Regulation of human intestinal nutrient absorption by adipocyte-derived factors

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Obesity is a complex disease related to having excess body fat. Obesity is highly prevalent in the United States, where approximately one of every three adults is considered obese, and it is becoming increasing common worldwide. It is particularly prevalent in the Appalachian region, with West Virginia having the highest obesity rate in America. There are several serious health issues linked to obesity, including cardiovascular disease, type 2 diabetes mellitus, hypertension, and several cancer types including colon cancer. Intestinal nutrient absorption is altered in obesity by mechanisms that are not well understood. Our overall hypothesis is that during obesity, adipocyte-derived factors alter nutrient transporter function in intestinal epithelial cells (IECs) and colon cancer cells, which affects nutrient homeostasis. Recent work showed that inflammatory signaling occurs between IECs and adipocytes when co-cultured in the absence of immune cells. The studies proposed here will provide insight into the regulation of intestinal nutrient absorption processes by adipocyte-derived factors. Our overall aim is to determine the effect and regulation of adipocyte-derived factors on activity and expression of nutrient transporters in human IECs and colon cancer cells. Using patient-derived intestinal epithelial organoidbased culture models, we will examine the uptake of key nutrients in human IECs co-cultured with primary human adipocytes. We will also determine the effect of adipocyte-derived factors on uptake of key nutrients in colon cancer cells. Identifying and understanding the molecular mechanisms underlying obesity-related alterations in nutrient absorption is key for designing future therapeutics.