Estradiol Protects Hypothalamic Neurons Against Insulin Resistance

Obesity is a worldwide health problem that leads to a number of serious diseases of which metabolic syndrome associated with insulin and leptin resistance is of the most serious. Males exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex difference diminishes sharply in hypoestrogenic states as during menopause. Importantly the gonadal hormone 17β-estradiol (E₂) has been found to protect obese females against insulin resistance during the reproductive years by actions on hypothalamic anorexigenic and orexigenic neurons. Thus E₂ helps maintain the insulin-mediated excitation of canonical transient receptor potential 5 (TRPC 5) channels in proopiomelanocortin (POMC) neurons and the hyperpolarizing effects of insulin via activation of K_ATP channels in neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons in obese females, but not in obese males. These studies, therefore, have identified a sex difference in the hypothalamic development of insulin resistance with obesity, which will be the topic of this review.