A recent article published in Advances in Experimental Medicine and Biology reported that obesity and metabolic syndrome display disparate prevalence and regulation between males and females. It was stated that females with regular menstrual cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). The article explained that E2 exerts its actions through multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). Further, it stated that the roles of GPER in metabolic homeostasis are emerging, but are complex and still obscure. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. On the contrary, pharmacologic stimulation of GPER, in vivo, limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.