The long-term objective of our research is to understand the mechanisms by which obesity, and specifically upper body obesity, causes insulin resistance and the other health problems such as Type 2 Diabetes. Our focus is on the why the release of free fatty acids (FFA) from adipose tissue lipolysis is abnormal in humans who develop upper body/visceral obesity (UBO) and Type 2 Diabetes (T2DM).
The specific aims of this proposal are to: 1) test whether impaired insulin-induced suppression of lipolysis (FFA release) is related to the inflammatory and adipocyte characteristics in groups of individuals known to vary widely with regards to regulation of adipose tissue lipolysis;2) whether the reductions in adipose tissue inflammation and improvements in adipocyte function that accompany weight loss are predictive of improved insulin-regulation of lipolysis;3) define if, and so how, the omega-3 fatty acid-induced improvements in adipose inflammatory cell content correlate with reductions in adipose cytokine content and improvements in the insulin IC50 for FFA. We will measure of insulin-regulated adipose tissue lipolysis in vivo and assess adipose tissue inflammation in obese humans with widely varying degrees of insulin resistance before and after weight loss and before and after treatment with omega-3 fatty acids vs. placebo. Omega-3 fatty acids have been shown to reduce adipose tissue macrophage content in humans. Our hypothesis is that the amount and type inflammation predicts adipose insulin resistance;TNF is believed to down regulate perilipin, which would result in under-restrained access of lipases to lipid droplets, whereas IL-6 it believed to impair insulin signaling. We will measure the inflammatory cell content of adipose tissue, including classically activated macrophages and senescent preadipocytes, the tissue content of IL-6 and TNF, readouts of adipocyte TNF and insulin signaling, as well as adipocyte perilipin content. Combined, we believe these studies will offer insights as to why adipose tissue lipolysis is abnormal in some obesity phenotypes and whether therapies directed towards reducing adipose inflammation can improve metabolic health.

Public Health Relevance

We wish to understand why people who gain weight primarily in the abdominal area are more prone to illnesses such as diabetes. We know that fat and muscle tissue are primarily affected and believe that inflammation of adipose tissue leads to excess fat release into the bloodstream, which can then adversely affects many other tissues and organs. The experiments we propose will measure whether inflammation in adipose tissue affects its function and whether interventions designed to reduce adipose inflammation improve the ability of the body to regulate fat release from fat cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK040484-26A1
Application #
8690236
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Maruvada, Padma
Project Start
1988-08-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
26
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Espinosa De Ycaza, A E; Donegan, D; Jensen, M D (2017) Long-term metabolic risk for the metabolically healthy overweight/obese phenotype. Int J Obes (Lond) :
Santosa, Sylvia; Bush, Nikki C; Jensen, Michael D (2017) Acute Testosterone Deficiency Alters Adipose Tissue Fatty Acid Storage. J Clin Endocrinol Metab 102:3056-3064
Chung, Jin Ook; Koutsari, Christina; Blachnio-Zabielska, Agnieszka U et al. (2017) Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans. Diabetes 66:2082-2091
Lu, Jin; Varghese, Ron T; Zhou, Lianzhen et al. (2017) Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146. Metabolism 68:55-63
Morgan-Bathke, Maria; Harteneck, Debra; Jaeger, Philippa et al. (2017) Comparison of Methods for Analyzing Human Adipose Tissue Macrophage Content. Obesity (Silver Spring) 25:2100-2107
Puig, Kendra L; Brose, Stephen A; Zhou, Xudong et al. (2017) Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain. Sci Rep 7:43725
Søndergaard, Esben; Espinosa De Ycaza, Ana Elena; Morgan-Bathke, Maria et al. (2017) How to Measure Adipose Tissue Insulin Sensitivity. J Clin Endocrinol Metab 102:1193-1199
Anthanont, Pimjai; Levine, James A; McCrady-Spitzer, Shelly K et al. (2017) Lack of Seasonal Differences in Basal Metabolic Rate in Humans: A Cross-Sectional Study. Horm Metab Res 49:30-35
Anthanont, Pimjai; Jensen, Michael D (2016) Does basal metabolic rate predict weight gain? Am J Clin Nutr 104:959-963
Vella, Adrian; Jensen, Michael D; Nair, K Sreekumaran (2016) Eulogy for the Metabolic Clinical Investigator? Diabetes 65:2821-3

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