Obesity is frequently associated with insulin resistance and constitutes the major risk factor for non insulin-dependent diabetes mellitus (NIDDM). In recent years, studies have indicated that in obesity, the elevated expression of TNFalpha by adipose cells plays a critical role in the development of insulin resistance. TNFalpha interferes with insulin action by inhibiting the tyrosine kinase activity of the insulin receptor (IR) both in cultured cells and in whole animals. This inhibition of IR signaling appears to be through TNFalpha-induced serine phosphorylation of insulin receptor substrate 1 (IRS-1). However, the molecular components that are involved in this process, especially concerning the proximal signaling events activated by TNF are not known. In this application we propose to address these components by studying the biological functions of TNFalpha mediated through its two identified receptors (TNFR1 and TNFR2) in relation to TNFalpha-induced insulin resistance and other aspects of energy metabolism in whole animals. We will address the role of each receptor in TNFalpha-induced insulin resistance by utilizing mice which carry targeted mutations in TNFR1, TNFR2 and both. We will first characterize the metabolic state of these animals in detail. These will be followed generating obese animals which are deficient for one or both of the TNF receptors. Initially, this will be accomplished by cross-breeding TNFR mutant mice into a genetic model of obesity and insulin resistance (ob/ob mice). The metabolic state of the resulting progeny will be studied with particular focus on glucose homeostasis and insulin action to understand which TNF receptor is primarily involved in this process. In addition, we will investigate the role of each TNF receptor in diet-induced obesity and insulin resistance, during which there is also elevated TNFalpha expression in adipose tissue. These experiments will be followed by reconstituting TNF receptor expression in the TNFR1/TNFR2-deficient mice in a adipose tissue- specific fashion. The aP2 promoter/enhancer region will be used to direct the transgenic expression of TNFR1 or TNFR2 to adipose tissue. The resulting mice will then be compared to both control and TNFR- deficient mice mainly focusing on glucose homeostasis and adipose tissue development in response to dietary or genetic manipulations to induce obesity. These experiments will allow us to study the role of TNF signaling through each TNF receptor in adipose tissue during the development of insulin resistance in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052539-03
Application #
6164543
Study Section
Endocrinology Study Section (END)
Program Officer
Haft, Carol R
Project Start
1998-03-01
Project End
2001-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
3
Fiscal Year
2000
Total Cost
$248,496
Indirect Cost
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Lunhua; Inouye, Karen Etsuko; Allman, Windy Rose et al. (2018) TACI-Deficient Macrophages Protect Mice Against Metaflammation and Obesity-Induced Dysregulation of Glucose Homeostasis. Diabetes 67:1589-1603
Arruda, Ana Paula; Pers, Benedicte Mengel; Parlakgul, Günes et al. (2017) Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity. Elife 6:
Hotamisligil, Gökhan S (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177-185
Hotamisligil, Gökhan S (2017) Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity 47:406-420
Yang, Ling; Licastro, Danilo; Cava, Edda et al. (2016) Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle. Cell Rep 14:422-428
Babaev, Vladimir R; Yeung, Michele; Erbay, Ebru et al. (2016) Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. Arterioscler Thromb Vasc Biol 36:1122-31
Ertunc, Meric Erikci; Hotamisligil, Gökhan S (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099-2114
Yilmaz, Mustafa; Claiborn, Kathryn C; Hotamisligil, Gökhan S (2016) De Novo Lipogenesis Products and Endogenous Lipokines. Diabetes 65:1800-7
Youssef, Osama A; Safran, Sarah A; Nakamura, Takahisa et al. (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112:5023-8
Yang, Ling; Calay, Ediz S; Fan, Jason et al. (2015) METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349:500-6

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