Inverse Regulation of Inflammation and Mitochondrial Function in Adipose Tissue Defines Extreme Insulin Sensitivity in Morbidly Obese Patients
- Mohammed Qatanani1,2,
- Yejun Tan1,3,
- Radu Dobrin1,3,
- Danielle M. Greenawalt1,3,
- Guanghui Hu1,3,
- Wenqing Zhao1,3,
- Jerrold M. Olefsky4,
- Dorothy D. Sears4,
- Lee M. Kaplan5 and
- Daniel M. Kemp1,2⇓
- 1Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, New Jersey
- 2Diabetes and Endocrinology, Merck Research Laboratories, Rahway, New Jersey
- 3Informatics and Analysis, Merck Research Laboratories, Rahway, New Jersey
- 4Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California
- 5Gastrointestinal Metabolism Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Corresponding author: Daniel M. Kemp,
M.Q. and Y.T. contributed equally to this study.
Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ∼320 nondiabetic (HbA1c <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment–insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0399/-/DC1.
- Received April 4, 2012.
- Accepted September 27, 2012.
- © 2013 by the American Diabetes Association.
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