Selective ERα Attenuates Hypothalamic ER Stress and Regulates Energy Homeostasis in Ovariectomized Mice Fed With High-Fat Diet

Obesity is often caused by an imbalance between energy intake and expenditure, with the hypothalamus essential in maintaining this balance, and any impairment in its function can contribute to obesity. Estrogen receptor alpha (ERα) plays a significant role in controlling body weight by influencing energy intake. However, the specific processes through which ERα exerts its anorexigenic effects remain insufficiently understood. This study investigates the impact of targeted ERα activation on endoplasmic reticulum (ER) stress in the hypothalamus of mice suffering from obesity induced by a high-fat diet (HFD). The animals were divided into two primary groups: ovarian-intact (Sham) and ovariectomized (OVX) mice, both of which were fed an HFD for 12 weeks. At the end, the OVX mice were further divided into two groups: OVX-HFD and OVX-HFD-PPT (ERα agonist). The findings showed that ovariectomy led to weight gain and increased energy intake in HFD mice, which were accompanied by increased levels of orexigenic neuropeptide Y (NPY) and ER-stress and decreased levels of anorexigenic α-melanocyte-stimulating hormone (α-MSH) and leptin signaling in the hypothalamus. In contrast, treatment with PPT significantly attenuated these effects, leading to reduced body weight and energy intake. Mechanistically, PPT treatment decreased the level of NPY and increased α-MSH in the hypothalamus. Furthermore, PPT treatment reduced hypothalamic ER stress markers, such as GRP78 and ATF6, and enhanced leptin signaling by increasing the phosphorylation of JAK2 and STAT3. We conclude that ERα activation may reduce hypothalamic ER stress and improve leptin sensitivity, thereby regulating energy intake and body weight.