Endothelin-1 Stimulates Leptin Production in Adipocytes

Abstract

Leptin is an adipocyte-derived hormone that regulates body fat stores and feeding behavior. In an effort to identify endogenous diffusible modulators of leptin production, we found that endothelin-1 (ET-1) up-regulates leptin expression in adipocytes. ET-1 is as potent and efficacious as insulin in stimulating leptin production in two different adipocyte cell lines. Endothelins stimulate leptin production via the endothelin-A receptor (ET A ), as judged by a potency rank order of ET-1 > > ET-3. We detected expression of ET A but not ET B in both cell lines by Northern blot analysis. In addition, the ET A -selective antagonist FR139317 inhibited ET-1-induced leptin expression more potently than did the ET B -selective antagonist BQ788. ET-1 and insulin positively interact with each other in increasing leptin production in adipocytes. In primary mouse white fat cells, we detected expression of both ET A and ET B by Northern blot and in situ hybridization analyses. We conclude that ET-1 stimulates leptin production via the ET A receptor in cultured adipocytes.The ob 1 (obese) gene product, leptin, is a 16-kDa protein secreted predominantly by adipocytes. Administration of recombinant leptin reduces food intake and increases thermogenesis and physical activity in ob/ob mice, resulting in reduced body weight in these mice (1-3). This fat-derived hormone regulates energy homeostasis through leptin receptors expressed in the central nervous system, particularly in the hypothalamus (4). It is also reported that leptin may acutely stimulate glucose metabolism by acting on peripherally expressed leptin receptors (5). Leptin receptor-deficient db/db mice have a similar phenotype as ob/ob mice, including obesity, diabetes, and infertility in females (6, 7). Mutations in either leptin (8) or leptin receptor (9, 10) genes are associated with early-onset obesity in humans. Recent studies demonstrate that leptin is a multifunctional hormone involved in not only energy homeostasis but also onset of puberty (11, 12), sympathetic nerve activity (13), hematopoiesis (14, 15), angiogenesis (16), and immune response (17). In addition to fat, stomach (18), placenta (19), and muscle (20) tissues are minor sources of leptin, suggesting possible undiscovered functions.Serum leptin levels are elevated in most obese individuals in accordance with their body adiposity (21). Feeding state (22, 23) also regulates leptin expression. These findings indicate that leptin expression is regulated through multiple central and peripheral mechanisms. The finding that subdermally implanted 3T3-F442A preadipocytes gave rise to fat pads and expressed much higher levels of leptin than cells differentiated in vitro also strongly argued for the existence of in vivo regulators of leptin gene expression (24). A number of factors regulate leptin expression in vivo or in vitro. Insulin (23,25), glucocorticoids (26,27), and some cytokines (28) are activators of leptin production. In contrast, catecholamine (26, 29) and peroxisome proliferator-activated receptor-...

Maturation of the expression of adrenomedullin, endothelin-1 and nitric oxide synthases in adipose tissues from childhood to adulthood

“…Examples for such hormones are leptin, a signal hormone for the regulation of body fat and feeding behavior, and resistin, which plays a controversial role in the pathophysiology of insulin resistance. 16,29,30 Under cell culture conditions, ET-1 upregulates leptin production as efficaciously as insulin via the ET-A receptor. 16 In addition, ET-1 diminishes insulinstimulated and basal resistin secretion in vitro.…”

“…16,29,30 Under cell culture conditions, ET-1 upregulates leptin production as efficaciously as insulin via the ET-A receptor. 16 In addition, ET-1 diminishes insulinstimulated and basal resistin secretion in vitro. 29 Adipocytes can be regarded as a target for circulating as well as for paracrine acting ET-1, also affecting the NO system.…”

“…14,15 Additionally, it has been shown that ET-1 may stimulate leptin secretion in cultured adipocytes. 16 Short-time incubation of adipocytes with ET-1 also enhances the secretion of adiponectin, an insulin-sensitizing hormone, whereas a longer exposure time decreases the stimulatory effects of ET-1 and insulin on adipocyte-derived adiponectin secretion. 17 Nitric oxide (NO) is produced by many different cells via an enzymatic reaction catalyzed by one of the three isoforms of NOS, endothelial NOS (eNOS), inducible NOS (iNOS) or neuronal NOS (nNOS), depending on the cell type.…”

Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8

“…Culture of Xenopus laevis melanophores and DNA transfections by electroporation were done as described (9). For purifying NPB, the acid͞acetone extraction of frozen bovine hypothalami was performed as described (10,11). The details of HPLC procedures and the following cDNA cloning are described in supporting information.…”

G protein signaling controls the differentiation of multiple cell lineages

“…In addition to fatty acid signaling, peptide ligands also play a critical role in leptin regulation. For example, endothelin-1 (ET-1) was shown to stimulate leptin production and lipolysis in adipocytes, mainly through activating endothelin-A receptor [48][49][50]. Melanocortin (ACTH and α-MSH)…”