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J Lipid Res. 2014 Jul;55(7):1434-47. doi: 10.1194/jlr.M050047. Epub 2014 May 15.

The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations.

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Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Departments of Urology and Biochemistry, Boston University School of Medicine, Boston, MA.
Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.


Here, we investigated how LDL receptor deficiency (Ldlr(-/-)) modulates the effects of testosterone on obesity and related metabolic dysfunctions. Though sham-operated Ldlr(-/-) mice fed Western-type diet for 12 weeks became obese and showed disturbed plasma glucose metabolism and plasma cholesterol and TG profiles, castrated mice were resistant to diet-induced obesity and had improved glucose metabolism and reduced plasma TG levels, despite a further deterioration in their plasma cholesterol profile. The effect of hypogonadism on diet-induced weight gain of Ldlr(-/-) mice was independent of ApoE and Lrp1. Indirect calorimetry analysis indicated that hypogonadism in Ldlr(-/-) mice was associated with increased metabolic rate. Indeed, mitochondrial cytochrome c and uncoupling protein 1 expression were elevated, primarily in white adipose tissue, confirming increased mitochondrial metabolic activity due to thermogenesis. Testosterone replacement in castrated Ldlr(-/-) mice for a period of 8 weeks promoted diet-induced obesity, indicating a direct role of testosterone in the observed phenotype. Treatment of sham-operated Ldlr(-/-) mice with the aromatase inhibitor exemestane for 8 weeks showed that the obesity of castrated Ldlr(-/-) mice is independent of estrogens. Overall, our data reveal a novel role of Ldlr as functional modulator of metabolic alterations associated with hypogonadism.


apolipoprotein E; diabetes; low density lipoprotein receptor-related protein 1; metabolic rate; metabolic syndrome; plasma glucose homeostasis; testosterone; uncoupling protein 1 • metabolic activation of white adipose tissue

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