Regulation of Energy Expenditure by NF-kB. NF-kB is a transcription factor that is activated in adipose tissue in obesity. NF-kB induces cytokine expression and inhibits lipid accumulation in adipocytes, which contribute to the pathogenesis of insulin resistance according to data derived from cellular models. To test the NF-kB activity in vivo, we enhanced and decreased NF-kB activity by overexpressing and knocking out of the p65 subunit. Fat-selective NF-kB activation induced a low grade inflammatory response in the fat tissue, and inhibited adiposity in the aP2-p65 mice. However, the inflammation did not impair systemic insulin sensitivity in the mice on either chow or high fat diet. The mice exhibited an increase in energy expenditure at room temperature and an elevation in thermogenesis in the cold environment. In fat-selective p65-KO mice, the thermogenesis was significantly impaired in the cold response leading to hypothermia in mice. The thermogenic alterations were associated with functional changes in brown adipose tissue (BAT) and white adipose tissues (WAT). The preliminary data suggests that NF-kB activation in adipose tissue may promote thermogenesis by enhancing BAT function and WAT browning. This possibility will be tested in three aims. The study will uncover the NF-kB activity in brown adipocytes and beige adipocytes for the first time. The results may provide answers to observations that the anti-inflammation therapies induce weight gain in humans, failure of anti-inflammatory therapy in insulin sensitization in most clinical trials, and disassociation of inflammation with insulin resistance in rodent models.

Public Health Relevance

Obesity increases risk of type 2 diabetes through impairing insulin action, a phenomenon called insulin resistance in the pathogenesis of type 2 diabetes. Animal study suggests that insulin resistance is a result of chronic inflammation in obesity. However, the human studies suggest that inflammation is not a major cause of insulin resistance. It is not known why there is a discrepancy in the role of inflammation. In this study, we will address this issue by studying the beneficial effects of inflammation using transgenic mice of NF-kB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK068036-10A1
Application #
9001394
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Abraham, Kristin M
Project Start
2004-06-01
Project End
2017-04-30
Budget Start
2015-05-18
Budget End
2017-04-30
Support Year
10
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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