Novel Roles for Trpa1 and Trpv1 in Nutrient Sensing and Obesity

In the first part of this thesis I explored a role for the capsaicin receptor TRPV1 in the regulation of feeding and body mass. On a diet containing 4.5% fat, wild-type and TRPV1-null mice gained equivalent body mass. On a diet containing 11% fat, however, TRPV1-null mice gained significantly less mass and adiposity; at 44 weeks the mean body weights of wild-type and TRPV1-null mice were 51 and 34 g respectively. Both groups of mice consumed equivalent energy and absorbed similar amounts of lipids. TRPV1-null mice, however, exhibited a significantly greater thermogenic capacity. In contrast to earlier reports, I found that TRPV1-null animals have higher blood glucose levels. Further, I demonstrate that 3T3-L1 preadipocytes expressed functional calcitonin gene-related peptide (CGRP) receptors suggesting a potential neurogenic mechanism by which TRPV1-expressing sensory neurons may regulate adiposity. Taken together, these data support a role for TRPV1 expressing sensory nerves in regulating energy and fat metabolism. In the second part of this thesis I investigated the role of TRPA1, a nociceptive ion channel, as a fatty acid receptor and modulator of gastric function. Polyunsaturated fatty acids are known agonists for a variety of receptors including members of the transient receptor potential ion channel family. Long chain polyunsaturated fatty acids such as DHA and EPA, predominately found in oily fish, are recognized by their aversive, pungent quality. These properties make DHA a prime candidate to activate TRPA1 within the intestinal mucosa. Indeed, iv I found that DHA directly activates TRPA1 without covalently binding to the channel. Further, activation of TRPA1 on intestinal-derived cell lines induces secretion of CCK. Taken together these studies suggest DHA can modulate digestive mechanisms through TRPA1. v This thesis is dedicated to my parents, Robert and Lila Motter. I am and always will be grateful for your love and support.