Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice.

Tara Alami,Jun-Li Liu

doi:10.3390/ijms222413418

Abstract

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored.

Highlights

We have reported a significant induction by insulin-like growth factors (IGFs)-1 of the expression of matricellular protein CCN5/WISP2 and its in vitro effects on promoting pancreatic β-cell proliferation and survival [1,2]
While searching for novel growth factors to promote the proliferation and survival While searching for novel growth factors to promote the proliferation and survival of pancreatic islets, we revealed the expression of CCN5/WISP2 (cellular communication of pancreatic islets, we revealed the expression of CCN5/WISP2 in resting pancreatic β-cells and network factor 5, Wnt inducible signaling protein 2) in resting pancreatic β-cells and its its robust inductions by IGF-1, and further reported that recombinant human protein robust inductions by IGF-1, and further reported that recombinant human protein promotes mouse β-cell proliferation and survival in vitro [1,2]
CCN5 knockout would result in increased adipocyte differentiation, activated transforming growth factor (TGF)-β/Smad3 pathway, and the expression of adipogenic genes, which all contribute to mild obesity

Summary

Introduction

We have reported a significant induction by IGF-1 of the expression of matricellular protein CCN5/WISP2 and its in vitro effects on promoting pancreatic β-cell proliferation and survival [1,2]. The CCN/WISP family, which consists of six matricellular proteins, regulates development, cell adhesion and proliferation, extracellular matrix (ECM) remodeling, inflammation, and tumorigenesis. Most of these proteins contain four functional domains (Figure 1): the IGF-BP domain, which has a sequence homology similar to the six classic IGF-BPs, but confers only

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Increased Lipid Accumulation and Fibrosis in the Heart

13 Increased including SREBP

Metabolic Effects of Adipocyte-Specific and Systemic Overexpression of CCN5