potential of a new drug to be useful in treating obesity. Specifically you are hoping that the drug either stimulates anorexigenic peptide release or inhibits orexigenic peptide release. You discover that addition of the drug to water consumed by your test animals results in inhibition of glucose oxidation within the hypothalamus. Based upon your findings what peptide would you most likely expect to see increased in these test animals?

      A. agouti-related peptide, AgRP

      B. cocaine- and amphetamine-regulated transcript, CART

      C. galanin

      D. melanin-concentrating hormone, MCH

      E. neuropeptide Y, NPY

Answer E: The activation of NPY neurons in the hypothalamus exhibits fuel source specificity in that oxidation of glucose and fatty acids exert differing effects. Glucose oxidation signals ample energy supply and thus results in reduced NPY expression. On the other hand, fatty acid oxidation has limited, if any, effect on NPY release. Inhibition of glucose oxidation results in dramatically increased NPY release even in the presence of fatty acid metabolism. Thus, a compound that blocks glucose oxidation in the hypothalamus would be expected to result in a significant increase in the level of NPY expression.

14. A defect in activity of which of the following hormones has been associated with the sleep disorder known as narcolepsy?

      A. agouti-related peptide, AgRP

      B. cocaine- and amphetamine-regulated transcript, CART

      C. galanin-like peptide, GALP

      D. melanin-concentrating hormone, MCH

      E. orexin A

Answer E: The orexin peptides function to increase food consumption. However, in addition to increased feeding behavior central orexin action increases wakefulness and suppresses REM sleep. These latter observations demonstrate that orexins play a causative role in the regulation of sleep-wake cycles. Indeed, loss of orexin function results in a condition in animals that mimics the sleep disorder in humans known as narcolepsy.

15. Vagal afferents are involved in the responses of the CNS to certain gastrointestinal hormones. Which of the following gut hormones exerts some of its orexigenic responses via these vagal pathways?

      A. cholecystokinin, CCK

      B. ghrelin

      C. glucose-dependent insulinotropic peptide, GIP

      D. GLP-1

      E. protein tyrosine tyrosine, PYY

Answer B: Ghrelin is produced and secreted by the X/A-like enteroendocrine cells of the stomach oxyntic (acid-secreting) glands. The major effect of ghrelin is exerted within the central nervous system at the level of the arcuate nucleus where it stimulates the release of neuropeptide Y (NPY) and agouti-related protein (AgRP). The actions of NPY and AgRP enhance appetite and thus, food intake.

16. Which of the following gut hormones is responsible for the feeding phenomenon referred to as the ileal brake?

      A. CCK

      B. ghrelin

      C. GIP

      D. oxyntomodulin, OXM

      E. protein tyrosine tyrosine, PYY

Answer E: PYY produced by and secreted from intestinal enteroendocrine L cells of the ileum and colon. The release of PYY results in reduced gut motility, a delay in gastric emptying, and an inhibition of gallbladder contraction. All of these actions are associated with the ileal brake.

17. Although the level of leptin secretion is proportional to the amount of fat in adipose tissue, obese individuals are resistant to the anorexigenic effects of the increased hormone levels. Which of the following hypothalamic hormones would be expected to have the greatest increase in expression as a consequence of obesity-induced leptin resistance?

      A. cocaine- and amphetamine-regulated transcript, CART

      B. galanin-like peptide, GALP

      C. α-melanocyte stimulating hormone, α-MSH

      D. neuropeptide Y, NPY

Answer D: Peripheral hormones that act on the ARC and thereby affect the actions of NPY (and AgRP) are leptin and ghrelin. Leptin binds to its receptor present on NPY neurons and inhibits their firing resulting in reduced GABA release onto POMC neurons. This leptin-induced reduction in GABA action at POMC neurons is a disinhibition and allows for increased release of the anorexigenic peptide, α-MSH. This is, in part, the mechanism by which leptin decreases feeding behaviors. Loss of leptin effects on NPY and POMC neurons would lead to increased orexigenic responses contributing to obesity.

18. You are studying a strain of laboratory mice that get obese even on a low-fat lab chow. In examination of the brains of these mice you find an abnormal poorly developed area of the hypothalamus. A defect in which of the following regions would most likely account for the observed obesity?

      A. lateral hypothalamic area (LHA)

      B. nucleus of the solitary tract (NTS, NST)

      C. paraventricular nucleus of the hypothalamus (PVN, PVH)

      D. suprachiasmatic nucleus (SCN)

      E. ventromedial hypothalamus (VMH, VMN)

Answer E: The hypothalamus is involved in control of feeding behavior as well as the secretion of various pituitary releasing hormones. Specific nuclei within the hypothalamus exert different effects on appetite and the desire for food. The ventromedial hypothalamic nucleus (VMH), and to a lesser extent the dorsomedial hypothalamic nucleus (DMH) is involved in the sensation of satiety and lesions in these regions of the hypothalamus result in hyperphagia (excessive hunger) and obesity.

19. Which of the following brain regions sends and receives information to the visceral organs via the vagal nerve?

      A. arcuate nucleus (ARC)

      B. area postrema

      C. nucleus of the solitary tract (NTS, NST)

      D. perifornical lateral hypothalamus (PFLH)

      E. ventromedial hypothalamus (VMH)

Answer C: Satiety signals from the liver and gastrointestinal tract signal through the vagus nerve to the nucleus of the solitary tract (NTS) to cause meal termination, and in combination with the hypothalamus, integrate the various signals to determine the feeding responses of the organism.

20. Which of the following hormones is expressed and released from the stomach and is involved in the stimulation of food intake?

      A. cholecystokinin, CCK

      B. ghrelin

      C. GLP-1

      D. neuropeptide Y, NPY

      E. protein tyrosine tyrosine, PYY

Answer B: Ghrelin is produced and secreted by the X/A-like enteroendocrine cells of the stomach oxyntic (acid-secreting) glands. The major effect of ghrelin is exerted within the central nervous system at the level of the arcuate nucleus where it stimulates the release of neuropeptide Y (NPY) and agouti-related protein (AgRP). The actions of NPY and AgRP enhance appetite and thus, food intake.

21. Which of the following correctly reflects the consequence of insulin binding its receptor in the hypothalamus?

      A. activation of melanin-concentrating hormone (MCH) release

      B. activation of α-melanocyte stimulating hormone (α-MSH) release

      C. activation of neuropeptide Y (NPY) release

      D. inhibition of cocaine- and amphetamine-regulated transcript (CART) release

      E. inhibition of galanin release

Answer B: Within the brain insulin exerts anorexigenic effects. These effects are responses to insulin binding its receptor on POMC and NPY neurons in the hypothalamus. Insulin-mediated effects include activation of POMC neurons causing release of α-MSH which exerts the anorexigenic effects, and inhibition of NPY neurons, thus blocking the orexigenic effects of NPY.

22. Genome-wide screens for gene polymorphisms associated with a predisposition to obesity have identified several loci. Which of the following hormone genes could be expected to most likely lead to an increased propensity for obesity if it were defective?

      A. Agouti-related peptide, AgRP

      B. cocaine- and amphetamine-regulated transcript, CART

      C. neuropeptide Y, NPY

      D. oxyntomodulin, OXM

      E. peptide tyrosine tyrosine, PYY

Answer D: Central anorexigenic effects of OXM involve induced release of anorexigenic peptides and suppression of the orexigenic effects of circulating ghrelin. Of potential significance to the treatment of obesity, when OXM is administered intravenously to human subjects there is an observed reduction in food intake. Additionally, when OXM is administered subcutaneously to overweight and obese subjects over a period of 4 weeks there is a significant reduction in body weight. Thus, defective OXM function would likely result in an exacerbation of the propensity to obesity.

23. Agouti-related peptide (AgRP) is an orexigenic hormone that functions to increase the desire for food intake by antagonizing the actions of which of the following anorexigenic hormones?

      A. cocaine- and amphetamine-regulated transcript, CART

      B. galanin-like peptide (GALP)

      C. GLP-1

      D. α-melanocyte stimulating hormone, α-MSH

      E. peptide tyrosine tyrosine, PYY

Answer D: AgRP together with NPY represent a distinct set of ARC-expressed orexigenic peptides. AgRP is classically referred to as a member of the central melanocortin system, which in addition to AgRP comprises α-melanocyte stimulating hormone, α-MSH (see below for description of α-MSH actions) and 2 melanocortin receptors identified as melanocortin receptor 3 (MC3R) and melanocortin receptor 4 (MC4R). Whereas, α-MSH is an agonist of both MC3R and MC4R, AgRP serves to antagonize the actions of α-MSH at these same receptors with highest antagonist activity on MC4R.

24. Patients with functional dyspepsia (disturbed indigestion) and prominent nausea frequently experience spurts of excessive acid exposure to the upper duodenum. This results in pancreatic secretion, mainly through the action of which of the following substances?

      A. cholecystokinin

      B. gastrin

      C. glucagon

      D. secretin

      E. vasoactive intestinal polypeptide

Answer D: The strongest stimulator for the release of secretin from cells in the upper small-intestinal mucosa is the contact with acidic chyme. Increased serum secretin levels stimulate water and alkali secretions from the pancreas and the hepatic ducts and inhibit gastrin release. The most potent stimulators for the release of cholecystokinin are not acid but digestion products of fat and protein. Vasoactive intestinal polypeptide does stimulate intestinal and pancreatic secretion but it acts as neurotransmitter in the enteric nervous system and is mainly released by mechanical and neuronal stimulation.

25. A 30-year-old man seeks help because he lost weight and feels full after eating only a small amount of food. He is diagnosed with a delay in gastric emptying. Which of the following hormones has at physiological levels the strongest effect in inhibiting gastric emptying?

      A. cholecystokinin

      B. gastrin

      C. glucose-dependent insulinotropic peptide

      D. motilin

      E. pancreatic polypeptide

Answer A: The major control mechanism for gastric emptying involves duodenal gastric feedback, hormonal as well as neural. The major hormone involved in the inhibition of gastric emptying is cholecystokinin (CCK), which is released by fat and protein digestion products.

26. A 60-year-old woman is admitted to the hospital with a fever and severe diarrhea for the last 24 hours. Cultures of blood, cerebrospinal fluid, urine, and stool are all negative for pathogens. The profile of gut hormones reveals elevated levels of vasoactive intestinal polypeptide (VIP). An analogue of which of the following would most likely lower her VIP levels?

      A. erythromycin

      B. histamine

      C. motilin

      D. somatostatin

      E. trypsin

Answer D: Vasoactive intestinal polypeptide (VIP) is a neurotransmitter in the brain and in the parasympathetic nerves of the digestive tract. It also acts as a hormone. VIP has a secretin-like effect on the pancreas. It increases the volume of water and bicarbonate output and affects GI blood flow and motility. All this contributes to severe secretory diarrhea in the case of VIP overproduction. Somatostatin is the best choice because it has a broad range of inhibitory effects, inhibiting GI secretions, slowing GI motility, and reducing splanchnic blood flow.

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