Neuronal Androgen Receptor Regulates Insulin Sensitivity via Suppression of Hypothalamic NF-κB–Mediated PTP1B Expression

Abstract

Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)–mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.

Androgen Receptor (AR) Physiological Roles in Male and Female Reproductive Systems: Lessons Learned from AR-Knockout Mice Lacking AR in Selective Cells1

“…Both PMC-ARKO and SM-ARKO mice exhibited normal testicular descent [59,65], suggesting that the AR ablation in gubernacular fibroblasts and smooth muscle cells in these models might not be critical for normal testicular descent. Various neuronal ARKO mice [85][86][87] also displayed normal testicular descent, although it is not certain whether the AR in GFN was knocked out in these mice.…”

The LIM Domain Only 4 Protein Is a Metabolic Responsive Inhibitor of Protein Tyrosine Phosphatase 1B That Controls Hypothalamic Leptin Signaling

“…HFD increases hypothalamic PTP1B and induces leptin resistance through leptindependent and -independent mechanisms (White et al, 2009). A leptin-independent mechanism involves HFD-induced inflammation and activation of nuclear factor-B signaling (Cai et al, 2005;Zabolotny et al, 2008), which then upregulates PTP1B (Yu et al, 2013). Elevated hypothalamic expression of SOCS3 and PTP1B, molecules that terminate leptin signaling, account for impaired central leptin signaling after a chronic HFD (Münzberg et al, 2004;White et al, 2009).…”

The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

“…We first examined whether insulin is capable of increasing mTORC1 activity in a mouse hypothalamic neuroblastoma GT1-7 cell line, which expresses the endogenous IR (23). The dose of insulin (100nM) was selected based on previous studies in cells (24,25).…”