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Adiponectin Suppresses GH and LH In Vitro« Back to Volume 23, Issue 1, March 2007 - Table of Contents Leptin is the prototypic adipokine, a newly recognized class of hormones originating in adipose tissue. Leptin relays the degree of body fatness back to the hypothalamus as part of the homeostatic mechanisms for regulating body energy balance. In addition to its hypothalamic effects, leptin directly stimulates pituitary secretion of leutenizing hormone (LH) and growth hormone (GH), facilitating reproductive, growth, and anabolic functions during times of nutrient abundance. The more recently discovered adiponectin is the most abundantly secreted of the known adipokines. Adiponectin expression has also been detected in human and murine skeletal muscle, cardiac myocytes, osteoblastic cells, placenta, and chicken pituitaries. Adipocyte expression of both adiponectin and its receptor (AdipoR) have been shown to be regulated, at least in part, by GH.1,2 Thus, Rodriguez-Pacheco et al sought to investigate whether adiponectin plays a central role, akin to leptin, in regulating somatotroph and gonadotroph function. Anterior pituitary glands were isolated from male Sprague-Dawley rats, minced, enzymatically dissociated and mechanically dispersed to create in vitro cultures of adenohypophyseal cells. After 3 days in culture, and 2 hours in serum-free medium, the pituitary cells were switched to fresh medium and experimental conditions. Growth hormone secretion was decreased by 34% to 52% after 4 hours incubation in adiponectin at concentrations of 10-9 to 10-7 M. After 24 hours exposure, only the highest dose of adiponectin (10-7 M) changed GH secretion, and that change was a doubling. Focusing on the short-term (4 hours), adiponectin exposure (10-7 M) inhibited the stimulation of GH release by 10-8 M ghrelin, but not that of 10-8 M GH releasing hormone (GHRH). This adiponectin dose increased pituitary cell expression levels of ghrelin receptor (GHS-R) by 34% and GHRH receptors (GHRH-R) by 448%; in the short-term 10-8 M adiponectin also significantly induced GHRH-R expression. In contrast, long-term (24 hour) exposure to adiponectin at concentrations of 10-9 to 10-7 M did not alter expression levels of either GHS-R or GHRH-R. Like GH, LH secretion was suppressed by 4-hours’ incubation in adiponectin at concentrations of 10-9 to 10-7 M, and the suppression was gone by 24 hours. Four hours of 10-7 M adiponectin caused a 74% reduction in the LH secretion stimulated by 10-8 M gonadotropin-releasing hormone (GnRH). At 4 hours GnRH receptor expression was halved by adiponectin at concentrations of 10-9 to 10-7 M, but only the highest concentration of adiponectin significantly reduced GnRH receptor expression at 24 hours. Rodriguez-Pacheco et al also examined the pituitary adiponectin system. Expression of adiponectin and its 2 receptors (AdipoR1 and AdipoR2) were demonstrated by RT-PCR in extracts of rat and human pituitaries. Returning to the rat pituitary cell culture model, the authors found that 4 hours of adiponectin exposure at concentrations of 10-9 to 10-7 M increased its own expression by almost 70% (at the highest dose only), but did not alter the expression levels of either of its 2 receptors. However, after 24 hours’ exposure, adiponectin (10-8 M only) increased its own expression (by 300%), decreased expression of AdipoR1 (by 10-8 M only), and increased expression of AdipoR2 (by 10-7 M only). Editor’s CommentRodriguez-Pacheco et al showed that short-term adiponectin exposure suppressed both basal and stimulated (by ghrelin [but not GHRH] and GnRH) secretion of GH and LH, respectively, by rat pituitary cells in vitro. They further laid the groundwork for a pituitary adiponectin autocrine/paracrine system in which both adiponectin and its receptors are expressed and further modulated by adiponectin exposure. Thus, adiponectin seems to serve like the classic adipokine leptin, in centrally linking growth, anabolic, and reproductive function to fat cell activity. These relationships warrant in vivo confirmation. From the evidence so far, it seems that neither endocrine leptin nor endocrine adiponectin underlie the old clinical observation that obesity suppresses GH secretion; circulating leptin levels are increased in obesity but leptin stimulates GH release, and although adiponectin suppresses GH secretion, as shown in this paper, circulating adiponectin levels are reduced in obesity. Nonetheless, adiponectin attracts tremendous clinical interest. Adiponectin seems to do what clinicians are desperately seeking to accomplish in the obesity epidemic: adiponectin acts as an insulin-sensitizing, anti-atherogenic, anti-inflammatory, anti-angiogenic, and anti-tumoral agent. The sooner we learn about adiponectin physiology, the sooner it can inspire novel therapeutic approaches.3,4 For example, it turns out that thiazolidinediones up-regulate adiponectin. Adiponectin’s reported insulin-sensitizing activities are multiple and peripheral: it enhances hepatic insulin action and decreases endogenous glucose production; it increases glucose uptake by adipocytes and myocytes, and it increases fatty acid oxidation in muscle. If the in vitro findings of this paper are confirmed in vivo, then we can add one more mechanism to the list: adiponectin centrally inhibits secretion of the counter-regulatory GH. Further, adiponectin was shown to decrease body weight in mice by stimulating energy expenditure.5 Not everything from fat is bad. Adda Grimberg, MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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