title: The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation.
abstract: In obesity, adipocytes distant from vasculature become hypoxic and dysfunctional. This hypoxic response is mediated by hypoxia-inducible factors (Hif1α, Hif2α, and Hif3α) and their obligate partner, Hif1β (Arnt). We show that mice lacking Hif1β in fat (FH1βKO) are lean, exhibit reduced adipocyte size, and are protected from age- and diet-induced glucose intolerance. There is also reduced Vegf and vascular permeability in FH1βKO fat, but diet-induced inflammation and fibrosis is unchanged. Adipocytes from FH1βKO mice have reduced glucose uptake due to decreased Glut1 and Glut4, which is mirrored in 3T3-L1 adipocytes with Hif1β knockdown. Hif1β knockdown cells also fail to respond appropriately to hypoxia with reduced cellular respiration and reduced mitochondrial gene expression. Some, but not all, of these effects are reproduced by Hif1α knockdown. Thus, Hif1β/Arnt regulates glucose uptake, mitochondrial gene expression, and vascular permeability to control adipose mass and function, providing a target for obesity therapy.
authors: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Kevin Y
authors: KY
authors: Lee
authors: Stephane
authors: S
authors: Gesta
authors: Jeremie
authors: J
authors: Boucher
authors: Xiaohui L
authors: XL
authors: Wang
authors: C Ronald
authors: CR
authors: Kahn
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D005260:Female; D005355:Fibrosis / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism
chemical_list: C497397:Arnt protein, mouse; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D005947:Glucose