p53 has been implicated in the pathogenesis of obesity and diabetes, in part, by regulating whole body energy homeostasis. Conflicting evidence from mice with global alterations in p53 expression suggests the effects of p53 on metabolism are tissue-specific. Despite the critical metabolic role of the hepatocyte, the role of hepatocyte p53 is undefined. Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and improves energy homeostasis at the cellular level. To define the role of hepatocyte p53 in metabolic regulation and the impact of VSG in this context, we performed VSG or sham (S) surgery in high fat diet-fed male hepatocyte-specific p53 knockout (KO) and wild type (WT) mice (n=9-12). Sham-operated mice were fed ad libitum (S-AL) or food restricted to match their body weight to VSG-operated mice (S-WM). Body weight, food intake, adiposity, energy expenditure, and oral glucose tolerance were measured. Hepatocyte p53 ablation increased body weight which was corrected by food restriction and VSG (final weight (g): S-AL-WT=33±1, S-WM-WT=27±1, VSG-WT=29±1, S-AL-KO=38±1, S-WM-KO=28±1, VSG-KO=28±1, P<0.05). Hepatocyte p53 ablation decreased energy expenditure which was corrected by VSG but not by food restriction (EE (kcal/kg/min x 24hr): S-AL-WT=452±19, S-WM-WT=428±13, VSG-WT=527±37, S-AL-KO=396±10, S-WM-KO=422±10, VSG-KO=533±31, P<0.05). Hepatocyte p53 ablation impaired glucose homeostasis which was improved by food restriction and to a greater extent by VSG (glucose iAUC (mg/dl x 120min): S-AL-WT=17390±2736, S-WM-WT=16191±742, VSG-WT=8769±1214, S-AL-KO=21975±1841, S-WM-KO=14764±1190, VSG-KO=8832±867, P<0.05). These data reveal hepatocyte p53 is a key regulator of body weight and glucose homeostasis, largely through regulation of energy expenditure. VSG overcomes energetic impairments induced by hepatocyte p53 ablation by improving energy expenditure and glucose metabolism.
M.M. Holter: None. D. Garibay: None. A.K. McGavigan: None. L. Nguyen: None. E. Moore: None. E. Daugherity: None. P. Cohen: None. K.M. Kelly: None. R. Weiss: None. B. Cummings: None.
Cornell University; National Cancer Institute (R21CA195002)