TSH signaling and cellular responses in preadipocytes and adipocytes

Abstract

Thyroid stimulating hormone (TSH) action in adipose tissue remains largely unknown. We demonstrate that TSH activates protein kinase B (PKB/Akt) and p70 S6 kinase (p70 S6K) in a phosphoinositide 3-kinase (PI3K)-dependent manner in 3T3-L1 preadipocytes. TSH had no effect on cAMP levels, suggesting adenylyl cyclase is not involved in TSH activation of the PI3K-PKB/Akt-p70 S6K pathway. 3T3-L1 preadipocyte cell death was reduced by 29 to 76%, in serum-deprived (6 h) preadipocytes treated with 1--20 muM TSH, respectively. In the presence of 20 muM TSH, an 88% reduction in TUNEL-positive cells was observed in serum-starved (3 h) 3T3-L1 preadipocytes, as well as a 93% reduction in the level of cleaved activated caspase 3. TSH acts as a survival factor for serum-deprived preadipocytes, reducing TUNEL-positive cells and caspase 3 activation. A role for TSH may exist in adipose tissue development and remodeling. Interleukin-6 (IL-6), a pro-atherogenic cytokine, is expressed and secreted by adipocytes, but little is known about its regulation. Since an elevated TSH serum level is a cardiovascular disease (CVD) risk factor, and since thyroid stimulating hormone receptor (TSHR) is expressed in adipocytes, we investigated whether TSH modulates IL-6 secretion in cultured 3T3-L1 and 3T3-F442A mouse adipocytes, and in primary cultures of human abdominal adipocytes differentiated in culture. TSH increased the secretion of IL-6 by 5-fold in 3T3-F442A adipocytes, by 2-fold in 3T3-L1 adipocytes, and by 3.5-fold in human differentiated adipocytes. TSH is a novel regulator of adipocyte IL-6 secretion, providing a potential mechanism for epidemiological observations identifying an elevated serum TSH level as a CVD risk factor.