Location: Obesity and Metabolism Research Unit
Project Number: 2032-51530-022-00
Start Date: Mar 16, 2014
End Date: Mar 15, 2019
We will use a multidisciplinary approach to test molecular, physiologic, and metabolic responses to diet patterns, specific nutrients, and physical activity levels to determine effects on or associations with chronic disease risks. We posit that consumption of a diet, patterned on the Dietary Guidelines for Americans (DGA), will rapidly improve cardiometabolic risk factors, improve gut barrier function and reduce metabolic dysfunction. Also, individual differences in chronic stress and stress system responsiveness will partially explain variation in metabolic responses to the DGA diet. A randomized, food-controlled trial will be conducted to test these hypotheses. We will also conduct a cross-sectional study using metabolomics to map an individual’s metabolic flexibility and link this phenotypic trait to lifestyle, including markers of health status, physical activity parameters, diet quality, food preferences and food choices. As part of this study, we will administer a meal challenge to test the hypothesis that behavioral phenotypes can be identified based on responses of known and putative satiety signals to the meal. Using the cross-sectional approach and metabolomic analyses, we will develop basal and stress-induced metabolite profiles to identify differential stress-response signatures. Ancillary studies will be conducted to examine underlying mechanisms that might explain metabolic dysfunction. To examine gut microbiota and metabolites in more depth, samples of adipose, liver, intestinal content, and blood from ‘healthy’ and ‘unhealthy’ obese undergoing gastric bypass surgery will be used to derive phenotypic signatures spanning several biological systems and adipose tissue structure/function to test the hypothesis that phenotypic signatures can predict improvement in insulin resistance and inflammation. Using a murine model of diet-induced obesity, we will test the hypothesis that obesity disrupts the normal association between peripheral nervous system (PNS) sensing of ambient temperature and communication to the brain to coordinate temperature-control of feeding and energy expenditure. This study will include functional tests in vivo, and PNS expression of temperature-sensing TRP channels will be evaluated in dorsal root ganglion ex vivo. Finally, cultured muscle cells will be used to examine the hypothesis that incomplete mitochondrial combustion of fatty acids in tissue such as muscle leads to increased acylcarnitine accumulation, and select acylcarnitines promote cell stress responses will be evaluated.