Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways

Abstract

The STAT (Signal Transducers and Activators of Transcription) family of transcription factors contributes to adipocyte development and function. STAT5A and STAT5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH). Studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. We have generated a mouse model lacking both STAT5 genes specifically in adipocytes (STAT5AKO). Notably, both sexes of STAT5AKO mice have increased inguinal adipose tissue without any changes in gonadal fat mass. However, both depots exhibit substantial differences in fat cell size. Study of STAT5AKO mice also have revealed that GH′s ability to induce insulin resistance is dependent upon STAT5 in adipocytes, but its ability to reduce adipose tissue mass is STAT5 independent. Additional observations, which were not predicted, indicate that the causes and regulation of increased fat mass in STAT5AKO mice are sex- and depot-dependent.

Adipocyte STAT5 deficiency does not affect blood glucose homeostasis in obese mice

“…Remarkably, the impaired lipolysis observed in lean Stat5 Adipoq mice was associated with improved whole-body insulin sensitivity [ 11 ]. While these attributes may in part be sex-specific [ 14 ], similar effects have been reported in mouse models with adipocyte-specific deletion of adipose triglyceride lipase (ATGL) [ 15 ] as well as of other mediators of GH-signalling (i.e., GH receptor [ 16 ], JAK2 tyrosine kinase [ 17 ]).…”

“…The signal transducer and activator of transcription (STAT5) plays a central role in adipose tissue with involvement in the regulation of adipogenesis [ 6 ], adipocyte differentiation [ 7 ], fat browning [ 8 , 9 ], adaptations to food restriction [ 10 ], brown adipose tissue thermogenesis [ 10 ], and lipolysis [ 11 ]. Specifically, there is evidence that STAT5A and STAT5B mediate the mobilisation of lipid from the adipocyte induced by growth hormone (GH) [ 12 , 13 ], albeit recent findings suggest that GH may modulate lipolysis also in a STAT5-independent manner [ 14 ]. We recently reported that male mice lacking both STAT5 proteins in their mature adipocytes ( Stat5 Adipoq mice) show impaired lipolysis in white adipose tissue and increased accumulation of subcutaneous fat mass [ 11 ].…”

“…As of yet, the evidence for altered lipid trafficking and metabolic improvement due to adipocyte STAT5 deficiency stems from chow-fed lean Stat5 Adipoq mice [ 11 , 14 , 18 ]. In the present study, we aimed at investigating whether STAT5 deficiency exerts positive metabolic effects also in mice challenged with a high-fat diet (HFD, i.e.…”

Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism

“…Given these challenges, many researchers interested in studying metabolic function using mouse models have transitioned to housing within the thermal neutral zone (28-30 • C). A few groups focusing on the GH-axis function have implemented this strategy [48][49][50], but none, to date, have specifically studied the impact on the GH-mediated regulation of hepatic metabolism under thermoneutral conditions.…”

“…However, this GH-mediated impairment in canonical insulin signaling has not been observed in humans. The anti-insulin effects of GH in adipocytes may be mediated by STAT5, since the adipocyte-specific loss of either GHR [103] or STAT5 [50,104] leads to an increase in adipose tissue mass under chow-fed conditions and improves whole body insulin sensitivity. However, in contrast to the adipocyte-specific loss of GHR, the loss of adipocyte STAT5 is not associated with a reduction in WAT lipolysis and does not impact the ability of GH treatment to reduce WAT mass [50].…”