Estradiol Protects Neuropeptide Y/Agouti-Related Peptide Neurons against Insulin Resistance in Females

When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17 beta-estradiol (E-2) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E-2 would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Therefore, we did whole-cell recordings and single cell quantitative polymerase chain reaction in arcuate NPYGFP neurons from both female and male mice to test the efficacy of insulin with DIO. The resting membrane potential and input resistance of NPY/AgRP neurons were significantly increased in DIO versus control-diet fed males. Most notably, the efficacy of insulin to activate K-ATP channels in NPY/AgRP neurons was significantly attenuated, although the K-ATP channel opener diazoxide was fully effective in NPY/AgRP neurons from DIO males, indicating that the K-ATP channels were expressed and functional. In contrast, insulin was fully efficacious to activate K-ATP channels in DIO females, and the response was reversed by the K-ATP channel blocker tolbutamide. However, the ability of insulin to activate K-ATP channels was abrogated with ovariectomy but fully restored with E-2 replacement. Insulin resistance in obese males was likely mediated by an increase in suppressor of cytokine signaling-3 (SOCS-3), protein tyrosine phosphatase B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity, since the expression of all 3 mRNAs were upregulated in the obese males but not in females. As proof of principle, pre-incubation of hypothalamic slices from DIO males with the PTP1B/TCPTP inhibitor CX08005 completely rescued the effects of insulin. Therefore, E-2 protects NPY/AgRP neurons in females against insulin resistance through, at least in part, attenuating phosphatase activity. The neuroprotective effects of E-2 may explain sex differences in the expression of metabolic syndrome that disappears with the loss of E-2 in aging.