Hepatocyte PHB1 Deficiency Causes Sex-Specific Changes in Glycemic Control and Body Composition in Mice

Abstract

Prohibitin 1 (PHB1) is a dynamic lipid raft associated protein that is located in plasma membrane and in the inner mitochondrial membrane complexed with its homolog PHB2 in a tight 1:1 stoichiometric ratio. The PHB1/2 ‘supercomplex’ has been linked to many cellular processes including proliferation, apoptosis, transcription, inflammation, signaling and metabolism. Previous studies have shown that PHB1 plays a role in modulation of insulin signaling via PIP3→AKT pathway. Moreover, a recent report showed that male and female mice with adipocyte-specific PHB1 overexpression developed obesity, while only the obese males developed glucose intolerance and fatty liver. These and other findings strongly implicate a sex-specific role for adipocyte PHB1 as a key mediator in glucose metabolism, although mechanisms remain obscure and it is further unclear whether this sex-specific effect is exclusive to adipocytes. Here, we examined the role of hepatocyte PHB1 in regulating glucose metabolism with diet induced obesity. Mice with hepatocyte specific PHB1 deficiency (hPHB1def) were generated by crossing homozygous PHB1 floxxed mice (PHB1fl/fl) with Albumin-Cre (Alb-Cre+/+) mice. Male and female mice were randomly assigned to normal chow diet (CTL diet) or high fat high sucrose diet (HFHS) for 20 weeks. Female hPHB1def mice were found to have a lower body weight compared with WT in both diet groups. However, male hPHB1def mice had increased body fat (gonadal fat) and decreased lean mass compared with WT males, even on CTL diet. At the same time, female hPHB1def mice had reduced brown fat mass compared to WT females on HFHS diet, but not CTL diet. Male hPHB1def mice on CTL diet are insulin resistant compared with WT males; however, female hPHB1def mice have improved glucose tolerance compared with WT females, due in part to decreased gluconeogenic capacity in female hPHB1def mice. Surprisingly, circulating PHB1 levels decreased with diet induced obesity in both males and females, with hPHB1def having lower hepatocyte-PHB1 content compared with WT, regardless of diet. Collectively, these findings reveal that hepatocyte-PHB1 is an important regulator of systemic glucose metabolism and adiposity in a sexually dimorphic manner. American Heart Association (AHA) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.