Multiple roles of the androgen receptor in insulin resistance and metabolic syndrome: Tissue-specific perspectives

Increased prevalence of insulin resistance is associated with an epidemic of type 2 diabetes mellitus, representing a steadily increasing health risk worldwide. Insulin resistance can be defined as a diminished cell response to the action of insulin and develops as a multistep process caused by excess nutrient intake and chronic metabolic inflammation that may lead to metabolic syndrome. In men, testosterone deficiency contributes to the development of metabolic syndrome. By employing androgen receptor (AR) knockout mouse models, we have previously shown the pivotal role of AR in maintaining systemic and hepatic insulin sensitivity in males. In this thesis, we dissect out the role of AR in order to explore the complex inter-organ coordination of AR signaling among various insulin sensitive tissues.;The brain exhibits sexual dimorphic insulin sensitivity determined by gonadal hormones. However, mechanisms responsible for androgen/AR effects on insulin sensitivity in brain have yet to be defined. While loss of hypothalamic insulin signaling is sufficient to promote insulin resistance and obesity in mice, we show the importance of AR in insulin signaling in male brain by ablating AR in neurons, or selectively, in hypothalamic neuron populations. Loss of brain AR results in increased protein-tyrosine phosphatase 1B (PTP1B) expression which leads to hypothalamic insulin resistance, hepatic insulin resistance, and visceral obesity in male mice. Leptin resistance, associated with obesity and insulin resistance, is also affected by induction of PTP1B with AR deficiency. Mechanistic dissection demonstrates that AR suppresses hypothalamic NF-kappaB-mediated induction of PTP1B and suppressor of cytokine signaling 3 (SOCS3) in mice fed a high-fat diet. Results suggest that loss of, or decreased function of AR in the hypothalamus, makes males more susceptible to effects of high-fat food consumption and results in accelerated progression of insulin resistance and obesity.;The ability of pancreatic beta-cells to secrete insulin in response to glucose is a sine qua non for maintaining glucose homeostasis. Dysfunction of the beta-cell accompanies the onset of diabetes mellitus and involves defects in insulin secretion and compensatory changes of beta-cell mass, due to an unbalanced state between beta-cell proliferation and apoptosis. By examining the impact of AR deletion on pancreatic beta-cells, we observe normal islet morphology and retention of adequate insulin secreting function with relatively less apoptotic signals. Our results indicate the potential role of AR in islet cell apoptosis and survival, which could provide beneficial effects on islet cell transplantation.;Adipose tissue is an endocrine organ, and is capable of secreting a variety of cytokines that regulate metabolic processes. By examining adipose tissue specific AR knockout mice, we find that loss of AR signaling plays a direct regulatory role in leptin expression via elevated intra-adipose estrogens. While showing no leptin resistance or visceral obesity, markedly reduced circulating triglycerides and cholesterol levels suggest a beneficial effect of hyperleptinemia that is independent of fat deposition.;Overall, our studies reveal differential, tissue-specific roles of AR in insulin resistance and metabolic syndrome. A number of epidemiological and interventional studies indicate that testosterone supplementation is helpful in preventing or attenuating the metabolic syndrome in hypogonadal men. Our studies provide a potential tissue-specific approach for androgen receptor modulation rather than whole body testosterone treatment in aging men or patients receiving androgen ablation therapy. Treatment through selective, tissue-specific AR modulation would avoid the known negative complications of testosterone with regards to prostate cancer.