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 17β-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 (nNOSα), 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, nNOSα, 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.