title: Bradykinin inhibits hepatic gluconeogenesis in obese mice.
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.
authors.affiliation: Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Carlos Castilho
authors.initials: CC
authors.lastname: Barros
authors.forename: Anderson
authors.initials: A
authors.lastname: Haro
authors.forename: Fernanda Jaqueline
authors.initials: FJ
authors.lastname: Russo
authors.forename: Ines
authors.initials: I
authors.lastname: Schadock
authors.forename: Sandro Soares
authors.initials: SS
authors.lastname: Almeida
authors.forename: Felipe Castellani
authors.initials: FC
authors.lastname: Reis
authors.forename: Milton Rocha
authors.initials: MR
authors.lastname: Moraes
authors.forename: Andre
authors.initials: A
authors.lastname: Haidar
authors.forename: Aparecida Emiko
authors.initials: AE
authors.lastname: Hirata
authors.forename: Marcelo
authors.initials: M
authors.lastname: Mori
authors.forename: Reury Frank Pereira
authors.initials: RF
authors.lastname: Bacurau
authors.forename: Martin
authors.initials: M
authors.lastname: Würtele
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Joao Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Ronaldo Carvalho
authors.initials: RC
authors.lastname: Araujo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000378:metabolism*; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D016234:Kallikrein-Kinin System / Q000502:physiology; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D020738:Leptin; D047495:PPAR gamma; D018002:Receptors, Bradykinin; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D001920:Bradykinin