Bradykinin inhibits hepatic gluconeogenesis in obese mice

Item Type:	Article
Title:	Bradykinin inhibits hepatic gluconeogenesis in obese mice
Creators Name:	Castilho Barros, C. and Haro, A. and Russo, F.J. and Schadock, I. and Soares Almeida, S. and Castellani Reis, F. and Rocha Moraes, M. and Haidar, A. and Hirata, A.E. and Mori, M.A. and Pereira Bacurau, R.F. and Wuertele, M. and Bader, M. and Bosco Pesquero, J. and Araujo, R.C.
Abstract:	The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3±28.2 mg/dl vs 85.3±13.3 mg/dl), hyperinsulinemia (7.71±1.75 ng/ml vs 4.09±0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus.
Keywords:	Bradykinin, Gluconeogenesis, Kinin Receptor, Leptin, Ob/Ob, Obesity, Animals, Mice, Rats
Source:	Laboratory Investigation
ISSN:	0023-6837
Publisher:	Nature Publishing Group
Volume:	92
Number:	10
Page Range:	1419-1427
Date:	October 2012
Official Publication:	https://doi.org/10.1038/labinvest.2012.105
PubMed:	View item in PubMed

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