Table 1.
Summarised CCN Reports in Obesity, Insulin resistance and Pancreatic Beta-Cell Dysfunction
| CCN species | CCN function | CCN mechanism(s) of action | Relevant CCN regulation |
|---|---|---|---|
| CCN1 | NR | NR | NR |
| CCN2 | Inhibits mesenchymal stem cell commitment into adipogenesis; and inhibits fat cell differentiation | Wnt signaling dependent; TGF-beta pathway and CCEBP-beta and -delta dependent mechanisms | Levels fall in parallel with adipocyte differentiation in vitro; adipose tissue levels are increased in obese, insulin resistant wild type mice |
| CCN2 | Is required for pancreatic beta-cell proliferation, differentiation, and islet morphogenesis during development; CCN2 mediated adult beta-cell proliferation in the setting of a murine model of partial beta-cell ablation | Direct effects of CCN2 on pancreatic beta-cell proliferation - CCN2 is both required and sufficient to induce proliferation of embryonic pancreatic beta-cells; also indirect effects of CCN2 via reparative macrophages to cause beta-cell immaturity and shortening cell replicative refractory period | CCN2 is induced during normal embryonic pancreatic islet morphogenesis. Expression and protein levels are much lower in postnatal life. |
| CCN3 | Induction of obesity and insulin resistance, and impairment of adipocyte differentiation | Induction of pro-inflammatory cytokines in adipose tissue inflammation and possibly lesser thermogenesis during high fat feeding in mice | Blood levels rise with obesity, possibly from CCN3 produced by adipocytes in fat tissue. |
| CCN3 | Inhibits both: pancreatic beta-cell proliferation, and glucose-stimulated Ca(2+) entry thus impairing insulin secretion | CCN3 decreases glucose oxidation; CCN3 also impairs β-cell proliferation concomitantly with a reduction in cAMP levels | Present in pancreatic beta-cells and increased CCN3 protein levels in db/db and Irs2−/− mouse islets; the key transcription factor FoxO1 binds to a conserved response element in the CCN3 promoter to regulate its expression in beta-cells |
| CCN4 | NR | NR | NR |
| CCN5 | Promotes pancreatic beta- cell (insulinoma) proliferation and cell survival against streptozotocin-induced cell death | Direct effect of CCN5 on pancreatic beta-cells to promote cell proliferation induces AKT phosphorylation and cyclin D1 levels | Present in pancreatic beta-cells, stimulated by IGF-1 together with Wnt signaling. No reports of pancreatic expression in obesity or diabetes |
| CCN6 | NR | NR | NR |
NR no reports. For relevant references refer to the text