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

Abstract

SUMMARY 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.

Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet

“…In addition, this VAT accumulation process can be reversed by testosterone treatment, showing that testosterone replacement might be involved in the treatment strategy for abating VAT deposition caused by testosterone deficiency under HFC diet. These results are consistent with data observed from testosterone deficiency or androgen receptor knockout (ARKO) mice, which showed that castration induced abdominal obesity of HFD mice and this phenomenon could be eliminated by treating with antibiotics [20] and androgen deficiency under HFD significantly enhanced visceral and total fat accumulation of ARKO mice [21]. However, another study discovered there was no significant difference of VAT mass between obesogenic diet-fed (OGD, including greater amounts of sugars, saturated and monounsaturated fat and less protein and polyunsaturated fat compared to the standard rat chow diet) and orchiectomised (OGD + ORX) male mice [22].…”

Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

“…Testosterone administration in female to male transsexuals alters adipose tissue distribution, with long-term administration instigating increased visceral fat and decreased subcutaneous fat deposits (6). Additionally, ATMs have been found to express the androgen receptor, potentially contributing to the metabolic effects of androgens in males (43).…”

Gender and Sex Differences in Adipose Tissue

“…Castration studies have been conflicted showing decreased weight [35], improved glucose tolerance [36], increased insulin sensitivity [37], and improved triglycerides [38] even with increased fat mass, with other studies showing that castration impairs glucose tolerance and insulin resistance [39•]. AR-KO mice also show increased adiposity [40] and improved insulin sensitivity consistent with a deleterious role for androgens in adipose tissue [41]. Consistent with this, testosterone replacement in castrated mice decreases energy expenditure, decreases adiposity, elevates triglyceride levels, and impairs metabolism.…”