LAUSR

&NA; Diabetic gastroparesis (GP) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of Nrf2 (Nuclear factor (erythroid‐derived 2)‐like 2) led to reduced nNOS&agr; mediated gastric motility and DGE. The molecular signaling of cinnamaldehyde (CNM) mediated Nrf2 activation and its mechanistic role on DGE were further investigated in obese/T2D female mice. Adult female homozygous Nfe2l2−/− (C57BL/6J) and their wild‐type (WT) littermates (Nfe2l2+/+) mice were fed with high fat diet (HFD; Obese/T2D model), or normal diet (ND) with or without CNM (50 mg/kg b.w; i.p). Supplementation of CNM attenuated (p < 0.05) DGE in WT female but not in Nrf2 KO Obese/T2D mice. CNM (1) normalized serum estradiol‐17&bgr; levels, (2) induced gastric Nrf2 and phase II antioxidant enzymes through extracellular signal‐regulated kinase, (ERK)/c‐Jun N‐terminal kinase (JNK)/p38 mitogen‐activated protein kinase (MAPK), (3) reduced glucose synthase kinase 3 beta (GSK3&bgr;) and aryl hydrocarbon receptor (AhR) and this was associated with (4) increased estrogen receptor expression, BH4 (Cofactor of nNOS) biosynthesis enzyme GCH‐1 and nNOS&agr; dimerization in WT Obese/T2 diabetic female mice. In addition, CNM restored impaired nitrergic relaxation in hyperglycemic conditions. These findings emphasize the importance of Nrf2 in maintaining nNOS&agr; mediated GE and may have a translational relevance to treat obese/diabetic gastroparesis in women.