Estrogen Replacement Reverses Olanzapine-Induced Weight Gain and Hepatic Insulin Resistance in Ovariectomized Diabetic Rats

Abstract

Objectives: We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham). Methods: OVX diabetic rats were subcutaneously injected with estrogen replacement (17β-estradiol, 30 µg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets. Results: OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine-monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats. Conclusions: OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period.

Lack of Ovarian Secretions Reverts the Anabolic Action of Olanzapine in Female Rats

“…However, the fact that lipogenic gene expression levels were lower in OVX than in sham rats argues against the validity of this explanation, at least with regard to the whole set of metabolic alterations of OLZ. Notably, the effect of OLZ in OVX rats has been examined previously, but contrary to our findings, OLZ treatment was reported to induce hyperphagia and weight gain in OVX rats ( Park et al, 2010 ). However, the previous study was carried out on a diabetic background (90% pancreatectomy) in rats fed a high-fat diet, whereas here we used nondiabetic Sprague-Dawley rats fed standard chow.…”

Dose–response association between physical activity and non-alcoholic fatty liver disease: a case–control study in a Chinese population

“…The gender difference observed in this study may be explained by sex hormones. Mechanism research have found that sex hormones can upregulate insulin receptor expression and increase receptor phosphorylation protein kinase levels, thereby enhancing insulin signalling and preventing NAFLD 30 31. Furthermore, some sex hormones and their derivatives are strong endogenous antioxidants, which can inhibit the production of lipid peroxides in the liver and reduce its concentration, and play a protective role in the liver 32.…”

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

“…Preclinical models have demonstrated an effect of estrogen on AP-mediated accumulation of adipose tissue, changes in feeding and glucose homeostasis, in ovariectomized rats treated with olanzapine [35,46,112,113]. For example, the AP sulpiride, like olanzapine, has been observed to cause weight gain in female, but not male rats [114].…”