Introduction and Objective: The inflammatory cytokine tumor necrosis factor alpha (TNF) has been implicated in obesity-related glucose intolerance, but its contribution within the brain towards peripheral glycemia has not been fully resolved. In the current study, we investigated the role of central TNF in regulation of systemic glucose homeostasis in lean and obese mice using pharmacologic methods. Methods: Adult male wild-type mice were implanted with lateral ventricle cannulas and fed a low-fat (LF) or high-fat (HF) diet. Prior to all metabolic assessments, mice were administered an acute intracerebroventricular injection of a control immunoglobulin or the TNF inhibitors infliximab and etanercept. Glucose homeostasis was assessed by intraperitoneal glucose and insulin tolerance tests. Food intake was measured after intracerebroventricular injection alone or in combination with intraperitoneal lipopolysaccharide injection. Results: Mice administered low-dose peripheral lipopolysaccharide displayed moderate hypophagia that was ameliorated through pre-treatment with intracerebroventricular etanercept, indicating central inhibition of inflammation. HF mice developed glucose intolerance after four weeks of diet compared to LF controls. However, we did not observe a significant difference in glucose excursions between mice treated with TNF inhibitor or vehicle regardless of diet, inhibitor dose, or drug type. Obese HF mice had significantly reduced insulin tolerance compared to LF mice, but this was also not affected by central TNF blockade. However, central TNF inhibition reduced food intake in LF mice, but not HF mice, after a 6-hour fast. Conclusion: These findings suggest that TNF signaling within the brain may be involved in food intake but it is dispensable for systemic glucose and insulin tolerance. Disclosure G. Griepp: None. R.J. Dupar: None. A.M. Brkic: None. M.M. Hafez: None. J. Douglass: None. Funding Seattle Pacific University Faculty Research Grant (CAS 115113)
GRIEPP et al. (Fri,) studied this question.