A small-molecule methyltransferase as a direct target of metformin - Project Summary Metformin is the first-in-line medication for type II diabetes (T2D), though its efficacy is limited to mild or moderate cases. Despite its clinical use for over 70 years, metformin’s mechanism of action is still unclear. This is due to uncertainty in the direct protein target(s) of metformin. Rational drug design efforts will be more fruitful with better information on metformin’s protein target(s). We performed an unbiased proteome-wide experiment which predicted a single novel direct target: the small-molecule methyltransferase INMT. I validated this thoroughly biochemically and biophysically. We also provided in cellulo and in vivo evidence for INMT’s role in antidiabetic actions of metformin. The broad, long-term objective of this project is to provide new insights into metformin’s molecular mechanism of action using our validated direct target: INMT. I will achieve this through three aims. First, I will assess the effect of metformin treatment in WT and INMT KO mice with a mild diabetic phenotype via diet-induced obesity (DIO). Second, I will perform liver- specific INMT KO to see if it phenocopies the enhancement of glucose tolerance seen in our whole-body KO mice. Finally, untargeted metabolomics and respirometry measurements will be used to unravel the molecular mechanisms underlying INMT’s mediation of metformin’s effects. Insights from this project serve a dual benefit for the mission of NIDDK: Firmly establishing INMT’s contribution to metformin’s effects will offer a new protein target for improved T2D therapeutics and related metabolic diseases. Also, insights gleaned along the way will inform us of INMT’s role in glucose metabolism, which to date is unknown. I will perform this research at the Dana Farber Cancer Institute (DFCI) under the mentorship of Dr. Bruce Spiegelman, who has studied energy homeostasis for over 40 years. His work in this field has contributed to mechanistic understandings of metabolic diseases such as obesity and T2D. Half a dozen of his many mentees are themselves professors at DFCI working in related areas of metabolism. This tribe of metabolic experts, together with the ample institutional resources of DFCI, provides an unparalleled environment to carry out my project. My project is intimately tied to my training: Nearly all the experiments and techniques that will be used to carry out this research are new to me. I will be trained to work with mice by a staff scientist and another fellow in the lab, then implement this to study glucose homeostasis. I will build upon my nascent experience in metabolomics by learning how to perform tracing studies and how to perform novel metabolite ID with a neighboring lab and our core facility. Finally, bimonthly meetings with Bruce where I share my progress, and the myriad guest speakers and internal meetings hosted through DFCI and HMS, will give me broader perspectives in metabolism and help guide my professional development. This will help me keep my research program on track to eventually become an independent investigator.
