The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms

Abstract

The aim of this study was to validate the role of estrogen receptor a (ERa) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ERa-selective agonist propyl pyrazole triol (PPT) or 17b-estradiol (E 2 ) in ob/ob mice. Female ob/ob mice were treated with PPT, E 2 or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined from isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPTand E 2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E 2 treatment. However, PPT and E 2 had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E 2 treatment. In the liver, treatment with E 2 and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPTexerts anti-diabetic effects, and these effects are mediated via ERa.

Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract

“…Whether the improvements in liver lipid accumulation may have caused the favorable effects on hepatic insulin sensitivity is unclear, because there is ongoing debate whether or not there is mechanistic linkage between hepatic steatosis and hepatic insulin resistance (17). Whether it is ER␣ or ER␤ likely mediating the actions of BZA or the TSEC (CE ϩ BZA) on fatty liver is also difficult to conjecture, because in some reports elevations in liver triglyceride content with high-fat diet are not improved by an ER␣-specific agonist but instead by an ER␤-specific agonist (34,57), yet the hepatic steatosis found in male aromatase-null mice is effectively attenuated by an ER␣-specific agonist (5). Interestingly, ER␣ in hepatocytes per se may have negligible influence on either hepatic fat or hepatic insulin sensitivity because, although global ER␣ Ϫ/Ϫ mice have defective insulin suppression of endogenous glucose production, which is primarily derived from the liver (3), hepatocyte-specific ER␣ deletion does not alter liver lipid content or glucose or insulin sensitivity (36).…”

Resveratrol in cardiovascular disease: what is known from current research?

“…In addition, estrogen receptor (ER) activation, which attenuates insulin resistance, impaired glucose tolerance and adipocyte hyperplasia in both male and female rodents, mediates resveratrol-stimulated glucose uptake in skeletal muscle [82][83][84][85][86]. The increased glucose uptake/ metabolism normalizes serum glucose and the secondary hypertension or other histopathological changes in diabetes.…”

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

“…Nonalcoholic fatty liver disease (NAFLD), primarily manifested by excessive fat accumulation in hepatocytes, has become the most common chronic liver disease worldwide (Demir et al, 2015). A number of studies consistently showed that estrogen displays a fat-lowering effect by presumably inhibiting lipogenesis and promoting lipolysis in the liver in a variety of animal models, including genetically manipulated mice, ovariectomized rodents, spontaneous obese mice, and rodents with diet-induced metabolic syndrome (Jones et al, 2000;Hewitt et al, 2004;Gao et al, 2006;Bryzgalova et al, 2008;Lundholm et al, 2008;Pedram et al, 2013;Zhang et al, 2013a;Han et al, 2014). However, the mechanisms behind those observations, especially how the fat-lowering action of estrogen is modulated in the liver, remain elusive.…”