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Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice
Author(s) -
Holter Marlena M.,
Garibay Darline,
Lee Seon A.,
Saikia Mridusmita,
McGavigan Anne K.,
Ngyuen Lily,
Moore Elizabeth S.,
Daugherity Erin,
Cohen Paul,
Kelly Kathleen,
Weiss Robert S.,
Cummings Bethany P.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902214r
Subject(s) - hepatocyte , medicine , endocrinology , biology , knockout mouse , energy homeostasis , glucose homeostasis , sleeve gastrectomy , hepatocyte growth factor , diabetes mellitus , weight loss , obesity , insulin resistance , receptor , biochemistry , in vitro , gastric bypass
P53 has been implicated in the pathogenesis of obesity and diabetes; however, the mechanisms and tissue sites of action are incompletely defined. Therefore, we investigated the role of hepatocyte p53 in metabolic homeostasis using a hepatocyte‐specific p53 knockout mouse model. To gain further mechanistic insight, we studied mice under two complementary conditions of restricted weight gain: vertical sleeve gastrectomy (VSG) or food restriction. VSG or sham surgery was performed in high‐fat diet‐fed male hepatocyte‐specific p53 wild‐type and knockout littermates. Sham‐operated mice were fed ad libitum or food restricted to match their body weight to VSG‐operated mice. Hepatocyte‐specific p53 ablation in sham‐operated ad libitum ‐fed mice impaired glucose homeostasis, increased body weight, and decreased energy expenditure without changing food intake. The metabolic deficits induced by hepatocyte‐specific p53 ablation were corrected, in part by food restriction, and completely by VSG. Unlike food restriction, VSG corrected the effect of hepatocyte p53 ablation to lower energy expenditure, resulting in a greater improvement in glucose homeostasis compared with food restricted mice. These data reveal an important new role for hepatocyte p53 in the regulation of energy expenditure and body weight and suggest that VSG can improve alterations in energetics associated with p53 dysregulation.