The Adipocyte as an Active Participant in Energy Balance and Metabolism  Michael K. Badman, Jeffrey S. Flier  Gastroenterology  Volume 132, Issue 6, Pages 2103-2115 (May 2007) DOI: 10.1053/j.gastro.2007.03.058 Copyright © 2007 AGA Institute Terms and Conditions

Figure 1 The hormone leptin is produced in adipose tissue and has peripheral and central targets. Leptin is the best characterized of all secreted products of adipose tissue. It is secreted in proportion to adipose stores and immediate nutritional state. Leptin is transported across the blood-brain barrier and gains access to central nervous system targets. These include neurons within the hypothalamus and the ventral tegmental area. Resulting effects of central leptin action include changes in food intake, energy expenditure, and peripheral metabolic actions on glucose and lipid metabolism and neuroendocrine effects. Direct peripheral targets include pancreatic islet β-cells, immune cells, and other cell types. In addition to leptin, an increasing number of other adipocyte-secreted products have been identified. Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions

Figure 2 Leptin target neurons in the hypothalamus. Leptin from the periphery gains access to the arcuate nucleus where it activates POMC/cocaine and amphetamine-regulated transcript–containing neurons and inhibits NPY/AgRP neurons. The extent to which the passage of leptin to these arcuate sites is passive or requires transport remains unclear. POMC neurons then project to second-order neurons where α-melanocyte stimulating hormone (MSH) activates melanocortin receptor 3 and 4 (MC3/4) receptors. In addition, leptin inhibition of the NPY/AgRP neurons limits activation of Y1/5 receptors by NPY, while simultaneously relieving tonic inhibition of MC3/4 receptors by decreasing AgRP. Effects of second-order neurons after leptin stimulation include reduced appetite, increased thermogenesis and peripheral metabolism, together with neuroendocrine and other effects. Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions

Figure 3 Intracellular signaling cascades activated by leptin. When leptin binds to the long-form receptor JAK2 is activated and autophosphorylates a number of sites, which allows interaction with IRS proteins and subsequent activation of phosphoinositide-3 kinase signaling cascades. Phosphorylation of Tyr985 of the leptin receptor enhances association of the tyrosine phosphatase src homology 2 domain containing tyrosine phosphatase 2, which activates the p21ras-ERK signaling pathway. Phosphorylation of Tyr1138 of the leptin receptor recruits the transcription factor STAT3, which subsequently is tyrosine phosphorylated. Tyr705 phosphorylated STAT dimerizes and translocates to the nucleus to induce a number of genes including those encoding target neuropeptides and SOCS3. A negative regulatory loop is mediated by SOCS3, which binds phosphorylated moieties on the leptin receptor. Similarly, the intracellular inhibitor protein-tyrosine phosphatase 1b effects a reduction of leptin signaling in the cell. Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions

Figure 4 Structural determinants of adiponectin. The primary sequence of adiponectin includes an N-terminal signal sequence followed by a variable region, then a collagen-like tail domain, and finally a C-terminal globular head region. Nascent adiponectin forms lower molecular weight complexes in trimers. Dimers of trimers produce medium molecular weight complexes, which themselves trimerize to produce high molecular weight complexes. Alternatively, proteolytic cleavage of adiponectin yields a globular form of the molecule. Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions

Figure 5 11βHSD isoforms act in the tissue-specific metabolism of glucocorticoids. Active glucocorticoid hormone cortisol in human beings and corticosterone in rodents is metabolized to inactive cortisone or 11-dehydrocorticosterone by 11βHSD2 in numerous tissues including kidney, colon, and salivary glands. Inactive steroids are re-activated by 11βHSD1, present in liver adipose tissue, lung, macrophages, vascular tissue, and the brain. Notably hepatic 11βHSD1 is down-regulated in obesity, whereas in adipose tissue 11βHSD1 levels are increased. This increases local re-activation of glucocorticoid hormones and may predispose to visceral obesity. Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions

Jeffrey S. Flier, MD Gastroenterology 2007 132, 2103-2115DOI: (10.1053/j.gastro.2007.03.058) Copyright © 2007 AGA Institute Terms and Conditions