MECHANISMS OF PERIPHERAL FAT DETECTION

随着西方饮食的传播，世界范围内肥胖的发病率继续上升

The incidence of obesity worldwide continues to escalate with the spread of the Western diet and with it there has been a corresponding increase in cardiovascular disease, diabetes, end-stage renal disease and other obesity-related disorders. Of all the causes for obesity, the predominant one seems to be choice - the choice to eat more and exercise less. One of the choices that has been linked with obesity has been the selection of a high fat, calorically dense diet. Despite much research on the link between fat intake and obesity, relatively little is known about the chemosensory mechanisms that underlie the taste and texture of fat and how these mechanisms might contribute to dietary fat intake. Using obesity-prone and -resistant rat models we have previously identified differences in how the taste systems in these two strains respond to fatty acids, a cue for dietary fat, and how this was correlated to differences in gene expression and receptor function. Moreover, we have demonstrated that these chemosensory mechanisms are modulated by diet and the development of obesity. The proposal describes two main specific aims that seek to identify and characterize fat receptive mechanisms that underlie the taste and texture of fat and investigate how these chemosensory pathways are modulated by dietary experience and the pathophysiological state of obesity. Specifically, we will use an approach including a multidisciplinary approach to test the following hypotheses: 1. Taste receptor cells and trigeminal neurons share common transduction pathways for the chemoreception of fatty acids (e.g. fat). We will test this by using molecular and immunocytochemical approaches to identify putative fat receptors including fatty acid sensitive K channels, the fatty acid transporter CD36 and several G protein-coupled receptors we have identified in taste cells and trigeminal neurons. Cell-based assays (imaging, electrophysiology) will characterize these "fat receptors" functionally. 2. Fat receptor expression in taste cells and trigeminal neurons is altered during high fat feeding in a manner that results in a decreased responsiveness to fatty acids. Based upon our preliminary data showing a reduction in responsiveness to fatty acids after the development of obesity on a high fat diet, we will use our multidisciplinary approach from genes through behavior to measure changes in expression and function of fat receptors as a function of macronutrient content of the diet.