DGAT1 as a central regulator of diet-induced obesity

Evidence indicates an essential role for the central nervous system (CNS), particularly lipid-sensing neurons in the hypothalamus, in the regulation of whole-body energy balance. It is suggested that different classes of lipids are used by lipid-sensing neurons, not as nutrients, but as cellular messengers which relay information regarding whole-body energy status. Even though the enzymes responsible for TG synthesis, acyl-CoA:diacylglycerol acyltransferase-1 and -2 (DGAT-1 and -2), are expressed in the brain and are known to regulate of whole-body EB, their function in the CNS has yet to be investigated. The long-term objective of my research program is to understand the physiological relevance(s) of intracellular TG and how it impacts CNS processes.

The overall objectives for this proposal, which will establish the platform for achieving my long-term goal, areto identify the neuroanatomical expression and distribution of Dgat1, to elucidate the impact of central DGAT1 on the regulation of whole-body energy balance.

I hypothesize that intracellular TG metabolism in the CNS, mediated by DGAT1, impacts lipid-sensing in the brain and thus regulates of whole-body energy balance. The rationale for this proposal is that identification of specific cell-types and lipid messengers mediated by DGAT1 in the CNS will provide mechanistic insight into how and where intracellular TG metabolism impacts the regulation of whole-body energy balance. These data will open the door for discovery of new therapeutic approaches for the prevention and treatment of obesity, type 2 diabetes and mechanistically related disorders such as depression and anxiety.