Supplementation of 17β-Estradiol Normalizes Rapid Gastric Emptying by Restoring Impaired Nrf2 and nNOS Function in Obesity-Induced Diabetic Ovariectomized Mice

Gastroparesis (Gp) is a multifactorial condition commonly observed in females and is characterized by delayed or rapid gastric emptying (GE). The role of ovarian hormones on GE in the pathogenesis of obesity induced type 2 diabetes mellitus (T2DM) is completely unknown. The aims of our study are to investigate whether supplementation of 17 beta-estradiol (E-2) or progesterone (P-4) restores impaired nuclear factor erythroid 2-related factor 2 (Nrf2, an oxidative stress-responsive transcription factor) and nitric oxide (NO)-mediated gastric motility in ovariectomized (OVX) mice consuming a high-fat diet (HFD, a model of T2DM). Groups of OVX+HFD mice were administered daily subcutaneous doses of either E(2)or P(4)for 12 weeks. The effects of E(2)and P(4)on body weight, metabolic homeostasis, solid GE, gastric antrum NO-mediated relaxation, total nitrite levels, neuronal nitric oxide synthase (nNOS alpha), and its cofactor expression levels were assessed in OVX+HFD mice. HFD exacerbated hyperglycemia and insulinemia while accelerating GE (p< 0.05) in OVX mice. Exogenous E-2, but not P-4, attenuated rapid gastric emptying and restored gastric nitrergic relaxation, total nitrite levels, nNOS alpha, and cofactor expression via normalizing Nrf2-Phase II enzymes, inflammatory response, and mitogen-activated protein kinase (MAPK) protein expression in OVX+HFD mice. We conclude that E(2)is beneficial in normalizing metabolic homeostasis and gastric emptying in obese, diabetic OVX mice consuming a fat-rich diet.