Obesity and its associated disorders, including diabetes and cardiovascular disease, are growing in prevalence worldwide. An emerging therapeutic avenue for treating obesity and diabetes is to augment energy expenditure by activating thermogenic adipocytes. These cells are characterized by multiloclular lipid droplets, high mitochondrial content, and the expression of a membrane protein uncoupling protein 1 (UCP1) that generates heat. There are two distinct types of thermogenic adipocytes, brown and beige cells. That brown or beige fat confers metabolic benefit is now well established, at least in rodents. While significant progress has been made towards elucidating the transcriptional pathways that establish and maintain a thermogenic program, significantly less is known about circulating factors that regulate brown and beige fat function. An understanding of these signaling molecules and their mechanisms of action may reveal novel crosstalk in the heterogeneous cellular environment of adipose tissues and provide exciting opportunities to exploit thermogenic cells for the treatment of obesity and diabetes. My approach to this problem involves the development and application of several innovative, in vivo approaches to elucidate novel secreted factors that can activate brown and beige adipocytes. In this proposal, I will test the hypothesis that the circulating factors METRNL and PM20D1 can illuminate brown and beige fat physiology while providing potentially pharmacologically tractable nodes of intervention into metabolic diseases. Specifically, I propose to: 1) test the hypothesis that METRNL-deficient mice have perturbed adipose tissue homeostasis; 2) test the hypothesis that PM20D1 is a brown/beige fat-selective adipokine that can improve metabolic health; and 3) determine the mechanism by which PM20D1 promotes thermogenesis. I will use a combination of mouse genetics, metabolic analysis, and biochemical techniques to address these questions. If successful, I anticipate that these studies can provide pharmacologically tractable targets for the treatment of obesity and associated metabolic disorders. My immediate and long-term research objectives are to identify molecules and pathways that regulate adipose tissue physiology and homeostasis, always keeping in mind the potential therapeutic opportunities as they arise. My long-term career objective is to establish myself as an independent investigator in the field of metabolism and diabetes. During my graduate studies I experienced first-hand the remarkable capacity of technological advancements to push forward the frontiers of our understanding of mammalian physiology and behavior. This general theme has remained with me during my postdoctoral training and continues to influence my scientific thinking and planning. Projecting forward, I plan to leverage the chemical and technology development aspects of my training specifically to the problems of obesity and diabetes. The mentored phase of this research will be conducted in the laboratory of Dr. Bruce Spiegelman at Harvard Medical School. Dr. Spiegelman is a recognized leader in the field of molecular diabetes research. The NIH Pathway to Independence Award will be critical for my transition to independence because it will enable me to acquire additional training in the metabolic characterization of rodent obesity models, while also improving the communication, management, and writing skills that I will require for successful independence.
Obesity and its associated metabolic disorders, including cardiovascular disease, diabetes, stroke, and cancer, are estimated to cost American taxpayers $150 billion in 2008 US dollars. This proposal seeks to understand new pathways that could be used to treat this constellation of disorders.
|Lin, Hua; Long, Jonathan Z; Roche, Alexander M et al. (2018) Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration. J Med Chem 61:3224-3230|
|Long, Jonathan Z; Roche, Alexander M; Berdan, Charles A et al. (2018) Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception. Proc Natl Acad Sci U S A 115:E6937-E6945|