Visceral obesity associates with insulin resistance and chronic inflammation, which are major risk factors for the metabolic syndrome, diabetes, and cardiovascular disease. Although the cellular hallmark of obesity is neutral lipid expansion in adipocytes, adipose tissue of obese mice and humans also accumulate macrophages and other leukocytes. It is well accepted that adipose tissue macrophages (ATMs) play a critical role in systemic insulin resistance, suggesting that inflammatory mediators produced by ATMs are important factors linking excess fat mass to insulin sensitivity, glucose intolerance, and increased atherosclerotic risk. Pro-inflammatory pathways in ATMs are commonly attributed to classical activation (i.e. exposure to bacteria), thereby establishing molecular links between innate immunity and metabolic dysfunction. However, recent studies suggest that classical models fail to accurately represent the complex phenotype of ATMs in vivo, raising the possibility that inflammation in the context of metabolic disease is distinct from infection. We have exciting preliminary data that reconcile this complex phenotype and introduce a new mechanistic understanding of the pathways that drive ATM inflammation in metabolic disease. Using a proteomics approach we demonstrate that markers of classical activation are absent on ATMs from obese subjects, but readily detectable on airway macrophages of patients with cystic fibrosis, a disease of chronic bacterial infection. Moreover, treating human macrophages with glucose, insulin, and palmitate - conditions characteristic of the metabolic syndrome - produces a pro-inflammatory, `metabolically-activated' phenotype that is remarkably distinct from classical activation. Importantly, markers of metabolic activation are overexpressed by ATMs from obese subjects and correlate strongly with BMI. Furthermore, we provide evidence that similar pathways for metabolic activation are present in mouse macrophages in vitro and in ATMs from obese mice. Here we will test the hypothesis that metabolic disease-specific mechanisms drive adipose tissue macrophage inflammation, which in turn, promotes the development of insulin resistance. Specifically, we plan to 1) Dissect cellular mechanisms driving metabolic activation of macrophages in vitro, 2) Determine if metabolic activation causes ATM inflammation and insulin resistance in a mouse model of obesity-associated type 2 diabetes, and 3) Investigate relationships between metabolic activation of macrophages and insulin resistance in human subjects. By integrating mechanistic animal and cellular studies with human observation, our proposed work will define clinically relevant pathways of macrophage inflammation. Understanding the mechanistic basis of the pro-inflammatory ATM phenotype and ATM function is required to devise new strategies for attenuating inflammation in metabolic disease.

Public Health Relevance

Strong evidence supports the idea that macrophage inflammation is a key event in the pathogenesis of type 2 diabetes and insulin resistance. Although pro-inflammatory pathways in macrophages are commonly attributed to bacterial exposure, emerging evidence suggests that low-grade inflammation in the context of metabolic disease is fundamentally distinct from infection. The overall goal of this application is to delineate novel metabolic disease-specific pathways for macrophage inflammation and to determine their role in potentiating insulin resistance in humans and mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102960-03
Application #
9261521
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2015-05-05
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Coats, Brittney R; Schoenfelt, Kelly Q; Barbosa-Lorenzi, Valéria C et al. (2017) Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity. Cell Rep 20:3149-3161