Chemerin signalling in adipose tissue and intestinal homeostasis

Abstract

Chemerin is an adipokine and potent chemoattractant for cells expressing chemokine-like receptor 1 (CMKLR1) which plays important roles in metabolism and immunity. Chemerin is secreted as inactive prochemerin and undergoes extracellular processing to generate a variety of isoforms that range in bioactivity. Clinical studies have demonstrated that chemerin levels are positively associated with obesity and inflammatory disorders. However, the role of chemerin signalling in adipose tissue, and how elevated chemerin levels affect inflammatory disease progression, are poorly understood. In this thesis, I describe the development of techniques to modulate levels of chemerin signalling. I then investigate the role of chemerin signalling in three physiological contexts: mature adipocytes, pathogenesis of colitis, and intestinal microbiome composition. Using a microarray-based approach, I identified matrix metalloproteinase (MMP)3 and several chemokines as novel targets of chemerin signalling in adipocytes. Decreased chemerin levels resulted in increased MMP activity and macrophage migration towards adipocyte-conditioned media, via an NFkB-dependent mechanism. This suggests that elevated chemerin levels with obesity influence adipose tissue remodelling. Importantly, these effects were mediated through a unique adipocyte-processed chemerin isoform. I next demonstrated that local expression, secretion, and processing of chemerin were positively associated with colonic inflammation in a colitis model. CMKLR1 knockout (KO) mice developed signs of clinical illness more slowly than wildtype, but ultimately developed similar levels of inflammation. Intraperitoneal injection of bioactive chemerin had no effect on colitis severity, suggesting that local chemerin levels have a greater impact on the pathogenesis of colitis. Finally, I investigated differences in intestinal microbiome composition between wildtype, chemerin KO, and CMKLR1 KO mice. Significant differences in Akkermansia and Prevotella abundance were observed in the absence of CMKLR1. These bacterial populations are known to correlate with adiposity and glucose homeostasis, indicating that chemerin signalling might influence metabolic processes through modulation of microbiome composition. Considered altogether, this work demonstrates that local chemerin signalling and processing plays autocrine/paracrine roles in adipose tissue and intestinal homeostasis. Additionally, chemerin represents a novel biomarker in colon inflammation. Modulation of local, context-specific chemerin signalling therefore represents a potential therapeutic target for the treatment of metabolic and inflammatory processes.