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.
|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|
Showing the most recent 10 out of 84 publications