Macrophage TNF-{alpha} contributes to insulin resistance and hepatic steatosis in diet-induced obesity

Departments of 1 Medicine and 2 Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee Submitted 29 March 2007 ; accepted in final form 15 June 2007 Obesity is commonly associated with development of insulin resistance and systemic evidence of inflammation. Macrophages contribute to inflammatory amplification in obesity and may contribute directly to insulin resistance and the development of nonalcoholic fatty liver disease through the production of inflammatory cytokines, including tumor necrosis factor (TNF)- . To test this hypothesis, we transplanted male wild-type (WT) and TNF- deficient (KO) mice with either TNF- -sufficient (TNF- +/+ ) or TNF- -deficient (TNF- –/– ) bone marrow. After consuming a high-fat diet for 26 wk, metabolic and morphometric characteristics of the animals were analyzed. While there were no differences in terms of relative weight gain, body composition analysis yielded a lower relative adipose and higher relative lean mass in mice lacking TNF- , which was partially explained by reduced epididymal fat pad and liver weight. TNF- –/– KO mice exhibited enhanced insulin sensitivity compared with that observed in TNF- +/+ KO mice; remarkably, no protection against insulin resistance was provided by transplanting TNF- –/– bone marrow in WT mice compared with TNF- +/+ WT. The preserved insulin sensitivity seen in TNF- –/– KO mice provided protection against the development of hepatic steatosis. Taken together, these data indicate that macrophage-derived TNF- contributes to the pattern and extent of fat accumulation and insulin resistance in diet-induced obesity; however, this contribution is negligible in the presence of host-derived TNF- . cytokine; inflammation; hyperinsulinemic-euglycemic clamping Address for reprint requests and other correspondence: D. E. Vaughan, Vanderbilt Univ. Medical Center, Dept. of Medicine, Division of Cardiovascular Medicine, 383 Preston Research Bldg., Nashville, TN 37232 (e-mail: Douglas.e.vaughan{at}vanderbilt.edu )