Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis.
Obesity results from an excessive expansion of white adipose tissue (WAT) from hypertrophy of preexisting adipocytes and enhancement of precursor differentiation into mature adipocytes. We report that Nck2-deficient mice display progressive increased adiposity associated with adipocyte hypertrophy. A negative relationship between the expression of Nck2 and WAT expansion was recapitulated in humans such that reduced Nck2 protein and mRNA levels in human visceral WAT significantly correlate with the degree of obesity. Accordingly, Nck2 deficiency promotes an adipogenic program that not only enhances adipocyte differentiation and lipid droplet formation but also results in dysfunctional elevated lipogenesis and lipolysis activities in mouse WAT as well as in stromal vascular fraction and 3T3-L1 preadipocytes. We provide strong evidence to support that through a mechanism involving primed PERK activation and signaling, Nck2 deficiency in adipocyte precursors is associated with enhanced adipogenesis in vitro and adiposity in vivo. Finally, in agreement with elevated circulating lipids, Nck2-deficient mice develop glucose intolerance, insulin resistance, and hepatic steatosis. Taken together, these findings reveal that Nck2 is a novel regulator of adiposity and suggest that Nck2 is important in limiting WAT expansion and dysfunction in mice and humans.
Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
Julie
J
Dusseault
Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
Bing
B
Li
Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
Nida
N
Haider
Institut de Recherches Cliniques de Montréal (Université de Montréal), Montreal, Quebec, Canada.
Marie-Anne
MA
Goyette
Institut de Recherches Cliniques de Montréal (Université de Montréal), Montreal, Quebec, Canada.
Jean-François
JF
Côté
Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, Quebec, Canada louise.larose@mcgill.ca.
Louise
L
Larose
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D050154:Adiposity / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; C485544:NCK2 protein, human; C117758:Nck2 protein, mouse; D015513:Oncogene Proteins