The long-term objective of our research is to understand the mechanisms by which obesity, and specifically upper body obesity (UBO), causes insulin resistance and the other health problems such as Type 2 Diabetes. Our focus is on the release of free fatty acids (FFA) from adipose tissue lipolysis in humans and how those FFA affect the functioning of other tissues (lipotoxicity).
The specific aims of this proposal are to: 1) Determine whether impaired insulin-induced suppression of lipolysis (as measured by IC50) is related to the above mentioned lipolysis proteins in groups of volunteers known to vary widely with regards to abdominal adipocyte size and regulation of adipose tissue lipolysis; 2) Determine whether the improved insulin regulation of lipolysis resulting from treatment with the PPAR? agonist pioglitazone, with or without weight loss, can be linked to specific changes in sets of PPAR?-responsive adipocyte lipolysis proteins in UBO adults; 3) Determine whether the adipose inflammatory cell and cytokine content in Class III obesity is related to lipolysis insulin resistance and, if so, whether sustained, substantial weight loss one year following bariatric surgery reduces inflammation in parallel with improved insulin regulation of lipolysis. We will measure of insulin- regulated adipose tissue lipolysis in vivo and assess adipocyte lipolysis proteins, inflammation and insulin signaling in obese humans with widely varying degrees of insulin resistance. Our hypothesis is that proteins involved in the final steps of the regulation of lipolysis are altered in humans with large fat cells, and that these alterations are responsible for adipose insulin resistance. Combined, we believe these studies will offer insights as to why adipose tissue lipolysis is abnormal in some obesity phenotypes and provide information on what therapeutic strategies to treat adipose insulin resistance are most compelling.

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 tissue under the skin in the abdominal area releases excess fat release into the bloodstream, which then effects how the rest of our body is able to metabolize sugars. The experiments we propose will measure whether certain proteins in fat cells are present in abnormal amounts and whether this alters the ability of fat cells to respond to the body's signals that are supposed to reduce the release of fats into the bloodstream.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK040484-30
Application #
9523000
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Maruvada, Padma
Project Start
1988-08-01
Project End
2023-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
30
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
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
S√łndergaard, 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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