Type 2 diabetes (T2D) affects more than 25 million Americans and is a leading cause of heart disease, stroke, blindness, and kidney disease. A hallmark of T2D is insulin resistance;however, myriad poorly understood factors contribute to the pathophysiology of insulin resistance. Mounting evidence in humans suggests that life- long insulin resistance may be influenced by epigenetic mechanisms or changes in genomic regulation without alterations in DNA sequence. There is a critical need to better understand fundamental outputs of insulin signaling in order to better target insulin resistance. This project will meet this critical need by uncovering key signaling events downstream of target of rapamycin complex 2 (TORC2), a highly conserved protein kinase critical to the regulation of insulin sensitivity. Mice lacking mammalian TORC2 (mTORC2) in liver develop profound insulin resistance with diabetes-like phenotypes, hyperglycemia and defects in lipid metabolism. Our previous work indicates that TORC2 is a conserved regulator of lipid metabolism as C. elegans TORC2 (CeTORC2) mutants also show defects in lipid metabolism as well as growth, reproduction, and lifespan. Although a major output of TORC2 is activation of the protein kinase Akt, in C. elegans and in mice, there is evidence for additional, important outputs of TORC2 regulating metabolism. Our prior work shows significant similarity in signaling downstream of mTORC2 and CeTORC2, indicating that study of phylogenetically conserved elements of the TORC2 pathway in both systems will illuminate critical, fundamental aspects of insulin signaling. Our preliminary data are the first evidence that a conserved epigenetic pathway is central to the regulation of lipid metabolism, growth, and reproduction by TORC2 in C. elegans. We hypothesize that TORC2 normally activates a program of gene expression to modulate metabolism by communicating with the cellular epigenetic machinery. Our major goal is to elucidate the full spectrum of conserved, TORC2-regulated epigenetic changes that regulate metabolism.
In Aim 1, we will use C. elegans genetics and genomics to identify the mechanisms by which CeTORC2-regulated epigenetic changes lead to altered metabolism, and we will use liver specific mTORC2 knockout mice to demonstrate conservation of epigenetic mechanisms acting downstream of the complex.
In Aim 2 we will use genomic, biochemical and physiologic approaches in C. elegans and mice to define conserved mechanisms by which TORC2 regulates changes in gene expression via epigenetics. At the conclusion of these studies, we will have identified the major epigenetic mechanisms by which TORC2 regulates metabolism. These findings will have broad implications for study of states of insulin resistance and for futur design of more effective therapies and preventions for T2D, and will provide an inroad to study how lifelong insulin resistance is impacted by heritable changes in chromatin.

Public Health Relevance

Type 2 diabetes (T2D) affects more than 25 million Americans and is a leading cause of death and disability. T2D is associated with resistance to insulin, leading to high blood sugar levels, and yet the causes of insulin resistance remain incompletely understood. This project investigates the role of a conserved signaling complex central to the action of insulin and focuses on how the complex can lead to genomic changes which have implications for insulin sensitivity and the development of T2D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Silva, Corinne M
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Massachusetts General Hospital
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Webster, Christopher M; Pino, Elizabeth C; Carr, Christopher E et al. (2017) Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival. Cell Rep 20:627-640
Wu, Lianfeng; Zhou, Ben; Oshiro-Rapley, Noriko et al. (2016) An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell 167:1705-1718.e13
Lynn, Dana A; Dalton, Hans M; Sowa, Jessica N et al. (2015) Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans. Proc Natl Acad Sci U S A 112:15378-83
Webster, Christopher M; Wu, Lianfeng; Douglas, Denzil et al. (2013) A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2. Development 140:3601-12