Adipocyte EET-PGC1alpha-HO-1 in Obesity-driven Hypertension

New York Medical College, Valhalla NY

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Abstract

SUMMARY Obesity is a ?silent? epidemic disease and a risk factor for development of cardiovascular disease including hypertension. Although obesity/metabolic syndrome is theoretically treatable with modern medical, lifestyle and eating management methods, this is not a trivial undertaking and our national battle with this ?silent disease? is not going well. However, identifying novel pathways that mitigate the deleterious effects of oxidative stress and inflammation in obesity can lead to better future treatment options and health management. We have successfully implicated heme oxygenase-1 (HO-1) and cytochrome P450-epoxygenase-derived EETs in the implementation of anti-hypertensive and anti-adipogenic mechanisms that enhances insulin sensitivity, weight loss and energy expenditure. In obesity and diabetes, HO-1 expression is repressed and EETs in fat tissues are decreased. Relevant to this application we found that selective adipocyte HO-1 overexpression attenuated obesity-induced hypertension, while adipocyte-selective HO-1 deletion in null mice exhibit diminished levels of EETs and PGC1?, a transcription factor known to regulate mitochondrial biogenesis and peripheral insulin sensitivity. Preliminary results also revealed that amplification of the HO-1-EET circuit activates PGC-1?. Collectively, the aforementioned observations support the hypothesis that HO-1 of adipocytes is a positive regulator of adipocyte EET production and adiponectin, leading to activation of a signaling pathway involving PGC1? which controls mitochondrial function(s), decreases formation of ROS, and increases insulin sensitivity, all of which may contribute to set the levels of blood pressure. A corollary of this is that a deficit in the functionality of this adipocyte pathway (e.g., impaired HO-1 expression, EET synthesis, and/or PGC1? level), as appears to occur in adipocytes of animal models of obesity- induced hypertension and related conditions may be a contributor to the pathogenesis of such disease states. The proposed experimentation is designed to explore these concepts in relation to the involvement of a deficit in adipocytes of the HO-1-EET-PGC1? system in the pathogenesis of obesity and hypertension in fat fed mice. We will manipulate the expression of HO-1, CYP2C44(EETs) and PGC1? genes within adipocytes and assess the effect on metabolic and cardiovascular parameters including insulin sensitivity, oxygen consumption, weight gain, vascular function and blood pressure as well as on adipogenic markers and signaling molecules that are indices of adipocyte phenotype in health and disease. We will further focus on the key signaling components of the PGC1? pathway including MAP kinases, and insulin receptor phosphorylation in adipocyte stem cells and the reliance of PGC1? actions on active adipocyte HO-1 and CYP2C44-EETs during adipogenesis. The experiments outlined in this proposal will provide us with a solid working knowledge of how HO-1-EET interact with key signaling pathways to regulate insulin sensitivity and hypertension with an eye on the identification of new therapeutic targets for attenuation of obesity and metabolic disease.