The so-called """"""""metabolic syndrome"""""""" refers to a group of chronic diseases which appear to cluster in certain individuals. What appears to be central to these conditions is the existence of insulin resistance. Truncal adiposity, including fat stored in the intraperitoneal space may be a primary cause of the syndrome. Yet, the mechanism(s) underlying the linkage between visceral adiposity, insulin resistance and hyperinsulinemia remain obscure. We will examine the inter-organ signaling which is responsible for the link between obesity and insulin resistance.
Specific Aim I : we will examine long-term longitudinal changes associated with control, moderate fat, and high fat diets (saturated and unsaturated). We will examine changes in fat deposition in visceral and peripheral depots and hepatic, adipose and peripheral insulin resistance. We will test the """"""""overflow hypothesis"""""""": energy is stored initially in visceral fat resulting in hepatic resistance, and subsequently in subcutaneous fat causing peripheral resistance. We will measure expression of key genes in adipose, liver and muscle as well as putative inter-organ signals in peripheral and portal blood, including free fatty acids (FFA) and adipokines (IL-1, IL-6, adiponectin, resistin, TNFa). We will examine the importance of the markedly increased nocturnal FFA and adipokines in the development of the metabolic syndrome.
Specific Aim II : We will investigate the role of the sympathetic nervous system. In the previous funding period we confirmed the pulsatile release of FFA (6 cycles/hour) from the adipose depot, and confirmed that they are sympathetically driven (blocked with a (3-3 antagonist). We will test that hypothesis that night-time pulsatile release of FFA (and/or adipokines) is critical in the development of insulin resistance associated with omental adiposity.
Specific Aim III : we will investigate the role(s) of FFA, adipokines and the sympathetic nervous system in a model of latent pancreatic (3-cell defect. We plan to determine whether a relative reduction in islet function such as in the pre-Type 2 diabetic state will exacerbate the effects of FFA and/or adipokines to cause central storage of fat and insulin resistance. Insulin resistance and associated disorders causes untold suffering and mortality in westernized society. Understanding the physiological mechanisms underlying the relationship between obesity and insulin resistance may provide a path whereby intervention may prevent the associated morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK027619-27
Application #
8012814
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
1980-02-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
27
Fiscal Year
2011
Total Cost
$540,089
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J et al. (2017) Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure. Diabetes 66:823-834
Piccinini, Francesca; Polidori, David C; Gower, Barbara A et al. (2017) Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women. Diabetes 66:2564-2570
Polidori, David C; Bergman, Richard N; Chung, Stephanie T et al. (2016) Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data. Diabetes 65:1556-64
Iyer, Malini S; Bergman, Richard N; Korman, Jeremy E et al. (2016) Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet. Diabetes 65:3453-3463
Broussard, Josiane L; Castro, Ana V B; Iyer, Malini et al. (2016) Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity. Obesity (Silver Spring) 24:1922-8
Woolcott, Orison O; Gutierrez, Cesar; Castillo, Oscar A et al. (2016) Inverse association between altitude and obesity: A prevalence study among andean and low-altitude adult individuals of Peru. Obesity (Silver Spring) 24:929-37
Broussard, Josiane L; Nelson, Michael D; Kolka, Cathryn M et al. (2016) Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity. Diabetologia 59:197-207
Rojas, Jennifer M; Matsen, Miles E; Mundinger, Thomas O et al. (2015) Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response. Mol Metab 4:561-8
Kolka, Cathryn M; Castro, Ana Valeria B; Kirkman, Erlinda L et al. (2015) Modest hyperglycemia prevents interstitial dispersion of insulin in skeletal muscle. Metabolism 64:330-7
Woolcott, Orison O; Ader, Marilyn; Bergman, Richard N (2015) Glucose homeostasis during short-term and prolonged exposure to high altitudes. Endocr Rev 36:149-73

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