Lack of kinin B1 receptor potentiates leptin action in the liver


Kinins B1 and B2 receptors (B1R and B2R) are classically associated with inflammation, but our group has recently demonstrated new roles for B1R in metabolism using a knockout model (B1 −/−). B1 −/− mice display improvement on leptin and insulin sensitivity and is protected from high fat diet (HFD)-induced obesity. Here, we evaluate the hepatic effects of the B1R ablation and its role on hepatic function. Despite no expression of hepatic B1R, HFD-induced hepatic lipid accumulation was lower than in control animals. B1 −/− mice also presented lower hepatic lipogenesis and SCD1 protein content in the liver. When stimulated with exogenous leptin, B1 −/− mice exhibited increased hepatic pJAK2. Similarly, leptin signaling was enhanced in the liver of ob/ob–B1 −/− mice, as demonstrated by increased levels of pSTAT3 compared to ob/ob. Plasma concentrations of intercellular adhesion molecule 1, fetuin A, leukemia inhibitory factor, tissue inhibitor of metalloprotease-1, resistin, and oncostatin M were reduced in B1 −/−. Finally, B1 −/− mice have increased gene expression of hepatic B2 receptor, but no difference in leptin receptor expression. Our results show that B1 −/− mice are protected from non-alcoholic fatty liver disease (NAFLD) after HFD treatment. Since B1R expression was not observed in the liver after HFD, we propose that the cross talk between the adipose tissue and the liver, mainly through leptin, is an important factor contributing to the observed results. Besides that, several other inflammatory mediators already correlated with NAFLD or liver function were found to be altered in our model. Taken together, our data suggest that B1R plays an important role in hepatic steatosis development.

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  1. 1.

    Tilg H, Moschen AR (2008) Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab 19:371–379

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Alba LM, Lindor K (2003) Review article: non-alcoholic fatty liver disease. Aliment Pharmacol Ther 17:977–986

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL (2005) International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 57:27–77

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Bhoola KD, Figueroa CD, Worthy K (1992) Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 44:1–80

    PubMed  CAS  Google Scholar 

  5. 5.

    Mori MA, Araujo RC, Pesquero JB (2008) Kinin B1 receptor stimulation modulates leptin homeostasis. Evidence for an insulin-dependent mechanism. Int Immunopharmacol 8:242–246

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Mori MA, Araujo RC, Reis FC, Sgai DG, Fonseca RG, Barros CC, Merino VF, Passadore M, Barbosa AM, Ferrari B et al (2008) Kinin B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity. Diabetes 57:1491–1500

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Carvalheira JB, Ribeiro EB, Folli F, Velloso LA, Saad MJ (2003) Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver. Biol Chem 384:151–159

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM (2002) Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297:240–243

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, Mombaerts P, Friedman JM (2001) Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 108:1113–1121

    PubMed  CAS  Google Scholar 

  11. 11.

    Kakuma T, Lee Y, Unger RH (2002) Effects of leptin, troglitazone, and dietary fat on stearoyl CoA desaturase. Biochem Biophys Res Commun 297:1259–1263

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD (2002) Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A 99:11482–11486

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Araujo RC, Mori MA, Merino VF, Bascands JL, Schanstra JP, Zollner RL, Villela CA, Nakaie CR, Paiva AC, Pesquero JL et al (2006) Role of the kinin B1 receptor in insulin homeostasis and pancreatic islet function. Biol Chem 387:431–436

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Mori MA, Sales VM, Motta FL, Fonseca RG, Alenina N, Guadagnini D, Schadock I, Silva ED, Torres HA, Dos Santos EL et al (2012) Kinin b(1) receptor in adipocytes regulates glucose tolerance and predisposition to obesity. PLoS One 7:e44782

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Pesquero JB, Araujo RC, Heppenstall PA, Stucky CL, Silva JA Jr, Walther T, Oliveira SM, Pesquero JL, Paiva AC, Calixto JB et al (2000) Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc Natl Acad Sci U S A 97:8140–8145

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Stansbie D, Brownsey RW, Crettaz M, Denton RM (1976) Acute effects in vivo of anti-insulin serum on rates of fatty acid synthesis and activities of acetyl-coenzyme A carboxylase and pyruvate dehydrogenase in liver and epididymal adipose tissue of fed rats. Biochem J 160:413–416

    PubMed  CAS  Google Scholar 

  17. 17.

    Robinson AM, Williamson DH (1978) Control of glucose metabolism in isolated acini of the lactating mamary gland of the rat. Effects of oleate on glucose utilization and lipogenesis. Biochem J 170:609–613

    PubMed  CAS  Google Scholar 

  18. 18.

    Abe KC, Mori MA, Pesquero JB (2007) Leptin deficiency leads to the regulation of kinin receptors expression in mice. Regul Pept 138:56–58

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Araujo RC, Kettritz R, Fichtner I, Paiva AC, Pesquero JB, Bader M (2001) Altered neutrophil homeostasis in kinin B1 receptor-deficient mice. Biol Chem 382:91–95

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Barros CC, Haro A, Russo FJ, Schadock I, Almeida SS, Ribeiro RA, Vanzela EC, Lanzoni VP, Barros FC, Moraes MR et al (2012) Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes. PLoS One 7:e40573

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Merino VF, Todiras M, Mori MA, Sales VM, Fonseca RG, Saul V, Tenner K, Bader M, Pesquero JB (2009) Predisposition to atherosclerosis and aortic aneurysms in mice deficient in kinin B1 receptor and apolipoprotein E. J Mol Med (Berl) 87:953–963

    Article  CAS  Google Scholar 

  22. 22.

    Fishman S, Muzumdar RH, Atzmon G, Ma X, Yang X, Einstein FH, Barzilai N (2007) Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. FASEB J 21:53–60

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P et al (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350

    PubMed  CAS  Google Scholar 

  24. 24.

    Huang W, Dedousis N, Bhatt BA, O'Doherty RM (2004) Impaired activation of phosphatidylinositol 3-kinase by leptin is a novel mechanism of hepatic leptin resistance in diet-induced obesity. J Biol Chem 279:21695–21700

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    McGarry JD, Woeltje KF, Kuwajima M, Foster DW (1989) Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev 5:271–284

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Dias JP, Couture R (2012) Blockade of kinin B(1) receptor reverses plasma fatty acids composition changes and body and tissue fat gain in a rat model of insulin resistance. Diabetes Obes Metab 14:244–253

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Schulze-Topphoff U, Prat A, Bader M, Zipp F, Aktas O (2008) Roles of the kallikrein/kinin system in the adaptive immune system. Int Immunopharmacol 8:155–160

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Soderberg C, Marmur J, Eckes K, Glaumann H, Sallberg M, Frelin L, Rosenberg P, Stal P, Hultcrantz R (2011) Microvesicular fat, inter cellular adhesion molecule-1 and regulatory T-lymphocytes are of importance for the inflammatory process in livers with non-alcoholic steatohepatitis. APMIS 119:412–420

    PubMed  Article  Google Scholar 

  29. 29.

    Parsons CJ, Bradford BU, Pan CQ, Cheung E, Schauer M, Knorr A, Krebs B, Kraft S, Zahn S, Brocks B et al (2004) Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. Hepatology 40:1106–1115

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Krober SM, Machicao F, Fritsche A, Haring HU (2006) Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29:853–857

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Singhal NS, Patel RT, Qi Y, Lee YS, Ahima RS (2008) Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice. Am J Physiol Endocrinol Metab 295:E331–E338

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Ailhaud G (2006) Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. C R Biol 329:570–577, discussion 653-575

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Sookoian S, Gianotti TF, Rosselli MS, Burgueno AL, Castano GO, Pirola CJ (2011) Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 218:378–385

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Levesque L, Larrivee JF, Bachvarov DR, Rioux F, Drapeau G, Marceau F (1995) Regulation of kinin-induced contraction and DNA synthesis by inflammatory cytokines in the smooth muscle of the rabbit aorta. Br J Pharmacol 116:1673–1679

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Henkel J, Gartner D, Dorn C, Hellerbrand C, Schanze N, Elz SR, Puschel GP (2011) Oncostatin M produced in Kupffer cells in response to PGE2: possible contributor to hepatic insulin resistance and steatosis. Lab Invest 91:1107–1117

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM et al (1997) Crystal structure of the obese protein leptin-E100. Nature 387:206–209

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Tanaka M, Miyajima A (2003) Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol 149:39–52

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Duka A, Kintsurashvili E, Duka I, Ona D, Hopkins TA, Bader M, Gavras I, Gavras H (2008) Angiotensin-converting enzyme inhibition after experimental myocardial infarct: role of the kinin B1 and B2 receptors. Hypertension 51:1352–1357

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Marcon R, Claudino RF, Dutra RC, Bento AF, Schmidt EC, Bouzon ZL, Sordi R, Morais RL, Pesquero JB, Calixto JB (2013) Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptor through compensation of up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis. Br J Pharmacol 168:389–402

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Barros CC, Haro A, Russo FJ, Schadock I, Almeida SS, Reis FC, Moraes MR, Haidar A, Hirata AE, Mori M et al (2012) Bradykinin inhibits hepatic gluconeogenesis in obese mice. Lab Invest 92:1419–1427

    PubMed  Article  CAS  Google Scholar 

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This work was supported by grants of Fapesp Processo 2008/06676-8, CNPq, and CAPES.

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No potential conflicts of interest relevant to this article were reported.

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Correspondence to João Bosco Pesquero.

Additional information

Raphael Gomes Fonseca and Vicencia Micheline Sales contributed equally to this work.

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Fonseca, R.G., Sales, V.M., Ropelle, E. et al. Lack of kinin B1 receptor potentiates leptin action in the liver. J Mol Med 91, 851–860 (2013).

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  • Kinins
  • Liver
  • Leptin
  • Insulin
  • Non-alcoholic fatty liver disease