Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes

Abstract

The failure of pancreatic β cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from β cell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against β cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβ in a rat β cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα -/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα -/-mice were predisposed to islet lipid accumulation and β cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited β cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent β cell failure in T2D.

Selective estrogen receptor modulation in pancreatic β-cells and the prevention of type 2 diabetes

“…[1][2][3] In a recent study, we reported that 17β-estradiol (E2) protects against T2D in male Zucker Diabetic Fatty (ZDF) rats and mice fed a highfat diet by suppressing islet lipogenesis and toxic lipid accumulation, thus preventing lipotoxic β-cell failure. 4 We found that islets from ZDF rats displayed an imbalance between lipid synthesis and utilization. This was characterized by increased islet lipogenesis unmatched by islet lipid oxidation and lipolysis, leading to an increase in islet free fatty acids (FFAs) and mono-, di-and triglycerides (MAG, DAG, TG) accumulation.…”

“…1B), demonstrating that RLX acts as an ER agonist in β-cells with regard to preventing TG accumulation. Since we observed that estrogens similarly suppressed lipogenesis in INS-1 cell, rodent and human islets, 4 we anticipate that RLX would also suppress TG accumulation in human islets. Thus, in β-cells, RLX behaves as an ER antagonist with regard to nuclear ERE-dependent actions and as an ER agonist with respect to extranuclear anti-lipogenic actions.…”

“…Previously, we reported that ligand-activated ERs protect islet survival and enhance glucose-stimulated insulin biosynthesis via an extranuclear signaling in β-cells is not necessarily deleterious to β-cell protection since our results discussed above suggest that E2 protects against β-cell lipotoxicity via extranuclear ERs. 4 Thus, to address this issue, we studied the effect of RLX on the prevention of TG accumulation in INS-1 cells. Consistent with our published findings, 4 when cultured under lipogenic conditions (16 mM glucose w/o FFA), INS-1 cells accumulated TG and treatment with E2 reduced TG accumulation (Fig.…”

“…4 Thus, to address this issue, we studied the effect of RLX on the prevention of TG accumulation in INS-1 cells. Consistent with our published findings, 4 when cultured under lipogenic conditions (16 mM glucose w/o FFA), INS-1 cells accumulated TG and treatment with E2 reduced TG accumulation (Fig. 1B).…”

Estrogen and n-3 polyunsaturated fatty acid supplementation have a synergistic hypotriglyceridemic effect in ovariectomized rats

“…A previous study reported that the binding of E 2 to the ER induces phosphorylation of signal transducer and activator of transcription 3 (STAT3), which reduces FAS expression in liver (Gao et al 2006;Tiano et al 2011). STAT3 has been shown to decrease TG synthesis, which is independent of the fatty acid synthesis pathway through SREBP1 (Kinoshita et al 2008).…”