It is clear that insulin-like growth factor-1 (IGF1) is important in supporting growth and regulating metabolism. The IGF1 found in the circulation is primarily produced by the liver hepatocytes, but healthy mature hepatocytes do not express appreciable levels of the IGF1 receptor (IGF1R). Therefore, the metabolic actions of IGF1 are thought to be mediated via extra-hepatocyte actions. Given the structural and functional homology between IGF1/IGF1R and insulin receptor (INSR) signaling, and the fact that IGF1, IGF1R and INSR are expressed in most tissues of the body, it is difficult to separate out the tissue-specific contributions of IGF1/IGF1R in maintaining whole body metabolic function. To circumvent this problem, over the last 20 years, investigators have taken advantage of the Cre/loxP system to manipulate IGF1/IGF1R in a tissue-dependent, and more recently, an age-dependent fashion. These studies have revealed that IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver, where these actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.

Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high molecular weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered growth hormone (GH) signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH versus IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying the effects of GH on adiponectin are depot-specific. Interestingly rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity.

Fasting results in a reciprocal shift in hypothalamic neuropeptide Y (NPY) and GH-releasing hormone (GHRH) expression in the adult male rat. It is hypothesized that the fasting-induced rise in NPY is responsible for the GHRH decline and subsequent attenuation of pulsatile GH release. Fasting also leads to a decrease in circulating IGF-I, attributed to both reduced GH release and peripheral GH resistance. Although pituitary GH output is suppressed in the fasted rat, we report herein that pituitary GHRH receptor (GHRH-R) and GH secretagogue receptor (GHS-R) mRNA levels are increased, while pituitary expression of the somatostatin receptor subtype 2 (sst2) and 5 (sst5) is decreased, as determined by real-time reverse transcription (RT)-PCR. A shift in the expression of pituitary receptor subtypes to favor GH synthesis and release may be due, at least in part, to a decline in GH/IGF-I negative feedback. In order to test this hypothesis, we compared hypothalamic and pituitary response to fasting (72 h) in normal male rats and rats with isolated GH deficiency (spontaneous dwarf rats (SDR)). Circulating GH levels were undetectable in SDR, and IGF-I levels were less than 10% of normal controls. Fasting stimulated NPY mRNA levels in SDR; however, the rise in NPY mRNA levels was not accompanied by a fall in GHRH mRNA, as observed in fasted normal rats. In fact, GHRH mRNA levels paradoxically rose in the fasted SDR to 135% of fed controls. At the pituitary level, fasting did not alter sst2 and sst5 mRNA levels in SDR but did stimulate the expression of GHRH-R and GHS-R to 165% and 149% of fed controls, respectively. These results demonstrate that the fasting-induced changes in pituitary expression of sst2 and sst5, but not GHRH-R and GHS-R, are GH/IGF-I dependent. In addition, these results argue against the theory that the negative association of NPY and GHRH expression observed following fasting represents a simple cause-and-effect relationship and suggest that GH, either directly or indirectly, mediates the effects of fasting on hypothalamic GHRH expression.

Somatostatin and cortistatin have been shown to act directly on pituitary somatotrophs to inhibit growth hormone (GH) release. However, previous results from nonprimate species indicate that these peptides can also directly stimulate GH secretion, at low concentrations. The relevance of this phenomenon in a nonhuman primate model was investigated in the present study by testing the impact of somatostatin/cortistatin on GH release in primary pituitary cell cultures from baboons. High doses (> 10(-10) m) of somatostatin/cortistatin did not alter basal GH secretion but blocked GH-releasing hormone (GHRH)- and ghrelin-induced GH release. However, at low concentrations (10(-17)-10(-13) m), somatostatin/cortistatin dramatically stimulated GH release to levels comparable to those evoked by GHRH or ghrelin. Use of somatostatin receptor (sst) specific agonists/antagonists, and signal transduction blockers indicated that sst2 and sst1 activation via intact adenylate cylcase and mitogen-activated protein kinase systems mediated the inhibitory actions of high-concentration somatostatin. By contrast, the stimulatory actions of low-dose somatostatin on GH release were mediated by sst5 signalling through adenylate cylcase/cAMP/protein kinase A and intracellular Ca(2+) pathways, and were additive with ghrelin (not GHRH). Notably, low-concentrations of somatostatin, similar to sst5-agonists, inhibited prolactin release. These results clearly demonstrate that the ultimate impact of somatostatin/cortistatin on hormone release is dose-dependent, cell type-selective and receptor-specific, where the stimulatory effects of low-concentration somatostatin/cortistatin on GH release extend to primates, thereby supporting the notion that this action is relevant in regulating GH secretion in humans.