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

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

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.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Dietary Fats / adverse effects*
  • Dietary Fats / pharmacology
  • Hypogonadism / chemically induced
  • Hypogonadism / genetics
  • Hypogonadism / metabolism*
  • Hypogonadism / pathology
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / chemically induced
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Testosterone / genetics
  • Testosterone / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism

Substances

  • Apolipoproteins E
  • Dietary Fats
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Testosterone