Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity.

To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes. Beginning at 9 wk of age, ASKO mice weighed more than their littermate controls and had increased adipose tissue mass, associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced, but not isoproterenol-induced, lipolysis was impaired in ASKO adipocytes, which may partially explain the increased cell size. Despite reduced adiponectin and increased liver triacylglycerol, ASKO mice displayed normal glucose tolerance. Overall, these findings demonstrate that adipocyte STAT3 regulates body weight homeostasis in part through direct effects of leptin on adipocytes.

Midkine is an autocrine activator of signal transducer and activator of transcription 3 in 3T3-L1 cells.

Mitotic clonal expansion is believed to be necessary for 3T3-L1 adipocyte formation. Signal transducer and activator of transcription 3 (STAT3), a mitogenic signaling protein, is activated through tyrosine phosphorylation during the proliferative phases of adipogenesis. We hypothesize that this signaling protein plays a key role in mitotic clonal expansion and differentiation. Here we determined that the adipocyte differentiation cocktail containing isobutylmethylxanthine, dexamethasone, and insulin (MDI) induced STAT3 tyrosine phosphorylation indirectly through the synthesis of an autocrine/paracrine factor. We further determined that the factor has heparin binding properties and identified the factor as midkine, a pleiotrophic growth factor previously associated with neuronal development and oncogenesis. Recombinant midkine induced STAT3 tyrosine phosphorylation in a time- and dose-dependent manner and stimulated the proliferation of postconfluent 3T3-L1 cells. Midkine neutralizing antibodies inhibited differentiation-induced STAT3 tyrosine phosphorylation as well as adipogenesis. These results show that MDI-induced synthesis and release of midkine explains the delayed activation of STAT3 during adipogenesis and that the midkine-STAT3 signaling pathway plays a necessary role in mitotic clonal expansion and differentiation.