title: Regulation of B-type natriuretic peptide synthesis by insulin in obesity in male mice.
abstract: 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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Haihua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Yao
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Popovich
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D066248:High Fructose Corn Syrup; D007328:Insulin / Q000097:blood / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis*; D009765:Obesity / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014280:Triglycerides / Q000097:blood; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D066248:High Fructose Corn Syrup; D007328:Insulin; D020097:Natriuretic Peptide, Brain; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014280:Triglycerides; D000077191:Wortmannin