Endocrine Abstracts

Objectives: Testosterone deficiency is common in obese men with type 2 diabetes. Testosterone replacement therapy (TRT) improves insulin resistance, glycaemic control and cholesterol in hypogonadal men, and TRT reduces body fat mass. Adipose tissue plays a major role in glucose homeostasis and insulin sensitivity through the regulation of lipid and glucose metabolism. There are functional differences between subcutaneous and visceral adipose tissue. This study investigates the expression of key targets involved in lipid and glucose homeostasis in visceral and subcutaneous fat depots of the testicular feminised (Tfm) mouse, which exhibit non-functional androgen receptors and low circulating levels of testosterone.

Methods: Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received either TRT (intramuscular mixed testosterone esters) or placebo (saline) and were compared to wild-type littermates. Visceral and subcutaneous abdominal adipose tissue was collected and relative concentrations of mRNA was analysed by qPCR for the expression of gene targets involved in lipid metabolism (acetyl coA carboxylase, ACC; fatty acid synthase, FAS; hormone sensitive lipase, Lipe; lipoprotein lipase, LPL), cholesterol efflux (apolipoprotein E, ApoE; ATP-binding cassette transporter A1, ABC-A1), glucose control (glucose transporter 4, Glut4; hexokinase 2, HK2; phosphofructokinase, PFK) and master regulators of lipid and glucose metabolism (peroxisome proliferator-activated receptor-α, PPARα; PPARγ; liver X receptor, LXR; sterol regulatory element binding protein-1, Srebp-1; Srepb-2).

Results: Compared to littermates, Tfm mice had significantly lower subcutaneous mRNA expression of LPL, ApoE, Glut4 HK2, PFK, PPARα, PPARγ, LXR, Srebp-1 and Srebp-2 (P≤0.05, n=9) and increased Lipe. In visceral fat, only PPARγ was significantly reduced (P<0.001, n=9). TRT increased the expression of LXR, ApoE and Srebp-1 in subcutaneous fat (P≤0.05, n=9), showed a trend towards increased srebp-2 (P=0.07) and HK2 (P=0.09) and decreased Lipe. However, TRT had no significant effect on the expression of any targets in visceral fat.

Discussion: Subcutaneous fat is intrinsically different from visceral fat and testosterone acts differentially on targets of glucose and lipid metabolism in these depots to potentially influence whole-body metabolism.