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Changes in Hypothalamically Mediated Acute-Phase Inflammatory Responses to Lipopolysaccharide in Diet-Induced Obese Rats

Douglas Mental Health University Institute (J.P., G.N.L.), Department of Psychiatry, McGill University, Montreal, Quebec, Canada H4H 1R3; and Groupe de recherche en neurobiologie comportementale/Center for Studies in Behavioural Neurobiology (B.W.), Concordia University, Montreal, Quebec, Canada H4B 1R6

Address all correspondence and requests for reprints to: Giamal N. Luheshi, Douglas Mental Health University Institute, 6875 Boul LaSalle, Montreal, Quebec, Canada H4H 1R3. E-mail: Giamal.Luheshi{at}mcgill.ca.

Recent evidence suggests that inflammation may be a common underlying cause of many obesity-associated conditions. To test whether obesity changes the response to inflammation, we investigated its effects on the acute phase of the inflammatory response to an endogenous pathogen, lipopolysaccharide (LPS). Diet-induced obese male Wistar rats exhibited an increased and prolonged fever response to LPS (100 µg/kg) relative to lean rats. LPS-treated obese rats also showed a greater increase in circulating TNF-, IL-6, and IL-1 receptor antagonist within the first 8 h after LPS injection. LPS induced an increase in circulating leptin only in obese rats with no effect in lean rats. Analysis of expression of pyrogenic signaling in the hypothalamus demonstrated that obese rats show a greater increase in IL-1β peaking at 2 h after LPS injection and suppressor of cytokine signaling 3 and IL-6 peaking at the 8-h time point. LPS-treated obese rats showed a significantly higher expression of IL-1 receptor antagonist in white adipose tissue (WAT) than lean rats, and WAT from obese rats incubated in LPS-supplemented medium (100 ng/ml) secreted a significantly higher level of IL-6. Overall, these results suggest that diet-induced obesity induces changes in the inflammatory response rendering the obese rats more responsive to the effects of LPS. These data also support the hypothesis that qualitative changes in WAT associated with obesity may contribute to these effects.