Fatty acid oxidation, which is transcriptionally regulated by Peroxisome proliferator-activated receptor ? (PPAR?), produces 70% of cardiac ATP. Alterations in Ppara expression have been associated with changes in lipid metabolism and cardiac dysfunction in diabetes and obesity. Obesity leads to cardiac lipid accumulation, also known as lipotoxicity and causes cardiac dysfunction. Several studies have shown that the heart affects systemic metabolism by mechanisms that remain unclear. Our in vitro and in vivo preliminary data identify cardiac Kr?ppel-like factor 5 (KLF5) as a transcriptional activator of both Ppara and Med13. Thus, cardiac KLF5 emerges as a new regulator of cardiac FAO and systemic metabolism. We show that cardiac Klf5 expression is inhibited by hyperglycemia leading to reduced Ppara expression and cardiac FAO-related gene expression. Our data implicate cardiac FOXO1 as an inhibitor of Klf5. In addition, we show that KLF5 inhibition in cardiomyocytes accelerates diet-induced obesity (DIO). This change in weight gain is not associated either with reduced cardiac function or altered food intake and mouse activity. It is however associated with increased cardiac and plasma FGF21 and reduced SUMOylation of PPAR? in white adipose tissue, which indicates increased PPAR? activity that promotes adipocyte development. We hypothesize that cardiomyocyte Klf5 activation will lead to combined activation of cardiac FAO and inhibition of cardiac lipid accumulation and obesity. Our proposed research aims to elucidate the mechanism that links hyperglycemia with inhibition of cardiac Klf5, Ppara and FAO-related gene expression, as well as the pathway via which cardiac KLF5 regulates DIO. We also aim to apply Klf5 activation in cardiomyocytes as a way to increase cardiac FAO and reduce fat storage in obese mice. To address these questions we propose the following specific aims:
Aim 1 - To determine how diabetes inhibits cardiac Klf5 and Ppara expression.
Aim 2 - To identify how cardiomyocyte Klf5 ablation signals systemically to promote DIO.
Aim 3 - To investigate how cardiomyocyte Klf5 activation can prevent both cardiac lipotoxicity and WAT development in animal models of obesity.
Cardiovascular complications in diabetes and obesity constitute a major cause of death. About 29 million people are affected by diabetes in the USA and more than 78 million of U.S. adults are obese. The estimated annual cost for the U.S. is $245 billion for diabetes and $147 billion for obesity. Cardiovascular disease death rates are about 70% higher among adults aged 18 years or older with diagnosed diabetes than among adults without diagnosed diabetes. Hospitalization rates for heart attack were 80% higher in diabetic adults than those without diabetes. Cardiac dysfunction in diabetes relies largely on cardiac lipid accumulation. We have discovered a cardiac protein that has the potential to control both cardiac lipid accumulation in diabetes and the expansion of adipose tissue. Thus, our research will indicate a novel pharmacological target for the alleviation of diabetic cardiomyopathy and obesity. Elrod, JW
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