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

Jeremy C Sprouse,Chethan Sampath,Pandu R Gangula

doi:10.3390/antiox9070582

Jeremy C Sprouse, Chethan Sampath + Show 1 more

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https://doi.org/10.3390/antiox9070582

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Abstract

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 (E2) or progesterone (P4) 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 E2 or P4 for 12 weeks. The effects of E2 and P4 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 E2, but not P4, 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 E2 is beneficial in normalizing metabolic homeostasis and gastric emptying in obese, diabetic OVX mice consuming a fat-rich diet.

Highlights

Gastroparesis (Gp) is a chronic disease that presents with various clinical symptoms including early satiety, nausea, vomiting, and mild to severe abdominal pain
Our results show that the nNOSα expression level in Sham+high-fat diet (HFD) and OVX+ND was significantly (p < 0.05) lower than that of control mice (Sham+ND) (Figure 3A)
While E2 and P4 supplementation was beneficial in normalizing metabolic factors commonly observed in obesity-induced diabetes, only E2 contributed to attenuating delayed gastric emptying (GE) by restoring neuronal nitric oxide synthase (nNOS)-mediated nitrergic relaxation in OVX+HFD mice

Summary

Introduction

Gastroparesis (Gp) is a chronic disease that presents with various clinical symptoms including early satiety, nausea, vomiting, and mild to severe abdominal pain. The most common etiologies of Gp include idiopathic, post-surgical/iatrogenic, and a severe complication of uncontrolled diabetes mellitus (DM) [4]. Numerous lines of evidence suggest the loss of enteric neuronal nitric oxide synthase (nNOS). Nitric oxide (NO)-mediated relaxation of gastric smooth muscle as the primary culprits of Gp in diabetic patients [5,6,7,8]. Approximately 20% of diabetic patients exhibit accelerated GE while 30–40% show delayed GE. Growing evidence suggests rapid or accelerated GE to be indicative of early type 2 diabetes mellitus (T2DM) induction and Antioxidants 2020, 9, 582; doi:10.3390/antiox9070582 www.mdpi.com/journal/antioxidants

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