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.

Endotoxin and polycyclic aromatic hydrocarbons in ambient fine particulate matter from Fresno, California initiate human monocyte inflammatory responses mediated by reactive oxygen species.

In urban areas, a correlation between exposure to particulate matter (PM) from air pollution and increased cardiovascular morbidity and mortality has been observed. Components of PM include bacterial contaminants, transition metals, salts, polycyclic aromatic hydrocarbons (PAH), and carbonaceous material, which could interact with various cell types to produce systemic responses when inhaled. We examined the effects of PM collected from Fresno, California on activation of human monocytes and their interaction with vascular endothelium, a key event in atherogenesis. PM exposure increased cytokine expression and secretion from monocytes and enhanced monocyte adhesion to human aortic endothelial cells, both of which were attenuated by neutralizing endotoxin. PM also increased monocyte CYP1a1 expression, and inhibition of the aryl hydrocarbon receptor reduced the CYP1a1 and inflammatory responses. PM-treated monocytes accumulated intracellular reactive oxygen species (ROS), and antioxidants attenuated inflammatory and xenobiotic responses. Finally, supernatants from PM-treated pulmonary microvascular endothelial cells induced monocyte inflammatory responses that were not a consequence of endotoxin transfer. These results suggest that certain components of urban PM, namely endotoxin and PAH, activate circulating monocytes directly or indirectly by first stimulating other cells such as pulmonary endothelial cells, providing several mechanisms by which PM inhalation could induce pulmonary and/or systemic inflammation.