More than one-third of U.S. population is obese. The prevalence of obesity-related comorbidities such as type-2 diabetes and heart diseases emphasizes the need for concerted efforts to prevent and treat obesity. A decrease in ?5% of the body weight significantly reduces cardiovascular risk in humans which clearly demonstrates the urgency of weight management. Lifestyle intervention is primary albeit not sufficient in long term weight management. Thus, we need anti-obesity drugs. Due to partial effects of the current anti-obesity drugs that inhibit food intake or absorption, recent focus has shifted towards enhancing energy expenditure in metabolic tissues. Adipose tissue is a major regulator of energy metabolism. Therefore, adipose tissue function in normal and obese conditions are being extensively studied. Because of the complexity of the adipose tissue, a complete understanding of the mechanism and regulation of its metabolism is still lacking. Discovery of all the major components of adipose tissue metabolism will certainly help to design therapeutic strategies. In this proposal, we introduce IP6K1 as one such component with therapeutic potential. Our laboratory is interested in understanding the mechanism and regulation of adipose tissue metabolism in normal and obese conditions using mouse models. Utilizing the inositol hexakisphosphate kinase 1 (IP6K1) knockout (K1-KO) mice, we previously discovered that these mice are resistant to weight gain and insulin resistance, despite their unaltered food intake. The objective of the current proposal is to determine the mechanisms by which IP6K1 promotes lipid accumulation in the adipose tissue using whole body and adipose tissue specific IP6K1 mouse models. The central hypothesis is that IP6K1 is a major regulator of energy metabolism in the adipose tissue. To test this hypothesis, role of IP6K1 in; 1) adipose tissue browning and thermogenesis; 2) lipolysis and; 3) adipogenesis will be determined and underlying mechanisms by which IP6K1 regulates these processes will be identified. The proposed research is conceptually innovative, because it represents a new and substantive departure from the status quo, namely determining the mechanisms by which IP6K1 regulates adipose mass. The contribution is significant because it is the first step in a continuum of research that is expected to lead to development of novel pharmacologic strategies in obesity. Therefore, the proposed project is expected to have significant impacts on improving quality of life.
Obesity is associated with health risks such as type-2 diabetes, hypertension, cardiovascular diseases, dyslipidemia, arthritis and certain cancers which significantly decrease quality of life and reduce life expectancy. Extensive research is ongoing to identify the ideal protein or pathway which can be pharmacologically targeted to ameliorate obesity and associated diseases. This project investigates the role of inositol hexakisphosphate kinase 1 (IP6K1) in obesity and diabetes. The project proposes to identify the underlying mechanisms by which IP6K1 facilitates increase in adipose mass. By generating novel mouse and cellular models, this project demonstrates pleiotropic actions of IP6K1 on fat accumulation and proposes that targeting IP6K1 has significant anti-obesity and anti-diabetic potential.
