Chapter 12 Chemical Regulation of Feeding, Digestion and Metabolism Copyright © 2013 Elsevier Inc....

Chapter 12Chapter 12

Chemical Regulation of Feeding, Chemical Regulation of Feeding, Digestion and MetabolismDigestion and Metabolism

Copyright © 2013 Elsevier Inc. All rights reserved.

Figure 12-1 Integration of peripheral bioregulators with hypothalamic feeding areas to regulate food intake. Many bioregulators from adipose tissue (leptin), the pancreas (insulin), and the gastrointestinal tract (bombesin, enterostatin, ghrelin) modulate feeding by stimulating or inhibiting neurons in the arcuate nucleus of the hypothalamus that regulate appetite. Leptin and possibly other anorexigenic bioregulators (red) from the periphery turn on POMC neurons, producing alpha-melanocyte-stimulating hormone (-MSH) and cocaine- and amphetamine-related transcript (CART) in the arcuate nucleus, and inhibit the neurons producing the orexigenic peptides neuropeptide Y (NPY) and agouti-related protein (AgRP). In addition, chemosensory (cholecystokinin, CCK; glucose) andmechanosensory (stretch) signals are transmitted via thevagus nerve to the nucleus of the solitary tract (NTS) in the brainstem,which conveys signals to the paraventricular nucleus (PVN) of the hypothalamus where CRH is secreted to inhibit appetite. See Chapter 4 for hypothalamus and pituitary nomenclature and Appendix A for other abbreviations.

2Copyright © 2013 Elsevier Inc. All rights reserved.

Figure 12-2 Binding of leptin to its receptor leads to Janus kinase 2 (JAK2) tyrosine kinase phosphorylation of tyrosines (Y) in positions 985, 1077, and 1138. Phosphorylation of Y1138 leads to activation and translocation of signal transducer and activator of transcription 3 (STAT3) to the nucleus, where it modulates transcription of genes involved in leptin action— for example, proopiomelanocortin (POMC)—as well as suppressor of cytokine signaling (SOCS3), which inhibits further leptin action. (Adapted with permission from Ahima, R.S. and Lazar, M.A., Molecular Endocrinology, 22, 1023–1031, 2008.)


Figure 12-3 Leptin resistance occurs at the two levels during pregnancy. During pregnancy, leptin blood levels increase due to progesterone stimulation of adipose tissue, potentially harming both the health of both the mother and fetus by inhibiting appetite. However, circulating leptin becomes less available to target neurons in the hypothalamus due to an increase in circulating leptin binding protein (ObRe), which sequesters the circulating leptin, and reduced expression of the leptin transport protein (ObRa) in the choroid plexus, reducing leptin entry into the CNS. Reduced leptin signaling at the level of the arcuate (ARC) and ventromedial (VMN) nuclei of the hypothalamus leads to increased secretion of orexigenic peptides NPY and AgRP and increased appetite. Abbreviations: AgRP, agouti-related protein; NPY, neuropeptide Y; ObRa, short form of leptin receptor; ObRb, long form of leptin receptor; ObRe, plasma leptin binding protein; pSTAT3, phosphorylated signal transducer and activator of transcription 3; STAT3, signal transducer and activator of transcription 3. (Adapted with permission from Brunton, P.J. and Russell, J.A., Nature Reviews Neuroscience, 9, 11–25, 2008.)


Figure 12-4 Structure of ghrelin. See Appendix C for an explanation of amino acid abbreviations. (Adapted with permission from Korbonits, M. et al., Frontiers in Neuroendocrinology, 25, 27–68, 2004. © Elsevier Science, Inc.)


Figure 12-5 Daily pattern of ghrelin and leptin levels in blood. Note the rise in ghrelin occurs prior to each meal (B, breakfast; L, lunch; D, dinner), whereas there is a steady rise in appetite-suppressing leptin during the day. (Reprinted with permission from Cummings, D.E. et al., Diabetes, 50, 1714–1719, 2001.)


Figure 12-6 Mutations in the POMC gene result in obesity and red hair pigmentation. Three-year-old (top left) and five-year-old (top right) children with mutations in their proopiomelanocortin (POMC) genes. Notice the red pigmentation of the hair in both children due to melanocytestimulating hormone insufficiency. Growth charts for each patient are shown in the lower panels, showing the early age onset of obesity. (Reprinted with permission from Krude, H. et al., Nature Genetics, 19, 155–157, 1998.)


Figure 12-7 The anorexic peptide Nesfatin-1 is cleaved from the protein nucleobindin 2 and acts upon an as-yet unidentified G-proteincoupled receptor. The effective sequence of Nesfatin-1 on appetite is a 30 amino acid segment from the middle of the peptide (A). Nesfatin-1 acts on its receptor to open calcium channels via Gi/Go G proteins and to increase cAMP and transcription in target neurons through a protein kinase A pathway (B). See Appendix C for explanation of amino acid abbreviations. (Adapted with permission from Palasz, A. et al., Neuropeptides, 46, 105–112, 2012.)


Figure 12-8 Structure of Orexins. Orexin A (= hypocretin-1) and orexin B (= hypocretin-2) are derived from the same prohormone. See Appendix C for an explanation of amino acid abbreviations. (Adapted with permission from Samson, W.K. and Resch, Z.T., Trends in Endocrinology & Metabolism, 11, 257–262, 2000. © Elsevier Science, Inc.)


Figure 12-9 Orexin actions. (Adapted with permission from Samson, W.K. and Resch, Z.T., Trends in Endocrinology & Metabolism, 11, 257–262, 2000. © Elsevier Science, Inc.)


Figure 12-10 Distribution of some endocrine cells in the gastrointestinal tract and pancreas. High-density regions are in red; pink shaded areas indicate lower density. See text for an explanation of abbreviations. (Based on numerous sources.)


Figure 12-11 Peptides that stimulate gastric acid secretion. Caerulein is a peptide isolated from frog skin that has the common amino-terminal pentapeptide and hence similar activity to gastrin II. The same sequence occurs in all CCKs, although only CCK8 is shown. Y* indicates that a sulfate group is attached to that tyrosine in each of these peptides. See Appendix C for an explanation of the letters coding for individual amino acids. (Adapted with permission from Walsh, J.H. and Dockray, G.J., “Gut Peptides,” Raven, New York, 1994.)


Figure 12-12 Neurocrine, endocrine, and paracrine mechanisms controlling acid secretion by the stomach. Release of gastrin from G cells in the antral stomach can be induced by nutrients in the gut lumen or by the neuropeptide gastrin-releasing peptide (GRP) or by acetylcholine (ACh). Gastrin travels through the blood and by acting on CCKR2 receptors directly stimulates the parietal cell in the corpus to secrete H+ into the stomach lumen. Gastrin also stimulates histamine secretion from enterochromaffin-like (ECL) cells. Histamine in turn acts on histamine H2 receptors (HRH2) to stimulate HCl secretion from parietal cells. The parietal cell is also stimulated by ACh and GRP. D cells in the antrum and corpus secrete somatostatin (SST), which blocks gastrin release and parietal cell secretion, respectively, by acting on somatostatin subtype 2 receptors (SSTR2). D cells may be stimulated by H+ and inhibited by neurotransmitters. H+ in the stomach lumen also inhibits the G cell directly. ENK, enkephalins; Sub-P, substance P.


Figure 12-13 Enterogastrones. Several peptides released from the small intestine inhibit acid secretion and slow processing of food in the stomach. (Adapted with permission from Lloyd, K.C.K. and Walsh, J.H., in “Gut Peptides” (J.H. Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 147–173.)


Figure 12-14 Comparison of secretins from mammals and the chicken. Mammalian secretins are very conservative whereas more than half of the amino acids are different in the bird. See Appendix C for an explanation of the letters coding for individual amino acids. (Adapted with permission from Leiter, A.B. et al., in “Gut Peptides” (J.H. Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 147–173.)


Figure 12-15 Comparison of mammalian GIP structures. These peptides are highly conservative and there have been few substitutions. See Appendix C for an explanation of the letters coding for individual amino acids. (Adapted with permission from Pederson, R.A., in “Gut Peptides” (J.H. Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 217–259.)


Figure 12-16 Amino acid sequences of CGRPs and amylins. Mammalian CGRPs are compared to chicken CGRP. Although there is considerable conservatism among the CGRPs and among the amylins, there are numerous differences between these groups. Conserved sequences underlined in red. See Appendix C for an explanation of the letters coding for individual amino acids. (Data from Holzer, P., in “Gut Peptides” (J.H.Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 493–523.)


Figure 12-17 Amino acid sequences of canine and porcine motilins. See Appendix C for an explanation of the letters coding for individual amino acids. (Data from Poitras, P., in “Gut Peptides” (J.H. Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 261–304.)


Figure 12-18 Products from proglucagon in pancreas and small intestine. Cleavage of the prohormone in the pancreas produces glucagons and glucagon-related polypeptide (GRPP). Further cleavage of the remaining proglucagon major fragment yields one of the glucagon-related peptides (GLP-2). In the small intestine, proglucagon yields glicentin as well as GLP-1 and GLP-2. Glicentin may be cleaved further to yield GRPP and oxyntomodulin that includes the glucagon sequence. IP-2, intervening peptide 2; PG, proglucagon. (Adapted with permission from Holst, J.J., Trends in Endocrinology & Metabolism, 10, 229–235, 1999. © Elsevier Science, Inc.) 19Copyright © 2013 Elsevier Inc. All rights reserved.

Figure 12-19 Comparison of mammalian galanins with chicken galanin. All have the same 15 C-terminal amino acids with only moderate differences among the N-terminal sequence. See Appendix C for an explanation of the letters coding for individual amino acids. (Data from Rokaeus, A., in “Gut Peptides” (J.H. Walsh and G.J. Dockray, Eds.), Raven, New York, 1994, pp. 425–552.)


Figure 12-20 Pancreatic islet of Langerhans. This islet from the mouse pancreas exhibits insulin-producing B cells in green and glucagonproducing D cells in red. (Photograph by Christin Süß, Jakob Suckale, and Michele Solimena, Solimena Lab, University of Technology, Dresden, Germany.)


Figure 12-21 Regulation of insulin secretion from the B-cell and insulin regulation of growth, glucose entry, and metabolism in target (fat, muscle) cells. Glucose is transported into B cells by GLUT2. The B cell oxidizes glucose, resulting in ATP, which closes ATP-sensitive K+ channels in the plasma membrane, thereby preventing K+ efflux and depolarizing the B cell. Depolarization causes voltage-sensitive Ca2+ channels to open in the plasma membrane, allowing Ca2+ to enter the B cell and causing exocytosis of insulin-containing secretory granules. Insulin binds to its receptor, phosphorylating insulin receptor substrate proteins, which in turn dock with many intracellular signaling molecules to induce cell growth (Grb2 and SHP2) and metabolism (PI3K). Phosphorylation of insulin receptors also leads to phosphorylation of Cbl–CAP proteins, causing the translocation of GLUT4 proteins to the plasma membrane and glucose entry into the target cell. Abbreviations: CAP, Cbl-associated protein; Cbl, casitas B-lineage lymphoma (Cbl) protein; Crk, v-Crk sarcoma virus CT10 oncogene homolog; Grb2, growth factor receptor-bound protein 2; PI3K, phosphatidylinositol 3-kinase; SHP2, protein tyrosine phosphatase, non-receptor type 11. (Adapted with permission from Notkins, A.L., Journal of Biological Chemistry, 277, 43545–43548, 2002.)


Figure 12-22 Mouse insulin receptor substrate (IRS) protein. The amino terminus contains a pleckstrin homology (PH) domain and a phosphotyrosine- binding (PTB) domain. Other tyrosine phosphorylation residues in the mid-region and carboxy terminus of the protein allow for interaction with other signaling proteins in the cascade including phosphatidylinositol 3-kinase (PI3K), Src homology 2 domain-containing protein (SHC), growth factor receptor-bound protein 2 (Grb2), proto-oncogene tyrosine-protein kinase (Fyn) and protein-tyrosine phosphatase SHP2. The amino acid motifs in the IRS protein are indicated in parentheses, where x stands for any amino acid. See Appendix C for explanation of amino acid abbreviations. (Adapted with permission from Thirone, A.C.P. et al., Trends in Endocrinology & Metabolism, 17, 72–78, 2006.)


Figure 12-23 Oral insulins. These synthetic molecules cannot substitute for insulin but enhance the activity of insulin already present. These drugs are useful only in the treatment of type 2 diabetes.


Figure 12-24 Effects of epinephrine (E) and glucocorticoids (GC) on intermediary metabolism during stress. See text for explanation of abbreviations.


Figure 12-25 U.S. obesity trends. (Data from the Centers for Disease Control and Prevention, http://www.cdc.gov/obesity/downloads/obesity_trends_2010.ppt.)


Box Figure 12-A1 Adipokine regulation of pancreatic B cells. NEFA, non-essential fatty acids. (Adapted with permission from Dunmore, S.J. and Brown, J.E., Journal of Endocrinology, September 2, 2012 (Epub ahead of print) PMID: 22991412.)


Box Figure 12B-1 Irisin, a newly discovered hormone secreted by muscle tissue. Irisin recruits more heat-generating brown adipose tissue from white adipose tissue, thereby increasing metabolic rate. Irisin may be responsible in part for increasing metabolic rate during exercise. (Adapted with permission from Villarroya, F., Cell Metabolism, 15, 277–278, 2012.)


Box Figure 12B-2 Sequence similarity in vertebrate irisins. Red line marks the irisin sequence. (Reprinted with permission from Boström, P. et al., Nature, 481, 463–468, 2012.)


Chapter 12 Chemical Regulation of Feeding, Digestion and Metabolism Copyright © 2013 Elsevier Inc....

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