DESCRIPTION (provided by applicant): Fat is a major metabolic fuel and is the predominant fuel utilized by most tissues during periods of fasting and during intake of high fat diets. Research in the last two decades has focused on signals (notably, the hormone leptin) derived from stored fat, while the mechanisms through which circulating fats may alter food intake have been neglected. Yet circulating fatty acids have the inherent potential to influence food intake and other homeostatic functions acutely and therefore may be of special significance in controlling onset and size of daily meals. One important control of feeding by fatty acids is known as the lipoprivic control, a stimulatory control of feeding evoked experimentally by drugs such as 2-mercaptoacetate (MA) that block fatty acid oxidation. Despite being well accepted, the underlying mechanisms of this control are poorly understood. Although it is known to be dependent on vagal sensory neurons, the sites of action, mechanisms of action and central pathways through which MA evokes food intake are not known. In this application, we examine mechanisms underlying lipoprivic control of feeding. It has been assumed until now that this control of feeding arises entirely from reduced fatty acid oxidation. However, we found recently that MA, the drug most commonly used to study lipoprivic control, may also have fatty acid receptor blocking effects at G-protein coupled receptors (GPR40 and/or GPR120) that are independent of fat oxidation. Specific Aim 1 examines this potential mechanism of MA using calcium imaging in various tissues, including cultured cell lines known to express these receptors and GPR40 and GPR120 knockout mice. Using in vivo approaches, Specific Aim 2 examines the possibility that MA stimulates feeding in part by altering secretion of gut hormones that influence hunger and satiety, including MA's possible interaction with GPR40 and 120 in these effects. Specific Aim 3 addresses the poorly understood central pathways for control of feeding by MA, focusing on the orexigenic peptides, melanin concentrating hormone (MCH) and galanin, the only peptides so far known to be activated by MA. Results of the proposed experiments may be paradigm shifting with respect to our understanding of lipoprivic control of food intake and the broad spectrum of participation of free fatty acid receptors in this control. I addition, some results may have translational significance for diabetes, where beta cell GPR40 is already a target for drug development.

Most recent research on control of food intake by fat has focused on the role of signals from stored fat. Using in vivo and in vitro approaches we focus on lipoprivic control of feeding and investigate mechanisms by which circulating free fatty acids are detected by peripheral mechanisms that control feeding.