Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance

Abstract

Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17β-estradiol (E2) augments the excitability of the anorexigenic proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal-interaction molecule 1 mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation.

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

“…; Qiu et al . ). A group of 8‐week‐old female Sim1‐Cre:Rosa‐mEGFP mice were treated for 15 weeks with LF diet (starting weight = 17.8 ± 0.58 grams) and HF diet (starting weight = 18.6 ± 0.90 grams).…”

“…; Qiu et al . ). In our study, we used a genetically encoded reporter, mEGFP, to monitor whether exposure to a hypercaloric HF diet with elevated palm oil content induces injury to Sim1 neurons of the hypothalamus.…”

“…In male mice, exposure to HF diet impairs insulin‐dependent depolarization of POMC neurons (Qiu et al . ). Conversely, POMC neurons of female mice exposed to HF diet remain instead insulin responsive by a mechanism dependent on estrogen (Qiu et al .…”

“…Conversely, POMC neurons of female mice exposed to HF diet remain instead insulin responsive by a mechanism dependent on estrogen (Qiu et al . ). Here, we find that exposure to HF diet induces both hyperinsulinemia and hypothalamic injury to POMC neurons in male, but not female mice.…”

Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y

“…Loss of oestrogen uncouples the insulin receptor from downstream signalling in ArcN POMC neurons in obese mice (Qiu et al . ). Further work is required to determine whether a similar phenomenon occurs in NPY neurons.…”