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Influence of Atp10a and Atp10d on diet induced obesity and insulin resistance


Center Vanderbilt University
Award Year 2019
Pilot Study Influence of Atp10a and Atp10d on diet induced obesity and insulin resistance
Awardee Todd Graham PhD
Abstract

Nearly 40% of US adults and 19% of US children are clinically obese with Hispanic and non-Hispanic black populations being particularly overrepresented. This growing obesity epidemic leads to increased incidences of type 2 diabetes, heart disease, stroke and some cancers. At least 10% of the US population has diabetes with most of these cases being type 2 diabetes. In addition to the personal trauma associated with obesity-related diseases, annual costs of treatment are estimated to be $147 billion per year in the US (2008 dollars) (https://www.cdc.gov/obesity; https://www.cdc.gov/diabetes). It is essential to gain a better understanding of underlying genetic risk factors for obesity and type 2 diabetes in order to manage and ultimately resolve this major public health problem. ATP10A and ATP10D have been linked to diet-induced obesity and insulin resistance in mice and humans, but how these type IV P-type ATPases (P4-ATPases) contribute to metabolic disease is unknown. Recent studies indicate ATP10A and ATP10D transport specific sphingolipid species across the plasma membrane of cultured cells. However, the physiological consequences of this lipid transport activity are poorly understood. For example, existing mouse models are inadequate to determine if Atp10a/10d deficiency is sufficient to cause insulin resistance and dyslipidemia in mice fed a high fat diet. Therefore, new murine models bearing precise deletions or mutations have been generated. The current pilot and feasibility study proposes to test whether these Atp10a and Atp10d deficient mice display diet-induced obesity, insulin resistance and dyslipidemia (perturbations on serum lipid profiles) when fed a high fat diet.