Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis.

Androgen deficiency in men increases body fat, but the mechanisms by which testosterone suppresses fat deposition have not been elucidated fully. Adipose tissue macrophages express the androgen receptor (AR) and regulate adipose tissue remodeling. Thus, testosterone signaling in macrophages could alter the paracrine function of these cells and thereby contribute to the metabolic effects of androgens in men. A metabolic phenotyping study was performed to determine whether the loss of AR signaling in hematopoietic cells results in greater fat accumulation in male mice. C57BL/6J male mice (ages 12-14 weeks) underwent bone marrow transplant from either wild-type (WT) or AR knockout (ARKO) donors (n = 11-13 per group). Mice were fed a high-fat diet (60% fat) for 16 weeks. At baseline, 8 and 16 weeks, glucose and insulin tolerance tests were performed, and body composition was analyzed with fat-water imaging by MRI. No differences in body weight were observed between mice transplanted with WT bone marrow [WT(WTbm)] or ARKO bone marrow [WT(ARKObm)] prior to initiation of the high-fat diet. After 8 weeks of high-fat feeding, WT(ARKObm) mice exhibited significantly more visceral and total fat mass than WT(WTbm) animals. Despite this, no differences between groups were observed in glucose tolerance, insulin sensitivity, or plasma concentrations of insulin, glucose, leptin, or cholesterol, although WT(ARKObm) mice had higher plasma levels of adiponectin. Resultant data indicate that AR signaling in hematopoietic cells influences body fat distribution in male mice, and the absence of hematopoietic AR plays a permissive role in visceral fat accumulation. These findings demonstrate a metabolic role for AR signaling in marrow-derived cells and suggest a novel mechanism by which androgen deficiency in men might promote increased adiposity. The relative contributions of AR signaling in macrophages and other marrow-derived cells require further investigation.

Acute testosterone deprivation reduces insulin sensitivity in men.

OBJECTIVE: In men with prostate cancer, androgen deprivation reduces insulin sensitivity; however, the relative roles played by testosterone and estradiol are unknown. To investigate the respective effects of these hormones on insulin sensitivity in men, we employed a model of experimental hypogonadism with or without hormone replacement. DESIGN: Placebo-controlled, randomized trial. PARTICIPANTS: Twenty-two healthy male volunteers, 18-55 years old. METHODS: Following screening, subjects received the gonadotrophin-releasing hormone antagonist acyline plus one of the following for 28 days: Group 1, placebo transdermal gel and placebo pills; Group 2, transdermal testosterone gel 10 g/day plus placebo pills; Group 3, transdermal testosterone gel 10 g/day plus the aromatase inhibitor anastrozole 1 mg/day to normalize testosterone while selectively reducing serum estradiol. Fasting insulin, glucose, adipokines and hormones were measured bi-weekly. RESULTS: With acyline administration, serum testosterone was reduced by >90% in all subjects in Group 1. In these men, mean fasting insulin concentrations were significantly increased compared with baseline (P = 0·02) at 28 days, despite stable body weight and no changes in fasting glucose concentrations. Decreased insulin sensitivity was also apparent in the insulin sensitivity indices homeostasis model of insulin resistance (P = 0·03) and quantitative insulin sensitivity check index (P = 0·04). In contrast, in Groups 2 and 3, testosterone concentrations remained in the physiologic range, despite significant reduction in mean estradiol in Group 3. In these groups, no significant changes in insulin sensitivity were observed. CONCLUSIONS: Acute testosterone withdrawal reduces insulin sensitivity in men independent of changes in body weight, whereas estradiol withdrawal has no effect. Testosterone appears to maintain insulin sensitivity in normal men.

Pharmacogenomics of psychiatric disorders.

Pharmacogenomics, the utilization of genetic information to predict outcome of drug treatment (therapeutic and side-effects), holds great promise for clinical medicine. The pharmacotherapy of psychiatric disorders exhibits wide variability in therapeutic response with little scientific guidance for treatment on a patient-by-patient basis. The emerging field of pharmacogenomics holds great potential for refining and optimizing psychopharmacology. Key components for future development of the pharmacogenomics of psychiatric disorders include understanding the mechanism of drug action, identification of candidate genes and their variants, and well-conducted clinical trials. In this article, data from recent studies are examined with particular emphasis on methodological requirements and direction for future research.