Kinin B1 Receptor in Adipocytes Regulates Glucose Tolerance and Predisposition to Obesity

Abstract

BackgroundKinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B1 receptor knockout mice (B1 −/−) are leaner and exhibit improved insulin sensitivity.Methodology/Principal FindingsHere we show that kinin B1 receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B1 receptors. In these cells, treatment with the B1 receptor agonist des-Arg9-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B1 −/− mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B1 receptor was limited to cells of the adipose tissue (aP2-B1/B1 −/−). Similarly to B1 −/− mice, aP2-B1/B1 −/− mice were leaner than wild type controls. However, exclusive expression of the kinin B1 receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B1 −/− mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B1 receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B1/B1 −/− when compared to B1 −/− mice. When subjected to high fat diet, aP2-B1/B1 −/− mice gained more weight than B1 −/− littermates, becoming as obese as the wild types.Conclusions/SignificanceThus, kinin B1 receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.

Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial

“…Bradykinin, a neprilysin substrate, can improve insulin sensitivity and attenuate lipolysis. 27 Cyclic guanosine monophosphate, also increased by neprilysin inhibition, has known vasodilatory effects in skeletal muscle and facilitates lipolysis. 20 Moreover, GLP-1, a neuropeptide of the incretin family and potent antihyperglycaemic hormone with a very short circulating half-life, is partially degraded by neprilysin.…”

Kinin B1 receptor gene ablation affects hypothalamic CART productionb

“…Surprisingly, when fed a HFD B1 -/-diet mice remain lean while the WT mice become obese (Mori et al , 2008b ). When the kinin B1 receptor is expressed exclusively in the adipose tissue, the plasma insulin level is restored, as is the weight gain after HFD, but no change is seen in leptin levels (Mori et al , 2012 ). Kinin B1 receptor antagonism in rats is able to reduce plasma levels of insulin, glucose, and reverses the enhancing effect of glucose feeding on whole body and epididymal fat mass and on the expression of inflammatory markers in retroperitoneal adipose tissue and aorta (Dias and Couture , 2012a,b ).…”

Τhe role of sacubitril/valsartan therapy on renal function and glucose metabolism in chronic heart failure patients

“…However, the underlying pathophysiologic mechanisms are not yet clear and may be attributed to changes in the production and concentrations of various metabolically active peptides by neprilysin inhibition (i.e. atrial natriuretic peptide, BNP, bradykinin, glucagon like peptide) necessitated further investigation [37][38][39][40][41][42]. In the whole PARADIGH-HF trial the risk ratio for the primary outcome, in participants with diabetes, was 0.84 (95% CI 0.74-0.95), very similar to the overall treatment effect for the entire cohort (HR 0.80, 95% CI 0.73-0.87).…”

“…Inhibition of neprilysin with the dual ACE-neprilysin inhibitor omapatrilat improved whole-body insulin-mediated glucose disposal, induced profound insulin sensitisation, and increased myocardial glucose uptake in obese insulin-resistant Zucker rats [46]. In a study comparing the effects of sacubitril/valsartan and amlodipine on insulin resistance in obese hypertensive patients treated for 8 weeks, those treated with sacubitril/valsartan showed a significant increase in insulin sensitivity using the hyperinsulinaemic-euglycaemic clamp technique [39]. Additionally, LCZ696 attenuated cardiac remodeling and dysfunction after MI [50].…”