Prohibitin: a prime candidate for a pleiotropic effector that mediates sex differences in obesity, insulin resistance, and metabolic dysregulation.

Adipocytes and macrophages, the two major constituents of adipose tissue, exhibit sex differences and work in synergy in adipose tissue physiology and pathophysiology, including obesity-linked insulin resistance and metabolic dysregulation. Sex steroid hormones play a major role in sex differences in adipose tissue biology. However, our knowledge of the molecules that mediate these effects in adipose tissue remains limited. Consequently, it remains unclear whether these effector molecules in different adipose and immune cell types are distinct or if there are also pleiotropic effectors. Recently, a protein named prohibitin (PHB) with cell compartment- and tissue-specific functions has been found to play a role in sex differences in adipose and immune functions. Transgenic (Tg) mouse models overexpressing PHB (PHB-Tg) and a phospho-mutant PHB (mPHB-Tg) from the fatty acid binding protein-4 (Fabp-4) gene promoter display sex-neutral obesity; however, obesity-related insulin resistance and metabolic dysregulation are male-specific. Intriguingly, with aging, the male PHB-Tg mice developed hepatic steatosis and subsequently liver tumors whereas the male mPHB-Tg mice developed lymph node tumors and splenomegaly. Unlike the male transgenic mice, the female PHB-Tg and mPHB-Tg mice remain protected from obesity-related metabolic dysregulation and tumor development. In conclusion, the sex-dimorphic metabolic and immune phenotypes of PHB-Tg and mPHB-Tg mice have revealed PHB as a pleiotropic effector of sex differences in adipose and immune functions. In this mini-review, we will discuss the pleiotropic attributes of PHB and potential mechanisms that may have contributed to the sex-dimorphic metabolic phenotypes in PHB-Tg and mPHB-Tg mice, which warrant future research. We propose that PHB is a prime candidate for a pleiotropic mediator of sex differences in adipose and immune functions in both physiology and pathophysiology, including obesity, insulin resistance, and metabolic dysregulation.