Insulin resistance is a sine qua non of Type 2 diabetes and a frequent complication of obesity, lipodystrophy, inflammation, steroid use, critical illness, and a variety of other conditions and insults. It has long been a mystery how so many profoundly different stimuli all result in the same clinical phenotype. Furthermore, most studies of insulin resistance have posited the action of cytoplasmic, mitochondrial, and ER-related pathways, such as toxic lipid intermediates, oxidative stress, or ER stress. Very few studies have focused on nuclear mechanisms of insulin resistance, despite strong evidence that transcriptional and epigenetic factors must be in play. We have used a comparative model of insulin resistance in 3T3-L1 adipocytes treated with dexamethasone (Dex) or TNF? (TNF) to identify novel pathways that cause this disorder. Integrated transcriptional, epigenomic, and computational analysis have identified two nuclear hormone receptors as important; TNF-mediated glucocorticoid receptor (GR) action and the vitamin D receptor (VDR). This proposal will identify the mechanisms by which the GR and VDR promote insulin resistance in both murine and human cells, and will identify the specific gene targets that mediate this effect. Importantly, it will also validate our findings in vivo, using both gain- and loss-of-function approaches. Taken together, this proposal has the potential to characterize two novel pathways of insulin resistance with inherent therapeutic potential.

Public Health Relevance

Resistance to the metabolic actions of insulin is a sine qua non of Type 2 diabetes, but it is also seen in a wide variety of other clinical disorders, ranging from lipodystrophy to pregnancy to steroid use. Little is known about how the molecular mechanisms by which these varied insults cause a common phenotype, and even less is known about the transcriptional or epigenetic basis of this process despite a wealth of evidence that such factors play a major role. We have used an integrative approach combining transcriptional and epigenomic profiling of two models of insulin resistance to identify common transcriptional pathways that may be operating. Here we propose to identify the mechanisms by which these pathways cause insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102173-03
Application #
9212143
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
2015-04-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$411,731
Indirect Cost
$175,104
Name
Beth Israel Deaconess Medical Center
Department
Type
Independent Hospitals
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Ahmad, Rasheed; Al-Roub, Areej; Kochumon, Shihab et al. (2018) The Synergy between Palmitate and TNF-? for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation. J Immunol 200:3599-3611
Roh, Hyun Cheol; Tsai, Linus T Y; Shao, Mengle et al. (2018) Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity. Cell Metab 27:1121-1137.e5
De Filippis, Elena; Li, Ting; Rosen, Evan David (2018) Exposure of adipocytes to bisphenol-A in vitro interferes with insulin action without enhancing adipogenesis. PLoS One 13:e0201122
Kong, Xingxing; Yao, Ting; Zhou, Peng et al. (2018) Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin. Cell Metab 28:631-643.e3
Shen, Yachen; Roh, Hyun Cheol; Kumari, Manju et al. (2017) Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding. Mol Metab 6:1150-1160
Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496
You, Dongjoo; Nilsson, Emma; Tenen, Danielle E et al. (2017) Dnmt3a is an epigenetic mediator of adipose insulin resistance. Elife 6:
Kazak, Lawrence; Chouchani, Edward T; Lu, Gina Z et al. (2017) Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab 26:660-671.e3
Roh, Hyun Cheol; Tsai, Linus T-Y; Lyubetskaya, Anna et al. (2017) Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo. Cell Rep 18:1048-1061
Rosen, E D (2016) Epigenomic and transcriptional control of insulin resistance. J Intern Med 280:443-456

Showing the most recent 10 out of 11 publications