Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, Fat Specific Protein 27 (FSP27) at both the mRNA and protein level. These effects are mimicked in vivo as transgenic over-expression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK and STAT5 dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, over-expression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

Our results show that GH action is positively associated with an increase in WAT collagen content as well as a decrease in adipocyte size, particularly in the subcutaneous depot. This effect appears to be due to GH and not IGF-1 and reveals a novel means by which GH regulates WAT accumulation.

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IntroductionFemale sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear.MethodsIn this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice) to examine the effect on sexual responsiveness.ResultsMC4R knockout mice were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. These changes were independent of body weight. Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects.DiscussionThese results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.

Pro-opiomelanocortin (POMC) neurons in the hypothalamus play a role in both the control of metabolic state and sexual behavior. Along with the fast neurotransmitters glutamate and/or GABA, POMC neurons secrete cocaine- and amphetamine-regulated transcript (CART) and products of the POMC gene, including β-endorphin and α-melanocortin stimulating hormone (α-MSH). Published data from our lab demonstrate a lack of sexual interest in male mice when both the leptin receptor and insulin receptor are deleted from POMC neurons. Furthermore, this absence of interest correlates with a decrease in the POMC product α-MSH. However, it is not known whether these effects correspond to an increase in POMC neural activation. We hypothesized that activation of POMC neurons in male mice would lead to improved sexual interest. We have crossed mice with cre-dependent expression of the excitatory designer receptor, hM3Dq, with mice expressing cre under control of the POMC promoter. When these mice are administered intraperitoneal clozapine-N-oxide (CNO), POMC neurons exhibit increased activation. We completed a comprehensive mating analysis to measure the sexual desire and erectile and ejaculatory capabilities of these male mice under CNO or saline administration. Additionally, we sacrificed the mice after injection of CNO or saline to perform immunostaining for the protein c-fos as an indicator of neural activation. As expected, activation of POMC neurons with CNO increased c-fos expression, while the impact on male sexual interest was more nuanced. These experiments emphasize the need to investigate the specific neuropeptide and transmitter output by POMC neurons that influences sexual behavior and function.

Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for Hypoactive Sexual Desire Disorder (HSDD), but the neuronal pathways involved are unclear. In this study, female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) paired with males were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice). Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits. R01HD081792 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.