White UA, Maier J, Zhao P, Richard AJ, Stephens JM. The modulation of adiponectin by STAT5-activating hormones. Am J Physiol Endocrinol Metab 310: E129 -E136, 2016. First published November 25, 2015 doi:10.1152/ajpendo.00068.2015.-Adiponectin is a hormone secreted from adipocytes that plays an important role in insulin sensitivity and protects against metabolic syndrome. Growth hormone (GH) and prolactin (PRL) are potent STAT5 activators that regulate the expression of several genes in adipocytes. Studies have shown that the secretion of adiponectin from adipose tissue is decreased by treatment with PRL and GH. In this study, we demonstrate that 3T3-L1 adipocytes treated with GH or PRL exhibit a reduction in adiponectin protein levels. Furthermore, we identified three putative STAT5 binding sites in the murine adiponectin promoter and show that only one of these, located at Ϫ3,809, binds nuclear protein in a GH-or PRL-dependent manner. Mutation of the STAT5 binding site reduced PRL-dependent protein binding, and supershift analysis revealed that STAT5A and -5B, but not STAT1 and -3, bind to this site in response to PRL. Chromatin immunoprecipitation (IP) analysis demonstrated that only STAT5A, and not STAT1 and -3, bind to the murine adiponectin promoter in a GH-dependent manner in vivo. Adiponectin promoter/reporter constructs were responsive to GH, and chromatin IP analysis reveals that STAT5 binds the adiponectin promoter in vivo following GH stimulation. Overall, these data strongly suggest that STAT5 activators regulate adiponectin transcription through the binding of STAT5 to the Ϫ3,809 site that leads to decreased adiponectin expression and secretion. These mechanistic observations are highly consistent with studies in mice and humans that have high GH or PRL levels that are accompanied by lower circulating levels of adiponectin.signal transducer and activator of transcription 5 GROWTH HORMONE (GH) is known to have profound effects on adipocyte metabolism (reviewed in Ref. 8), such as attenuating lipogenesis and stimulating lipolysis (35,56). The effects of prolactin (PRL) have been well characterized in mammary tissues, and yet there is also evidence suggesting that this hormone can act within adipose tissue in mice and humans (31, 36) to modulate lipolysis (11,32). It is well known that GH and PRL induce signaling via the JAK/STAT pathway, and STAT5 proteins are potently activated by these hormones (reviewed in Ref. 46). However, few direct molecular targets for the actions of GH and PRL in fat cells have been identified.Multiple lines of evidence suggest that STAT5 proteins can modulate adipocyte function. During differentiation of 3T3-L1 adipocytes, the expression levels of STAT5A and -5B are highly induced (50). In addition, GH-dependent adipogenesis of 3T3-F442A cells is attenuated by STAT5 antisense oligonucleotides (58), and constitutively active STAT5 can replace the requirement for GH in adipogenesis of these cells (48). Moreover, ectopic expression of STAT5A has been shown to confer adipogenes...

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