We are witnessing a dramatic increase in the prevalence of obesity, which is driving an alarming increase in type 2 diabetes worldwide. Rational therapeutic approaches targeting the early stages of this disease continuum requires a comprehensive understanding of the mechanisms that link insulin resistance to excess caloric consumption. An association between skeletal muscle lipid accumulation, insulin resistance, and impaired glucose metabolism is widely recognized, yet the mechanistic underpinnings of the association remain elusive. Indeed, intramyocellular TAG accumulation can be associated with improved muscle performance and metabolic flexibility. During a period of R24 seed grant support, we have built a unified interdisciplinary research team, conducted feasibility and proof-of-concept studies, and designed a full R24 project to address this problem. We will test the central hypothesis that myocellular lipid accumulation triggers both adaptive and maladaptive (lipotoxic) responses, that these can influence glucose utilization via insulin signaling-dependent and -independent mechanisms, and that a dynamic balance between these responses determines the evolution of muscle insulin resistance. This project, which will harness the combined powers of unbiased chemical biology and functional genomics screening, is composed of five inter-connected Specific Aims. Chemical biology (Aim 1) and functional genomic (Aim 2) screens will be conducted using cultured skeletal myocytes loaded with excess fatty acid. To efficiently assess muscle autonomous vs. non-autonomous effects in vivo, a Drosophila model of obesity will be used to rapidly validate the genes (Aim 3). A Systems Integration Group will oversee the collection, storage, filtering, and analysis of the data generated by the studies of each Aim, to establish prioritized lists of genes, small molecule modifiers, and corresponding target pathways. After initial metabolic classification and prioritization, an iterative process of deep cellular and metabolic characterization together with metabolomic, lipidomic, and transcriptomic profiling, will be conducted to define phenotypic fingerprints or signatures representing adaptive and maladaptive sub-categories or """"""""bins"""""""" of relevant myocyte perturbations (Aim 4). The phenotypic signatures will then be compared with similar profiles collected for muscle biopsy specimens from well-characterized human volunteers across a range of fitness and metabolic disease cohorts (Aim 5). The long-term goal of this project is to identify new genes, pathways, and molecular probes relevant to muscle lipotoxicity, serving as a valuable hypothesis-generating resource for the field and establishing a pipeline for drug development and biomarker discovery aimed at the earliest stages of insulin resistance.

Public Health Relevance

We are witnessing a worldwide health crisis due to a dramatic increase in the prevalence of obesity, which in turn, is driving a sweeping upsurge in the incidence of type 2 diabetes. Our proposed research seeks to understand the mechanisms that link caloric excess to the development of diabetes, using a multi disciplinary, team-based approach. Our research team will identify new drug targets aimed at the early stages of this serious disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZDK1-GRB-J (M1))
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Margolis, Ronald N
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Ahn, Byungyong; Soundarapandian, Mangala M; Sessions, Hampton et al. (2016) MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. J Clin Invest 126:3567-79
Sugarman, Eliot; Koo, Ada; Suyama, Eigo et al. (2014) Identification of Inhibitors of triacylglyceride accumulation in muscle cells: comparing HTS results from 1536-well plate-based and high-content platforms. J Biomol Screen 19:77-87