Lack of Crosstalk between Leptin and Insulin Signalings in the Pathogenesis of Insulin Resistant Cardiomyopathy

The epidemic of obesity and sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025. Cardiovascular disease is responsible for 80% of deaths among diabetic patients much of which has been attributed to coronary artery disease (CAD). However, there is an increasing recognition that diabetic patients suffer from an additional cardiac insult termed “diabetic cardiomyopathy”. Although several mechanisms have been postulated for diabetic cardiomyopathy such as gene mutation, insulin resistance, sympathetic activation, and lifestyle factors, none of these factors has been considered the ultimate culprit of diabetic cardiomyopathy. Given the high propensity of heart diseases in obesity and the profound expression of the leptin receptor in cardiomyocytes, the regulatory effects of leptin on cardiac function and remodeling have drawn ever increasing attention recently. The mice lacking leptin (ob/ob) or its receptor (db/db) develop cardiac hypertrophy independent of body weight, strongly supporting a role for intact leptin signaling in maintaining of normal cardiac architecture and functions. However, it is still difficult to reconcile the fact that leptin deficiency actually leads to ventricular hypertrophy in the laboratory setting despite the fact that clinical cardiac hypertrophy is commonly found in hyperleptinemia. In addition to genetic factors, diet components are also an important factor which contributes to the development of type 2 DM and cardiovascular diseases. To mimic the Western eating habits, we fed rats with a high cholesterol fructose (HCF) diet for 15 weeks and found these rats have developed a phenotype of insulin resistance syndrome characterized by an increase in blood pressure, hyperlipidemia, hyperinsulinemia, and insulin resistance. These HCF rats also exhibited cardiac insulin resistance and contractile dysfunctions. Interestingly, our preliminary result found that the plasma leptin level was increased by 17.8 folds in HCF rats. Since high-fat diet and leptin or leptin receptor knockout mice all exhibit insulin resistance. Although, the physiological functions of insulin and leptin are regulation of the metabolic homeostasis in the body. However, based on our preliminary and previous studies and other reports, we infer that insulin and leptin may play an important role in regulation of cardiac functions under both physiological and pathological conditions. Nevertheless, the reciprocation of insulin and leptin on the regulation of normal cardiac functions and the development of diabetic cardiomyopathy remain unclear; and furthermore the cellular mechanisms underlying their cardiac actions have not been elucidated. Therefore, the central hypothesis of this research proposal is that insulin and leptin signalings coordinate their efforts to regulate normal cardiac functions, and lack of crosstalk between these two signalings reflect the cardiac insulin resistance which may cause imbalance of cardiac metabolic homeostasis, impair contractile function, and consequently precipitate insulin resistance or diabetes-associated cardiomyopathy. To address these hypotheses, we will perform experiments based on the following four specific aims. Specific Aim 1: Determinate whether leptin can modulate insulin activities in the cardiomyocyte. In this aim, we will exposure cardiomyocytes to high dose of leptin to test whether insulin signaling pathway can be modulated by leptin treatment. Specific Aim 2: Study whether cardiac leptin signaling cascades can be modulated under the insulin resistant condition. We propose to investigate the leptin receptor signaling cascades in HCF-induced insulin resistant rat heart and in palmitate-induced insulin resistant cardiomyocytes. Specific Aim 3: Explore whether insulin resistance-induced perturbations in cardiac metabolism can be reversed by leptin antagonist. We plan to demonstrate the idea that HCF-insulin resistant rats treated with leptin antagonist improve insulin sensitive and restore the metabolic homeostasis in the heart. Specific Aim 4: Investigate whether insulin exerts positive inotropic effects can be attenuated by high dose of leptin treatment and further delineate its underlying mechanisms. We plan to demonstrate the idea that over stimulation of leptin receptor signaling cascade by hyperleptinemia may lead to down regulation of insulin signals and thereby decline the contractile functions. The experimental studies indicate that extensively perturb metabolism may cause both functional and structural alterations of the diabetic myocardium. Translational studies are, however, limited and only partly explain why diabetic patients are at increased risk of cardiomyopathy and heart failure. Although a range of diagnostic methods may help to characterize alterations in cardiac function in general, none are specific for the alterations in diabetes. Thus there is an urgent need to conduct pathogenetic, diagnostic, and therapeutic studies specifically in diabetic patients with cardiomyopathy to better understand the factors which initiate and progress diabetic cardiomyopathy and to develop more effective treatments.

Project ID:PA10108-0431
External Project ID:NSC101-2311-B182-002