title: Large size cells in the visceral adipose depot predict insulin resistance in the canine model.
abstract: Adipocyte size plays a key role in the development of insulin resistance. We examined longitudinal changes in adipocyte size and distribution in visceral (VIS) and subcutaneous (SQ) fat during obesity-induced insulin resistance and after treatment with CB-1 receptor antagonist, rimonabant (RIM) in canines. We also examined whether adipocyte size and/or distribution is predictive of insulin resistance. Adipocyte morphology was assessed by direct microscopy and analysis of digital images in previously studied animals 6 weeks after high-fat diet (HFD) and 16 weeks of HFD + placebo (PL; n = 8) or HFD + RIM (1.25 mg/kg/day; n = 11). At 6 weeks, mean adipocyte diameter increased in both depots with a bimodal pattern only in VIS. Sixteen weeks of HFD+PL resulted in four normally distributed cell populations in VIS and a bimodal pattern in SQ. Multilevel mixed-effects linear regression with random-effects model of repeated measures showed that size combined with share of adipocytes >75 µm in VIS only was related to hepatic insulin resistance. VIS adipocytes >75 µm were predictive of whole body and hepatic insulin resistance. In contrast, there was no predictive power of SQ adipocytes >75 µm regarding insulin resistance. RIM prevented the formation of large cells, normalizing to pre-fat status in both depots. The appearance of hypertrophic adipocytes in VIS is a critical predictor of insulin resistance, supporting the deleterious effects of increased VIS adiposity in the pathogenesis of insulin resistance.
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, California, USA. morvarid@usc.edu
authors.forename: Morvarid
authors.initials: M
authors.lastname: Kabir
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Hsu
authors.forename: Malini
authors.initials: M
authors.lastname: Iyer
authors.forename: Orison O
authors.initials: OO
authors.lastname: Woolcott
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.forename: Karyn J
authors.initials: KJ
authors.lastname: Catalano
authors.forename: Jenny D
authors.initials: JD
authors.lastname: Chiu
authors.forename: Stella P
authors.initials: SP
authors.lastname: Kim
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Harrison
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Maya
authors.initials: M
authors.lastname: Lottati
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Richey
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D048429:Cell Size; D059305:Diet, High-Fat; D004285:Dogs; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D023421:Models, Animal; D009765:Obesity / Q000503:physiopathology; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant