The Low Density Lipoprotein Receptor Modulates the Effects of Testosterone on White Adipose Tissue Metabolic Activation through Estrogen Independent Mechanisms

Abstract

AIMThe aim of the study was the delineation of the role of estrogens in the functional cross‐talk between LDL receptor (LDLR) and testosterone (T).METHODSIn vivo indirect calorimetry studies, and metabolic and biochemical analyses were performed.RESULTSThough sham operated male Ldlr‐/‐ mice fed western‐type diet for 12 weeks became obese, their castrated littermates were resistant to diet‐induced obesity. T replacement confirmed that TD was crucial in the resistance in diet‐induced body weight gain of castrated Ldlr‐/‐ mice. Sham operated Ldlr‐/‐ mice treated with exemestane, a third generation irreversible aromatase inhibitor, showed a similar body weight gain to placebo‐treated animals, providing a first indication that the resistance of castrated Ldlr‐/‐ mice towards diet‐induced obesity was specific to TD and not due to estrogen deficiency. Ovariectomized female Ldlr‐/‐ mice further confirmed that the resistance of castrated Ldlr‐/‐ mice towards diet‐induced obesity is directly due to TD. Additionally, these experiments showed that estrogen counteracts the functions of testosterone in the regulation of plasma triglyceride levels in Ldlr‐/‐ mice. The observed elevated metabolic activity of castrated Ldlr‐/‐ mice was directly attributed to the markedly increased mitochondrial cytochrome c and UCP1 protein levels in white adipose tissue (WAT) of castrated mice providing strong evidence of metabolic activation (browing) of WAT.CONCLUSIONSOur data indicate that LDLR modulates the effects of testosterone on WAT metabolic activation through estrogen independent mechanisms.