Regulation of B-type natriuretic peptide synthesis by insulin in obesity in male mice

New Findings: What is the central question of this study? The plasma concentration of brain natriuretic peptide (BNP) is decreased in obesity, a finding that may be deleterious from a cardiovascular, renal and metabolic standpoint. The present study used a mouse model of high-fructose, high-fat (HFHF) diet and isolated cardiomyocytes to investigate the mechanisms involved in this decrease. What is the main finding and its importance? The gene expression level of BNP is decreased in the left ventricle of mice fed a HFHF diet for 4 weeks and in cardiomyocytes exposed to prolonged high doses of insulin. A decrease in BNP synthesis may contribute to the decreased BNP plasma concentrations observed in obesity and insulin resistance. Human studies suggest that insulin resistance and obesity are associated with a decrease in B-type natriuretic peptide (BNP) plasma concentrations. The objective of the study was to gain insights into the mechanisms involved in the association between insulin resistance and decreased BNP plasma concentrations. Mice fed a high-fat, high-fructose (HFHF) diet for 4 weeks developed mild obesity and systemic insulin resistance. Elevated plasma concentrations of insulin, glucose and triglycerides were noted. The HFHF diet was also associated with myocardial insulin resistance, characterized by an impaired response of the phosphoinositide 3-kinase–AKT (PI3K–AKT) pathway to insulin in the left ventricle. Myocardial BNP expression and protein were decreased in HFHF-fed mice compared with control animals. Exposure of cardiomyocytes to 100 nm insulin activated PI3K–AKT signalling (15 min) and induced a 1.9 ± 0.3-fold increase in BNP gene expression (6 h). Prolonged exposure of cardiomyocytes to a high insulin concentration (100 nm) for 48 h induced insulin resistance, characterized by an impaired response of the PI3K–AKT signalling pathway and a decreased response of the BNP gene expression to insulin. The decreased response in BNP gene expression was reproduced by treating cardiomyocytes for 7 h with a PI3-kinase inhibitor (wortmannin). In conclusion, HFHF diet in vivo, prolonged exposure to an elevated concentration of insulin or inhibition of the PI3K–AKT pathway in vitro all decrease BNP mRNA levels; this decrease may in turn contribute to the decreased BNP peptide concentrations in plasma observed in insulin-resistant individuals.