212-OR: Testosterone Deficiency Increases Hypothalamic Gliosis and Metabolic Risk

Abstract

Obesity is associated with metabolic syndrome and gliosis, the activation of microglia (brain macrophages) and astrocytes, in the mediobasal hypothalamus (MBH) of humans and rodents. Similarly, hypogonadism in males is associated with increased susceptibility to weight gain, metabolic syndrome and MBH gliosis. Interventions that reduce glial activation in rodents result in protection from diet-induced obesity. Thus, we hypothesize that the combination of low testosterone and western diet causes gliosis, which in turn increases obesity susceptibility. To test this hypothesis in a rodent model, we combined gonadectomy (GDX) or sham surgery with high-fat diet (HFD) feeding in adult male mice. GDX and HFD feeding synergistically induced a striking activation of MBH astrocytes along with increased numbers of MBH microglia. This gliosis response was reversed to sham levels by testosterone replacement. After only 4 weeks of HFD feeding, differences in adiposity between GDX and sham groups were minimal with only a mild worsening of glucose tolerance. Thus, testosterone deficiency combined with HFD exposure elicits gliosis prior to substantial weight gain, suggesting a direct impact on glial cell function. To characterize the transcriptional response to testosterone deprivation and HFD exposure, we have developed mouse strains with GFP-tagged ribosomes (L10A) in astrocytes and microglia to allow purification of glial cell-specific mRNA from whole hypothalamic tissue samples (tagged ribosome affinity purification (TRAP)). In preliminary analyses, we have confirmed >10-fold enrichment of cell-specific mRNAs with de-enrichment of neuronal transcripts. These studies help reveal novel mechanisms by which hypogonadism increases the predisposition to metabolic disease. Disclosure M.D. Dorfman: None. J. Frey: None. K.M. Ness: None. A. Niraula: None. J.E. Kanter: None. K. Bornfeldt: None. K. Rubinow: None. E. Schur: None. J. Thaler: None. Funding American Heart Association (16SDG27010018); Diabetes Research Center (P30DK017047); Novo Nordisk (A116079); National Institutes of Health (R01DK119754)