Androgens Activate Myeloid Cells during High-Fat Diet Exposure Promoting Sex Differences in Metabolic Disease

Men have a higher risk of metabolic and cardiovascular disease than pre-menopausal women, but the mechanisms of these differences are elusive. Chronic myeloid inflammation during obesity contributes to metabolic disease risk and is significantly more robust in males. Given the paucity of data on male sex hormones contributing to macrophage responses in obesity, our objective was to understand the role of androgens in promoting obesity-induced myeloid inflammation. Male and female C57Bl/6J mice were fed a 60% high fat diet for 24 weeks. Glucose tolerance and insulin sensitivity were measured. Monocyte transfer experiments assessed sex differences in bone marrow myeloid responses to obesity independent of host sex. Gonadectomy, mice deficient of androgen receptor signaling (ARtfm) and monocyte specific androgen receptor (AR) knockout mice (LysMAR-/y) were used to model androgen deficiency. Compared to males, females had dampened inflammatory responses with reduced CD11c+ ATMs and cytokines, even with increased adiposity. RNASeq demonstrated sex differences in gene pathways of both metabolic and inflammatory activation in ATMs. Male monocytes transferred into females remained primed for pro-inflammatory response and induced an increase in adiposity. Castrated males exposed to high fat diet had impaired glucose tolerance and increased insulin sensitivity with increased adiposity and lower numbers of CD11c+ ATMs. These same findings were seen in ARtfm mice. Testosterone enhanced palmitate-stimulated myeloid colony production, and this response was dampened in castrated, ARtfm, and LysMAR-/y mice. These studies demonstrate that androgens play a critical role in enhanced metabolic dysfunction and enhanced myeloid inflammation in response to obesogenic cues. Androgen driven myeloid inflammation leads to metabolic dysfunction in a cell-autonomous manner driving sex-differences in obesity induced meta-inflammation. Disclosure C.A. Griffin: None. S. Abrishami: None. M. Varghese: None. K. Singer: None.