Growing evidence suggests that inflammation may be a central mechanism behind the development of many obesity-related diseases that include the metabolic syndrome and diabetes. Inflammatory changes in obesity include the infiltration of fat tissue with inflammatory macrophages. Adipose tissue macrophages (ATMs) can perturb normal adipocyte function and are necessary and sufficient to generate systemic insulin resistance in mouse models of obesity. This proposal seeks to understand the mechanisms by which ATMs alter adipocyte function and contribute to insulin resistance. The candidate's goals are (1) to increase his proficiency in immunology, (2) to become adept at the assessment of metabolism in animal models of obesity, and (3) through achieving the first two goals, to become an independent investigator with expertise in the mechanisms by which obesity generates inflammation and how this impacts human disease. The career development plan includes interdisciplinary mentorship from an expert in the obesity and metabolism, co-mentorship from an expert in chemokine biology, and collaboration with specialists in inflammation and diabetes. Preliminary studies indicated that obesity induced a switch in ATM activation state from an anti- inflammatory alternatively (M2) activated state in lean mice to a pro-inflammatory (M1) activated state in obese mice. While M1 macrophages rendered adipocytes insulin resistant, IL-10 produced from M2 macrophages protected adipocytes from the negative effects of TNFalpha. Experiments will test the hypothesis that IL-10 can prevent inflammatory changes in adipose tissue induced by obesity. The research plan will (1) assess the mechanisms by which IL-10 promotes normal adipocyte function, (2) assess the suppressive effects of IL-10 on ATM accumulation and activation in obese mice, and (3) test the hypothesis that IL-10 overexpression in macrophages will prevent adipose tissue inflammation and improve insulin sensitivity in obese mice. At the end of the funding period, the candidate expects to apply for independent funding based on his findings to further dissect the inflammatory changes caused by obesity in humans and mice. Relevance: This proposal examines the hypothesis that insulin resistance in obese mice can be prevented by blocking the inflammatory activation of macrophages in fat tissue. This will advance our understanding of the relationship between obesity, inflammation, and Type 2 Diabetes in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK078851-05
Application #
8098231
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$133,424
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Lumeng, Carey N (2013) Innate immune activation in obesity. Mol Aspects Med 34:12-29
Singer, Kanakadurga; Morris, David L; Oatmen, Kelsie E et al. (2013) Neuropeptide Y is produced by adipose tissue macrophages and regulates obesity-induced inflammation. PLoS One 8:e57929
Morris, David L; Cho, Kae Won; Delproposto, Jennifer L et al. (2013) Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62:2762-72
Morris, David L; Oatmen, Kelsie E; Wang, Tianyi et al. (2012) CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. Obesity (Silver Spring) 20:1189-99
Ramirez, Ixsy; Lumeng, Carey N (2012) Daily and intermittent corticosteroids have similar impact on recurrent wheezing in young children. J Pediatr 160:881
Lumeng, Carey N; Saltiel, Alan R (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-7
Cho, Kae Won; Lumeng, Carey N (2011) SirT1: a guardian at the gates of adipose tissue inflammation. Diabetes 60:3100-2
Deiuliis, Jeffrey; Shah, Zubair; Shah, Nilay et al. (2011) Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6:e16376
Morris, David L; Singer, Kanakadurga; Lumeng, Carey N (2011) Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care 14:341-6
Lumeng, Carey N; Liu, Jianhua; Geletka, Lynn et al. (2011) Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol 187:6208-16

Showing the most recent 10 out of 18 publications