The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations.
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.
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Caterina
C
Constantinou
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Diogenis
D
Mpatsoulis
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Anastasios
A
Natsos
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Peristera-Ioanna
PI
Petropoulou
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Evangelia
E
Zvintzou
Departments of Urology and Biochemistry, Boston University School of Medicine, Boston, MA.
Abdulmaged M
AM
Traish
Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Peter J
PJ
Voshol
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Iordanes
I
Karagiannides
Department of Medicine, Pharmacology Unit, University of Patras Medical School, Rio Achaias, Greece.
Kyriakos E
KE
Kypreos
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D007006:Hypogonadism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D004041:Dietary Fats; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D013739:Testosterone
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