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 has been on regional adipose tissue lipolysis and fat storage, as well as FFA released as a result of lipolysis affect the functioning of other tissues (lipotoxicity).
The specific aims of this proposa are to: 1) assess the contribution of plasma FFA and muscle FFA uptake to the intramyocellular lipid metabolites (ceramides and diacylglycerols - DG) most closely linked to impaired activation of insulin signaling pathways in muscle and reduced glucose uptake;2) define the improvements in muscle FFA uptake and FFA incorporation into intramyocellular lipid metabolites associated with improved activation of insulin signaling pathways and muscle glucose uptake following overnight suppression of FFA with intravenous niacin in UBO and T2DM;3) measure the effects of sub-acute, moderate elevations of physiological FFA on muscle lipid metabolite trafficking, insulin signaling and muscle glucose uptake in healthy, non-obese adults. We will measure insulin stimulated glucose disposal (muscle glucose uptake) and muscle insulin signaling in obese humans with widely varying degrees of insulin resistance. We will also measure muscle FFA uptake as a function of FFA concentrations using 11C-palmitate PET scan approaches to understand if variations in muscle FFA uptake beyond those predicted by concentration contributes to greater lipotoxicity. We also measure muscle FFA trafficking using will use stable isotope/mass spectrometry approaches to determine how FFA are trafficked into long chain acyl-CoA, DG, TG, ceramides and long chain acyl-carnitines in muscle of these same volunteers. Our hypothesis is that trafficking of FFA into ceramides and/or DG, specifically subsarcolemmal lipids, is more closely linked with muscle insulin resistance. We will also test how lowering of FFA by an overnight, intravenous niacin infusion alters intramyocellular FFA trafficking and insulin action. Finally, by raising FFA via a duodenal infusion of palm oil vs. Intralipid(R), we will test whether a physiological elevation of FFA (as opposed to isolated increases in polyunsaturated FFA) mimics the muscle trafficking profile of insulin resistant obesity. Combined, we believe these studies will offer insights as to why some obesity phenotypes have even more variability in muscle insulin action than would be predicted based solely upon plasma FFA concentrations.

Public Health Relevance

The proposed studies are to help understand how fat tissue and muscle tissue interact in health and disease. We will study how fat molecules that are released by fat cells are taken up by muscle cells and converted into new molecules that can serve either as energy for muscle or can interfere with the normal function of muscle. We are especially interested in whether fat molecules block the ability of insulin to help muscle burn sugar.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK045343-23
Application #
8755927
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Evans, Mary
Project Start
1992-09-30
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Chung, Jin Ook; Koutsari, Christina; Blachnio-Zablieska, Agnieszka Urszula et al. (2018) Effects of meal ingestion on intramyocellular ceramide concentrations and fractional de novo synthesis in humans. Am J Physiol Endocrinol Metab 314:E105-E114
Lu, Jin; Allred, Carolyn C; Jensen, Michael D (2018) Human adipose tissue protein analyses using capillary western blot technology. Nutr Diabetes 8:26
Bray, George A; Heisel, William E; Afshin, Ashkan et al. (2018) The Science of Obesity Management: An Endocrine Society Scientific Statement. Endocr Rev 39:79-132
Espinosa De Ycaza, A E; Donegan, D; Jensen, M D (2018) Long-term metabolic risk for the metabolically healthy overweight/obese phenotype. Int J Obes (Lond) 42:302-309
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
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
Anthanont, P; Ramos, P; Jensen, M D et al. (2017) Family history of type 2 diabetes, abdominal adipocyte size and markers of the metabolic syndrome. Int J Obes (Lond) 41:1621-1626
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

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