Satiety and Glucose Homeostasis

Satiety signals are produced in the gastrointestinal (GI) tract in response to the presence of nutrients. Several satiety signals (cholecystokinin, pancreatic polypeptide, peptide YY, and amylin) are peptides that interact with their cognate GPCRs to induce a sense of fullness — resulting in decreased food intake and, in some cases, modulation of nutrient metabolism. The receptors for satiety-inducing peptides may reside locally in the GI tract, on peripheral nerves running from the GI tract to the hindbrain (particularly the vagus nerve), and in some cases in the CNS itself.90 As is true for centrally produced peptide hormones, the ARC in the hypothalamus is responsible for integrating local and distal signals to regulate food intake, nutrient metabolism, and energy expenditure.

6.3.1.1 Cholecystokinin System

Cholecystokinin (CCK) is the best-studied satiety hormone. It is produced in intestinal duodenal cells in response to the presence of nutrients in the lumen of the GI

TABLE 6.1

Select Human GPCRs Relevant to Metabolic Disease

TABLE 6.1

Select Human GPCRs Relevant to Metabolic Disease

Entrez

Physiological

Abbreviation3

Description

Gene IDa

Ligand

Effect

5HT1B

Serotonin 1B receptor

3351

Serotonin

Anorexigenic

5HT2C

Serotonin 2C receptor

3358

Serotonin

Anorexigenic

ADRB3

p3-adrenergic receptor

155

Noradrenaline

Lipolysis

BRS3

Bombesin-like

680

Bombesin

Anorexigenic

receptor 3

CALCR

Calcitonin

799

IAPP

Anorexigenic

CALCRL

Calcitonin gene-related

10203

IAPP

Anorexigenic

peptide receptor

CB1

Cannabinoid receptor 1

1268

Endocannabinoid

Orexigenic

CB2

Cannabinoid receptor 2

1269

Endocannabinoid

Orexigenic

CCKAR

Cholecystokinin A

886

Cholecystokinin

Anorexigenic

receptor

CCKBR

Cholecystokinin B

887

Cholecystokinin

Anorexigenic

receptor

DRD2

Dopamine receptor D2

1813

Dopamine

Anorexigenic

GALR1

Galanin receptor 1

2587

Galanin

Orexigenic

GCGR

Glucagon receptor

2642

Glucagon

Anti-incretin

GHSR

Ghrelin receptor

2693

Ghrelin

Orexigenic

GIPR

Gastric inhibitory

2696

GIP

Incretin

polypeptide receptor

GLP1R

Glucagon-like peptide-

2740

GLP1; OXM

Anorexigenic;

1 receptor

incretin

GLP2R

Glucagon-like peptide-

9340

GLP2

Anorexigenic

2 receptor

GPR40

G protein-coupled

2864

LCFA

TBDc

receptor 40

GPR41

G protein-coupled

2865

Short-chain

TBDc

receptor 41

carboxylic acids

GPR43

G protein-coupled

2867

Short-chain

TBDc

receptor 43

carboxylic acids

HRH3

Histamine receptor 3

11255

Histamine

Orexigenic

MC3R

Melanocortin 3 receptor

4159

a-, ß-MSH

Anorexigenic

AGRPb

Orexigenic

MC4R

Melanocortin 4 receptor

4160

a-, ß-MSH

Anorexigenic

AGRPb

Orexigenic

MCHR1

Melanin-concentrating

2847

MCH

Orexigenic

hormone receptor 1

MCHR2

Melanin-concentrating

84539

MCH

Orexigenic

hormone receptor 2

NPY1R

Neuropeptide Y

4886

PP; PYY; NPY

Anorexigenic

receptor Y1

NPY2R

Neuropeptide Y

4887

PP; PYY; NPY

Anorexigenic

receptor Y2

Select Human GPCRs Relevant to Metabolic Disease

TABLE 6.1 (Continued)

Select Human GPCRs Relevant to Metabolic Disease

Entrez

Physiological

Abbreviation3

Description

Gene IDa

Ligand

Effect

NPY4R

Neuropeptide Y

5540

PP; PYY; NPY

Anorexigenic

receptor Y4; PPYR1

NPY5R

Neuropeptide Y

4889

PP; PYY; NPY

Anorexigenic

receptor Y5

OX1R

Orexin 1 receptor

3061

orexin A

Orexigenic

OX2R

Orexin 2 receptor

3062

orexin A and B

Orexigenic

a Abbreviations, as primary citations or aliases, and EntrezGene designations adopted from the National Center for Biotechnology Information (NCBI) site, [http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi? db=gene].

b Ligands are agonists at stated receptors, except as noted for AGRP, the endogenous antagonist of MC3R and MC4R.

c Physiologic consequences to be determined.

a Abbreviations, as primary citations or aliases, and EntrezGene designations adopted from the National Center for Biotechnology Information (NCBI) site, [http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi? db=gene].

b Ligands are agonists at stated receptors, except as noted for AGRP, the endogenous antagonist of MC3R and MC4R.

c Physiologic consequences to be determined.

tract. CCK interacts locally with receptors on the sensory fibers of the vagus, where the signal is passed on to the hindbrain and then to integrative feeding centers in the brain. This peptide also acts at the level of the exocrine pancreas and gall bladder to stimulate secretion of digestive enzymes. Administration of CCK to humans leads to a dose-dependent decrease in the meal size, whereas administration of a CCK receptor antagonist causes an increase in meal size and a reduction in the sensation of fullness.9192 The two known CCK receptors are CCKAR and CCKBR (also called CCK-1 and CCK-2 receptors, respectively). Specific antagonists are known for each receptor subtype, and rodents lacking CCKAR function have been studied, providing good evidence for distinct physiological contributions of each receptor type. CCKAR is expressed in pancreas, gall bladder, vagus nerve, and CNS, whereas CCKBR is expressed in the stomach, pancreas, vagus nerve, and CNS.9394 Rodents demonstrate 60% intraspecies homology between the CCKAR and CCKBR receptor subtypes. Specific CCKAR antagonists block meal-induced gall bladder contraction, gastric emptying, and lead to increased food intake, whereas CCKAR agonists potently inhibit food intake.95,96

Otsuka Long Evans Tokushima Fatty (OLETF) rats were identified as possible animal models for diabetes and obesity.97-99 They carry a spontaneous mutation of the CCKAR gene, with deletions in the promoter and first and second exons. OLETF rats do not respond to exogenously supplied CCK, tend to eat very large meals, and show increases in body weight over their lifetimes. In outbread Long Evans rats, administration of CCK over short periods was effective in reducing meal size but had little impact on total daily food intake and body weight.100 Likewise, mice with targeted mutations of the CCKAR gene were not obese.101 When CCK was administered chronically to mice, tolerance to the food intake effects of the peptide developed.102 Nevertheless, several pharmaceutical companies are investigating the use of CCKAR-specific agonists for the treatment of human obesity. The phenotype of CCKBR-deficient mice does not support a role for this receptor in regulation of food intake. Mice null for CCKBR exhibited defects in CNS regulation of memory, pain sensation, and anxiety.103

6.3.1.2 PP-Fold Peptide System

Pancreatic polypeptide (PP), peptide YY (PYY), and the potent orexigen, neuropeptide Y (NPY), all belong to the PP-fold peptide family. PP levels in the circulation are increased by food intake, adrenergic stimulation, and activities of other pancreatic and GI hormones, and also exhibit circadian changes.104 PP is secreted by cells within the endocrine and exocrine pancreas and inhibits secretion of digestive enzymes and bicarbonate from the pancreas.105 PP may play a role in regulation of food intake, as genetically obese rodents have decreased PP levels, and administration of PP improves hyperphagia and hyperinsulinemia in certain of these models.106 Children with Prader-Willi syndrome have reduced secretion of PP,107 and circulating levels of this peptide are increased in individuals with anorexia nervosa.108 PP overexpression in transgenic mice leads to a lean phenotype and decreased food intake.109 Peripherally administered PP has been found to decrease food intake in rodents and humans.110111 PP binds to the NPY1-5R family of GPCRs, with highest affinity for NPY4R and NPY5R.112 As PP appears unable to cross the blood-brain barrier, its effects seem to be mediated through areas in the CNS that have incomplete barriers, for example, the area postrema where NPY4R is known to be highly expressed.104

PYY is secreted from endocrine cells in the small intestine, colon, and pancreas in response to food intake. PYY exerts multiple effects on the GI tract, including inhibition of gastric acid secretion, gastric emptying, pancreatic enzyme secretion, and gastric motility.113 PYY is present in the circulation in two forms, PYY(1-36) and a proteolytically truncated form designated PYY(3-36).114 Whereas PYY(1-36) binds with similarly high affinity to all Y receptors, PYY(3-36) binds most tightly to NPY2R and NPY5R.112 Unlike PP, PYY is capable of crossing the blood-brain barrier and the actions of PYY(3-36) on decreasing food intake appear to be mediated by the receptors in the ARC. However, this peptide is not effective in NPY2R-null mice, pointing out a specific role for this receptor in modulating appetite.115 PYY(3-36) has been reported to inhibit food intake when administered peripherally in rodents and humans.115116 In contrast, administration of the peptide directly to the CNS potently stimulates food intake in mice, an effect that is reduced in animals deficient in both NPY1R and NPY5R.117

NPY is expressed throughout the central and peripheral nervous systems. It potently increases food intake and decreases energy expenditure in rodents when delivered ICV.118 Decreasing NPY activity by antisense oligonucleotide methodology119 or immunoneutralization120 results in decreased feeding. However, the NPY-null mouse does not exhibit an altered body weight phenotype,121 suggesting that redundant pathways in regulation of food intake may bypass the NPY circuitry, possibly through the melanocortin system. Expression of NPY is downstream from leptin,122 as this fat cell hormone decreases expression of NPY and AGRP co-expressed in ARC neurons. Studies with selective pharmacological agents indicate that the relevant receptors mediating the orexigenic effects of NPY are NPY1R and NPY5R.123 Mice that lack these receptors demonstrate mild obesity phenotypes, and only mice lacking NPY5R showed reduced feeding responses to NPY.124125

6.3.1.3 Calcitonin Receptors

Amylin (also known as islet amyloid polypeptide or IAPP) is a pancreatic peptide hormone secreted along with insulin in response to a meal. This peptide is known to reduce food intake, decrease adiposity, and inhibit gastric acid secretion and gastric emptying.126 Individuals with type 1 diabetes are characterized by amylin deficiency, and animal studies have identified a role for this peptide in glucose homeostasis through inhibition of postprandial glucagon secretion.127 Pramlintide, a stable analog of amylin, has been evaluated in diabetic subjects and may have a therapeutic benefit.127 High affinity binding sites have been identified for amylin in brain, kidney, and skeletal muscle.

Amylin is structurally related to calcitonin, calcitonin gene-related peptide, and adrenomedullin. Two GPCRs, the calcitonin receptor and the calcitonin gene-related peptide receptor, form the basis of all the receptors for this peptide family.128 129 Differentiating receptor specificities are determined through association of the GPCR with one of three receptor activity-modifying proteins (RAMPs). RAMPs are thought to be involved in transport of the GPCRs to the plasma membrane, converting them to active forms of the receptor.130 Upon association with RAMP1 or RAMP3, the calcitonin receptor becomes a high affinity binding site for amylin. Antagonism of the RAMP1- or RAMP3-calcitonin receptor complex increases food intake.131

6.3.1.4 Glucagon Receptor Family

Several peptide hormones produced from the preproglucagon gene exert effects on food intake and glucose metabolism. These include glucagon-like peptide-1 (GLP1), GLP2, oxyntomodulin (OXM), and glucagon itself. Preproglucagon is cleaved through the action of prohormone convertases 1 and 2, generating different products in specific tissues. In the pancreas, glucagon is produced, whereas the segment containing GLP1 and GLP2 is secreted as an inactive peptide. In the gut and brain, the glucagon sequence remains in a larger peptide (glicentin) thought to be inactive, while the two GLP peptides are cleaved and secreted separately. OXM is produced from glicentin. OXM and GLP1 are secreted from L cells of the small intestine following a meal. These peptides induce satiety and are involved in inhibition of gastric motility, both acting on the same receptor, GLP1R.132 GLP1 is one of the primary incretin factors responsible for stimulating secretion of insulin following a meal. It is also known to stimulate insulin synthesis and inhibit glucagon secretion.133

Peptide homologs are undergoing clinical trials as anti-diabetic agents.134-136 GLP1R is expressed in pancreatic beta cells, lung, stomach, kidney, and heart.137 GLP1R is expressed in several brain regions as well, and ICV administration of GLP1 decreased food intake in animal models.138139

GLPlR-knockout mice are glucose intolerant and exhibit deficient insulin secretion in response to orally delivered glucose.140 Null mice also exhibited deficits in learning, consistent with possible involvement of this receptor in memory.141

GLP2 is produced in the gut by neuroendocrine cells in response to nutrients. It regulates gastric acid secretion and gastric motility, stimulates enterocyte glucose uptake, and functions as a trophic factor for the intestinal epithelium.142 GLP2R is expressed in the GI tract and in the brain.143 GLP1R and GLP2R are closely related GPCRs with ~50% amino acid identity and are related to other members of the glucagon-secretin GPCR superfamily. Peripherally administered GLP2 showed no effect on food intake,144 although the peptide administered directly to the CNS in rats was able to reduce food intake.145

Glucagon is a peptide hormone produced in the alpha cells of the pancreatic islets.146 The major biological actions of glucagon involve regulation of glucose homeostasis through actions in the liver to increase glycogenolysis and gluconeo-genesis. It is a counter-regulatory hormone to insulin and serves to maintain blood levels of glucose during stress and between meals. In diabetic patients, high levels of glucagon relative to insulin are thought to contribute to hyperglycemia and other metabolic perturbations.147 Development of glucagon receptor antagonists represents an approach to decrease hepatic glucose output in diabetes.148

Although the physiological effects of glucagon acting on its hepatocyte receptor have been studied for decades,149 the receptor was cloned and characterized relatively recently.150 It shares ~42% identity with the GLP1R and is expressed in liver, kidney, brain, and adipose tissue.

Expression in pancreatic islet beta cells is thought to contribute to glucose sensitivity of insulin release.151 Targeted disruption of the glucagon receptor in mice leads to viable animals with mild hypoglycemia and improved glucose tolerance relative to wild-type animals.152 153 In addition, glucagon receptor-null animals showed greatly increased circulating levels of glucagon and GLP1 and exhibited increases in total pancreas weight with alpha cell hyperplasia, reflecting the increased glucagon production.

6.3.1.5 Glucose-Dependent Insulinotropic Polypeptide Receptor

Glucose-dependent insulinotropic polypeptide (GIP; also known as gastric inhibitory polypeptide) is related in sequence to the glucagon and secretin family of hormones. It is synthesized and released from K cells in the duodenum and jejunum in response to a meal, particularly in response to dietary fat.154 GIP and GLP1 are considered major incretin factors, leading to meal-induced insulin secretion. The GIP receptor (GIPR) shows 41% sequence identity to GLP1R and has a wide tissue distribution, including expression in pancreas, gut, adipose tissue, heart, adrenal cortex, and brain. GIP has been reported to stimulate fatty acid synthesis, increase fatty acid incorporation into triglycerides, and increase sensitivity of insulin-stimulated glucose transport. A decrease in the number of pancreatic islet GIPRs in diabetes may contribute to poor glucose control in these patients.155156 As diminished GIP responsiveness occurs in non-diabetic relatives of type 2 diabetic patients, a defect in this signaling pathway may contribute to diminished beta cell function and development of glucose intolerance.157

In support of this hypothesis, mice with targeted disruptions of the GIPR gene had higher blood glucose levels and impaired insulin secretion after oral glucose challenge.158159 GIPR-null mice were also protected from obesity and insulin resistance when fed a high-fat diet.160 Because wild-type mice fed a high fat-diet exhibited increased levels of GIP, it was concluded that GIPR links overeating to increased adiposity and may therefore serve as a potential target for anti-obesity drugs.

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