Obesity has become an epidemic disease and a major risk factor for the development of insulin resistance and type 2 diabetes. Two types of adipose tissues exist in humans and rodents. White adipose tissue (WAT) is essential for maintaining whole body energy homeostasis by storing excessive energy when nutrients are in surplus and releasing free fatty acids as fuels during energy shortage. Pathological expansion of WAT is the basis for obesity development. WAT derived inflammatory events characterized by macrophage infiltration in obese state are considered as a causal factor for the development of obesity-related insulin resistance. In contrast, brown adipose tissue (BAT) is a thermogenic organ and can dissipate energy as heat and enhanced BAT function is desired for treating obesity. In this proposal, sucrose non-fermenting related kinase (SNRK) has been identified as a potential suppressor of WAT inflammation in response to over-nutrition as well as a critical factor for BAT development and adaptive thermogenesis. Our studies demonstrate that SNRK is most abundantly expressed in WAT and BAT, and the expression levels as well as activities are significantly decreased in both tissues in obese mice. Global SNRK deficiency is perinatal lethal and pups can only survive for 1 day. Reduction of SNRK expression induces inflammation in cultured white adipocytes, in WAT of global SNRK heterozygous mice and in WAT of adipose specific SNRK knockout mice. In BAT, SNRK expression can be induced by cold exposure and leptin treatment. SNRK deficiency significantly reduces expression of PRDM16 and UCP1 in BAT of new born pups, impairs mitochondria morphology, and significantly reduces oxygen consumption of primary brown adipocytes. We hypothesize that SNRK is a critical regulator to integrate nutrient input and metabolism, and SNRK deficiency will lead to WAT inflammation and impairment of BAT function. The following aims will be pursued: 1) Investigate the role of SNRK in WAT development and inflammation; 2) Determine the effect of inducible SNRK deficiency on WAT inflammation of adult mice; 3) Dissect the role of SNRK in BAT development and function. The main method is to use loss-of-function adipose tissue specific, inducible adipose tissue specific and BAT specific SNRK knockout mouse models. If the proposed goals are accomplished, the results will provide novel information to understand the molecular mechanism of obesity-related metabolic disorders and shed light on potential new therapeutic direction.

Public Health Relevance

Adipose tissue plays a critical role in maintaining energy homeostasis and obesity is associated with white adipose tissue inflammation and impaired brown adipose function. A novel factor was recently found to repress white adipose inflammation and was essential for preserving brown adipose function. Results generated from research outlined in this proposal will provide key information to understand the mechanism of action of this protein and evaluate its candidacy as a new therapeutic target for treating obesity-related metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK103699-01A1
Application #
8958657
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2015-08-28
Project End
2019-07-31
Budget Start
2015-08-28
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$387,020
Indirect Cost
$140,009
Name
Brown University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912