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

Abstract

This article is available online at http://www.jlr.orgTestosterone , a steroid hormone with an important role in male sexual differentiation, maintenance of libido, and erectile function ( 1, 2 ), is also a central modulator of key metabolic processes associated with metabolic syndrome. In humans, testosterone defi ciency (TD) alters carbohydrate, lipid, and protein metabolism, thus contributing to oxidative stress, endothelial dysfunction, and increased production of proinfl ammatory factors ( 3 ). TD is considered as a primary risk factor for a number of disorders including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, vascular disease, insulin resistance, and type 2 diabetes mellitus ( 4-8 ). Likewise, data from the Massachusetts Male Aging Study suggest that obesity leads to decreased levels of total and free testosterone, with follow-up levels lowest among men who remained or became obese ( 9 ).Additional insights into the role of androgens in maintaining human health have been obtained following androgen deprivation therapy (ADT), which is often used in the treatment of prostate cancer (PCa). Metabolic complications of ADT, such as metabolic syndrome, insulin resistance, and type 2 diabetes mellitus have highlighted key avenues of human pathology associated with this treatment ( 10 ). ADT in men with PCa resulted in increased total cholesterol, LDL cholesterol (LDL-C), and TG levels ( 11, 12 ). Abbreviations: ADT , androgen deprivation therapy; AUC, area under the curve; BAT, brown adipose tissue; Cox4, cytochrome c oxidase subunit 4; EE, energy expenditure; GTT, glucose tolerance test; hCetp, human cholesteryl ester transfer protein; HDL-C, HDL cholesterol; LBM, lean body mass; Ldlr, LDL receptor; Lrp1, LDL receptor-related protein 1; PCa, prostate cancer; RER, respiratory exchange ratio; TD, testosterone defi ciency; Ucp1, uncoupling protein 1; VCO 2 , carbon dioxide production expressed as the difference of carbon dioxide exiting from carbon dioxide entering the metabolic cage; VO 2 , oxygen consumption expressed as the difference between oxygen entering and oxygen exiting the metabolic cage; WAT, white adipose tissue.

Testosterone undecanoate improves lipid profile in patients with type 1 diabetes and hypogonadotrophic hypogonadism

“…These findings suggest that increased serum cholesterol levels associated with testosterone deficiency may be attributed to impaired LDL cholesterol clearance. Furthermore, a study in testosterone deficient-LDLr-/-mice suggests a functional modulator role of LDLR in processes associated with hypogonadism-induced metabolic alterations [23].…”

Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition

“…For the semiquantitative analysis of total and phosphorylated AMPK in liver lysates, a rabbit antimouse AMPK antibody (Cell Signaling, cat# 2532) and a rabbit antimouse P(Thr172)AMPK antibody (Cell Signaling cat# 2535) were used. Western blotting analysis of murine cytochrome c (CytC), uncoupling protein 1 (UcP1), and cytochrome c oxidase subunit 4 (COx4) from BAT mitochondrial lysates was performed using IgG primary rabbit anti-mouse antibodies (cat# 4272, Cell Signaling, Danvers, MA; cat# GTX10983, Acris, Herford, Germany; cat# Ab165056, AbCam, Cambridge, UK, respectively), as described previously (Constantinou et al, 2014).…”

“…2.14 RT-PCR analysis of gene expression RT-PCR for fatty acid synthase (fasn), peroxisome proliferator-activated receptor gamma (ppargamma), diacylglycerol O-acyltransferase 1 (dgat-1), microsomal triglyceride transfer protein (mttp) and the housekeeping gene 40S ribosomal protein S18 (rps18) was performed as described previously (Constantinou et al, 2014;Karavia et al, 2012).…”

“…2.3 Fasting glucose determination, glucose tolerance test and pyruvate tolerance test Prior analysis, mice were fasted for 16 h. Blood glucose determinations and glucose tolerance tests (GTT) were performed as described previously (Constantinou et al, 2014).…”

“…Pure mitochondria from brown adipose tissue (BAT) were isolated, as described previously (Constantinou et al, 2014).…”