title: Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis.
abstract: 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.
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Rubinow
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: den Hartigh
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morton
authors.affiliation: Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: F W
authors.initials: FW
authors.lastname: Buaas
authors.affiliation: Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lamont
authors.affiliation: Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gray
authors.affiliation: Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Braun
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Page
mesh_terms: D017667:Adipocytes / Q000502:physiology; D052242:Adiponectin / Q000097:blood; D050154:Adiposity; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D050155:Lipogenesis; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication; D011897:Random Allocation; D011944:Receptors, Androgen / Q000172:deficiency*
chemical_list: D052242:Adiponectin; D011944:Receptors, Androgen; D005947:Glucose
keywords: androgen receptor; androgens; immunology; metabolic syndrome; obesity; testosterone