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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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.

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