Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice.
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.
Dobrzyn
Pawel
P
Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland. adobrzyn@nencki.gov.pl
Dobrzyn
Agnieszka
A
Miyazaki
Makoto
M
Ntambi
James M
JM
D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism; D004822:Epididymis / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D006321:Heart / Q000503:physiopathology*; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010084:Oxidation-Reduction; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency* / Q000235:genetics*; D016277:Ventricular Function, Left / Q000235:genetics
D002518:Ceramides; D005227:Fatty Acids; D020738:Leptin; D052247:Nitric Oxide Synthase Type II; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D053148:Caspase 3