title: Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats.
abstract: This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPARγ expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPARγ remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.
authors.affiliation: Division of Endocrinology, Department of Medicine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Michaël
authors.initials: M
authors.lastname: Shum
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinard
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Guimond
authors.forename: Sébastien M
authors.initials: SM
authors.lastname: Labbé
authors.forename: Claude
authors.initials: C
authors.lastname: Roberge
authors.forename: Jean-Patrice
authors.initials: JP
authors.lastname: Baillargeon
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Langlois
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
authors.forename: Charlotta
authors.initials: C
authors.lastname: Wallinder
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: André C
authors.initials: AC
authors.lastname: Carpentier
authors.forename: Nicole
authors.initials: N
authors.lastname: Gallo-Payet
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D005632:Fructose / Q000009:adverse effects; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D034741:RNA, Small Interfering; D044139:Receptor, Angiotensin, Type 2; D005632:Fructose