title: Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance, and insulin resistance.
abstract: Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.
authors: Obesity Research Center, University of Tennessee (UT), Knoxville, Tennessee, USA.
authors: Nishan S
authors: NS
authors: Kalupahana
authors: Florence
authors: F
authors: Massiera
authors: Annie
authors: A
authors: Quignard-Boulange
authors: Gérard
authors: G
authors: Ailhaud
authors: Brynn H
authors: BH
authors: Voy
authors: David H
authors: DH
authors: Wasserman
authors: Naima
authors: N
authors: Moustaid-Moussa
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D018149:Glucose Intolerance / Q000378:metabolism*; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016328:NF-kappa B; D000808:Angiotensinogen; D016753:Interleukin-10; D002216:Captopril; D005993:Glycerolphosphate Dehydrogenase