Mesenteric fat is known to undergo inflammatory changes after 2,4,6,-trinitrobenzensulphonic
acid (TNBS)-induced
colitis.
Neurotensin (NT) and
neurotensin receptor 1 (NTR1) have been shown to play a major role in the pathogenesis of intestinal
inflammation. This led us to explore whether NT and NTR1 are expressed in the mesenteric fat depots during TNBS-induced
colitis and whether NT participates in the increased
interleukin (IL)-6 secretion in this inflammatory response. TNBS-induced
inflammation in the colon increases NT and NTR1 expression in mesenteric adipose tissues, including mesenteric preadipocytes. Compared with wild-type mice, NT knockout (KO) mice have reduced TNBS-induced
colitis accompanied by diminished inflammatory responses in mesenteric adipose tissue. Specifically,
IL-6 and p65 phosphorylation levels in mesenteric fat of NT KO mice are also reduced compared with wild-type mice. Mouse 3T3-L1 preadipocytes express NTR1 and its expression is increased after stimulation of preadipocytes with proinflammatory
cytokines. NT stimulation of 3T3-L1 preadipocytes overexpressing NTR1 causes PKCdelta phosphorylation and
IL-6 secretion in a time- and dose-dependent fashion. Moreover, NT-mediated
IL-6 expression is
nuclear factor-kappaB and PKCdelta dependent. We also found that supernatants from NT-exposed 3T3-L1-NTR1 preadipocytes and mesenteric fat obtained from wild-type mice 2 days after TNBS administration stimulate an IL-6-dependent macrophage migration measured by a macrophage migration assay, whereas this response is reduced when mesenteric fat from NT KO mice is used. These results demonstrate an important role for NT in acute
colitis and adipose tissue
inflammation associated with experimental
colitis that involves direct NT proinflammatory responses in preadipocytes.