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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.

Author information

1
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
2
Departments of Urology and Biochemistry, Boston University School of Medicine, Boston, MA.
3
Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Abstract

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.

KEYWORDS:

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

PMID:
24837748
PMCID:
PMC4076071
DOI:
10.1194/jlr.M050047
[Indexed for MEDLINE]
Free PMC Article

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