Neuropeptides, mesenteric fat, and intestinal inflammation

Abstract

The ability of fat tissue cells to produce proinflammatory cytokines and the concept that obesity represents a low-grade inflammatory response have been well documented during the past decade. The effects of fat-mediated inflammation on metabolic pathologies have also been drawing increasing interest. However, very little is known on the potential effects of adipose tissue in the pathophysiology of gastrointestinal diseases with an inflammatory component, such as inflammatory bowel disease (IBD). The development of large fat masses around the inflamed intestine during Crohn's disease makes this tissue a candidate for more intense investigation in studies aiming to gain insights into the pathogenesis and progress of the disease. Furthermore, neuropeptides act in many cases in a proinflammatory manner and are shown to participate in the pathogenesis of intestinal inflammation in animal models of IBD. However, the potential of these molecules to interact with fat cells in the context of IBD has not been investigated. In this review the authors' most recent data related to the effects of neuropeptides on noninflammatory fat tissue components are described. In addition, a discussion to associate neuropeptide-induced, adipose tissue-mediated responses with the generation of intestinal inflammatory conditions such as Crohn's disease is included.

Figure 1. TNBS-induced colitis results in increased inflammation in the mesenteric fat depots of CD1 mice

Male CD1 mice received a single intra-colonic dose of TNBS, sacrificed after 48 hrs and mesenteric fat depots proximally to the inflamed intestine were removed for observation under a light microscope. (A) Mesenteric fat depot removed from a control mouse (received a single mock injection of ethanol) showing normal blood vessels without the presence of inflammatory infiltrate. (B) Mesenteric fat depot from a TNBS-treated mouse showing inflammatory changes in this tissue evident by the venular dilatation and congestion, neutrophil margination and diapedesis as well as perivascular accumulation of neutrophils (from Karagiannides et al. 2006. Proc Natl Acad Sci U S A. 103: 5207–5212, by permission).

Figure 2. Schematic representation of the Substance P- and Neurotensin-induced inflammatory changes in mesenteric fat depots

Interaction of both SP and NT with their receptors on mesenteric preadipocytes leads to activation of NF-kB subunit p65 and release of IL-8 and IL-6 respectively. IL-8 acts as a chemotactic agent to attract neutrophils into the fat depot which in turn are capable of releasing a number of chemokines that may lead to increases in mesenteric fat macrophages. Mesenteric fat depot macrophage numbers may also increase via the NT-induced IL-6 release and possibly other mechanisms described previously. Such fat depot inflammatory changes may participate in the development of Crohn’s Disease or even in the healing process of this condition.