CCN5/WISP2 and metabolic diseases

Abstract

Obesity and type 2 diabetes increase worldwide at an epidemic rate. It is expected that by the year 2030 around 500 million people will have diabetes; predominantly type 2 diabetes. The CCN family of proteins has become of interest in both metabolic and other common human diseases because of their effects on mesenchymal stem cell (MSCs) proliferation and differentiation as well as being important regulators of fibrosis. We here review current knowledge of the WNT1 inducible signaling pathway protein 2 (CCN5/WISP2). It has been shown to be an important regulator of both these processes through effects on both the canonical WNT and the TGFβ pathways. It is also under normal regulation by the adipogenic commitment factor BMP4, in contrast to conventional canonical WNT ligands, and allows MSCs to undergo normal adipose cell differentiation. CCN5/WISP2 is highly expressed in, and secreted by, MSCs and is an important regulator of MSCs growth. In a transgenic mouse model overexpressing CCN5/WISP2 in the adipose tissue, we have shown that it is secreted and circulating in the blood, the mice develop hypercellular white and brown adipose tissue, have increased lean body mass and enlarged hypercellular hearts. Obese transgenic mice had improved insulin sensitivity. Interestingly, the anti-fibrotic effect of CCN5/WISP2 is protective against heart failure by inhibition of the TGFβ pathway. Understanding how CCN5/WISP2 is regulated and signals is important and may be useful for developing new treatment strategies in obesity and metabolic diseases and it can also be a target in regenerative medicine.

Keywords: Adipose tissue; Fibrosis; Insulin resistance; Mesenchymal stem cells; Metabolism; WNT-signaling.

Fig. 1

Subcutaneous white adipose tissue visualized by nonlinear microscopy. Subcutaneous adipose tissue from (a) 19 week old control Black6/N mouse and (b) transgenic aP2-Wisp2 littermate.. Mice were fed high-fat diet for 12 weeks prior to termination and CARS analysis of adipose tissue. Mice were terminated and freshly isolated adipose tissue was stained with Rhodamine 123 for active mitochondria and analysed while being kept hydrated at 37 °C. A custom built coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), and two-photon excited fluorescence (TPEF) microscope was used to visualize lipids, collagen, and active mitochondria within the adipose tissue, respectively. Lipids were detected via the 2845 cm⁻¹ symmetric CH₂ stretching vibration. All signals were passed through matching bandpass filters and collected on single photon counting detectors. Lipid droplet analysis from CARS images has been described previously (Brannmark et al. 2014)

Fig. 2

Brown intrascapular adipose tissue visualized by nonlinear microscopy. Brown intrascapular adipose tissue from (a) 19 week old control Black6/N mouse and (b) transgenic aP2-Wisp2 littermate. Mice were fed high-fat diet for 12 weeks prior to termination and CARS analysis of adipose tissue