Role of angiotensin type 2 receptor in improving lipid metabolism and preventing adiposity
Recent studies on mice with null mutation of the angiotensin type 2 receptor (AT2R) gene have implicated the involvement of AT2R in regulating adipocyte size and obesity, a major risk factor for metabolic syndrome. However, the outcome from these studies remains inconclusive. Therefore, current study was designed to test whether pharmacological activation of AT2R regulates adiposity and lipid metabolism. Male mice (5-weeks old) were pre-treated with vehicle or AT2R agonist (C21, 0.3 mg/kg, i.p., daily, for 4 days) and fed normal diet (ND). Then these animals were subdivided into ND and high-fat diet (HFD) regimen and concomitantly treated with vehicle or C21 through day 14. Vehicle-treated HFD-fed mice demonstrated an increase in epididymal white adipose tissue (eWAT) weight and adipocyte size, which were associated with increased eWAT expression of the lipogenic regulators, fatty acid binding protein and fatty acid synthase, decreased expression of adipose triglyceride lipase and increased expression of hormone-sensitive lipase. Interestingly, C21 pre-treatment altered HFD-induced changes in lipogenic and lipolytic regulators. C21 pre-treatment prevented decrease in expression of uncoupler protein-1 in brown adipose in HFD-fed mice, which was associated with increased core temperature. In addition, C21 pre-treatment ameliorated plasma-free fatty acids, triglycerides, insulin and tumor necrosis factor-α in HFD-fed mice. Ex-vivo study in isolated primary epididymal adipocytes revealed that C21 inhibits long chain fatty acid transporter, via a nitric oxide synthase/guanylate cyclase/protein kinase G-dependent pathway. Collectively, we propose pharmacological activation of AT2R regulates fatty acid metabolism and thermogenesis and prevents HFD-induced adiposity in mice.
KeywordsAdipocyte AT2R Fatty acid transporter (FATP) Lipid metabolism Adiposity
SN and SP designed and performed the study and acquired, analyzed and interpreted data; SN, SP, SM and TH drafted the article and revised critically for important intellectual content; SN, SP, SM and TH approved the final version of the manuscript.
This work was supported by the National Institutes of Health grant R0I DK-61578 to TH and institutional funds.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 12.Kim JK, Gimeno RE, Higashimori T, Kim H-J, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu Z-X, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI (2004) Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest 113:756–763CrossRefGoogle Scholar
- 18.Jones ES, Black MJ, Widdop RE (2012) Influence of angiotensin II subtype 2 receptor (AT(2)R) antagonist, PD123319, on cardiovascular remodelling of aged spontaneously hypertensive rats during chronic angiotensin II subtype 1 receptor (AT(1)R) blockade. Int J Hypertens 2012:543062CrossRefGoogle Scholar
- 23.Namsolleck P, Boato F, Schwengel K, Paulis L, Matho KS, Geurts N, Thone-Reineke C, Lucht K, Seidel K, Hallberg A, Dahlof B, Unger T, Hendrix S, Steckelings UM (2013) AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression. Neurobiol Dis 51:177–191CrossRefGoogle Scholar
- 30.Osuga JI, Ishibashi S, Oka T, Yagyu H, Tozawa R, Fujimoto A, Shionoiri F, Yahagi N, Kraemer FB, Tsutsumi O, Yamada N (2000) Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci USA 97:787–792CrossRefGoogle Scholar
- 31.Sekiya M, Osuga J, Okazaki H, Yahagi N, Harada K, Shen WJ, Tamura Y, Tomita S, Iizuka Y, Ohashi K, Okazaki M, Sata M, Nagai R, Fujita T, Shimano H, Kraemer FB, Yamada N, Ishibashi S (2004) Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J Biol Chem 279:15084–15090CrossRefGoogle Scholar
- 32.Schoiswohl G, Stefanovic-Racic M, Menke MN, Wills RC, Surlow BA, Basantani MK, Sitnick MT, Cai L, Yazbeck CF, Stolz DB, Pulinilkunnil T, O’Doherty RM, Kershaw EE (2015) Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. Endocrinology 156:3610–3624CrossRefGoogle Scholar
- 40.Holloway GP, Chou CJ, Lally J, Stellingwerff T, Maher AC, Gavrilova O, Haluzik M, Alkhateeb H, Reitman ML, Bonen A (2011) Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance. Diabetologia 54:1457–1467CrossRefGoogle Scholar
- 48.Littlejohn NK, Keen HL, Weidemann BJ, Claflin KE, Tobin KV, Markan KR, Park S, Naber MC, Gourronc FA, Pearson NA, Liu X, Morgan DA, Klingelhutz AJ, Potthoff MJ, Rahmouni K, Sigmund CD, Grobe JL (2016) Suppression of resting metabolism by the angiotensin AT2 receptor. Cell Rep 16:1548–1560CrossRefGoogle Scholar
- 50.Ohshima K, Mogi M, Jing F, Iwanami J, Tsukuda K, Min LJ, Ogimoto A, Dahlof B, Steckelings UM, Unger T, Higaki J, Horiuchi M (2012) Direct angiotensin II type 2 receptor stimulation ameliorates insulin resistance in type 2 diabetes mice with PPARgamma activation. PLoS ONE 7:e48387CrossRefGoogle Scholar
- 51.Shum M, Pinard S, Guimond MO, Labbe SM, Roberge C, Baillargeon JP, Langlois MF, Alterman M, Wallinder C, Hallberg A, Carpentier AC, Gallo-Payet N (2013) Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. Am J Physiol Endocrinol Metabol 304:E197–E210CrossRefGoogle Scholar