STAT5 Deficiency in Mature Adipocytes Results in Metabolically Healthy Adiposity, Reduced Growth Hormone Signaling in Adipose Tissue, and Decreased Energy Expenditure

Abstract

STAT5 proteins promote adipocyte development and regulate adipose tissue function in vitro and in vivo. To further elucidate the role of STAT5 proteins in adipocytes, we used adiponectin-Cre and floxed STAT5 A/B mice to generate mice that lack both STAT5A and STAT5B in mature fat cells (STAT5AKO). Studies on several cohorts of both sexes of mice have revealed that STAT5AKO mice have increased adiposity. Notably, the adiposity phenotype disappears upon high fat feeding when growth hormone (GH) levels and GH signaling are diminished. Another striking observation is that obese STAT5AKO female mice are highly resistant to weight loss induced by low fat feeding when compared to floxed control mice that exhibit significantly enhanced weight loss and reduced adiposity. The adiposity of STAT5AKO mice is not a result of alterations in food intake or lean body mass. Furthermore, the increased adiposity in STAT5AKO mice is uncoupled from insulin resistance and metabolic dysfunction. It is well known that chronic elevation of GH is associated with insulin resistance. However, in most mammals a disruption of the IGF-1 axis accompanies altered GH signaling. Notably, STAT5AKO mice do not have alterations in circulating IGF-1 levels. In addition, the adiposity phenotype of STAT5AKO mice does not appear to be associated with alterations in basal or stimulated lipolysis. However, STAT5AKO female mice have a significant reduction in energy expenditure and fat oxidation. In summary, our extensive phenotypic characterization of STAT5AKO mice has shifted our understanding of the metabolic actions of growth hormone and functions of STAT5 proteins. Disclosure A.J. Richard: None. H. Hang: None. T.D. Allerton: None. C.M. Elks: None. J.M. Stephens: None.