Identification of new adipokines that potentially link obesity to insulin resistance represents a major challenge. We recently showed that NOV/CCN3, a multifunctional matricellular protein, is synthesized and secreted by adipose tissue, with plasma levels highly correlated with BMI. NOV involvement in tissue repair, fibrotic and inflammatory diseases, and cancer has been previously reported. However, its role in energy homeostasis remains unknown. We investigated the metabolic phenotype of NOV−/− mice fed a standard or high-fat diet (HFD). Strikingly, the weight of NOV−/− mice was markedly lower than that of wild-type mice but only on an HFD. This was related to a significant decrease in fat mass associated with an increased proportion of smaller adipocytes and to a higher expression of genes involved in energy expenditure. NOV−/− mice fed an HFD displayed improved glucose tolerance and insulin sensitivity. Interestingly, the absence of NOV was associated with a change in macrophages profile (M1-like to M2-like), in a marked decrease in adipose tissue expression of several proinflammatory cytokines and chemokines, and in enhanced insulin signaling. Conversely, NOV treatment of adipocytes increased chemokine expression. Altogether, these results show that NOV is a new adipocytokine that could be involved in obesity-associated insulin-resistance.

Both type 1 and type 2 diabetes are characterized by deficient insulin secretion and decreased b-cell mass. Thus, regenerative strategies to increase b-cell mass need to be developed. To characterize mechanisms of b-cell plasticity, we studied a model of severe insulin resistance in the adult mouse and defined how b-cells adapt. Chronic corticosterone (CORT) treatment was given to adult mice and led to rapid insulin resistance and adaptive increased insulin secretion. Adaptive and massive increase of b-cell mass was observed during treatment up to 8 weeks. b-Cell mass increase was partially reversible upon treatment cessation and reinduced upon subsequent treatment. b-Cell neogenesis was suggested by an increased number of islets, mainly close to ducts, and increased Sox9 and Ngn3 mRNA levels in islets, but lineagetracing experiments revealed that neoformed b-cells did not derive from Sox9-or Ngn3-expressing cells. CORT treatment after b-cell depletion partially restored b-cells. Finally, b-cell neogenesis was shown to be indirectly stimulated by CORT because serum from CORT-treated mice increased b-cell differentiation in in vitro cultures of pancreatic buds. Altogether, the results present a novel model of b-cell neogenesis in the adult mouse and identify the presence of neogenic factors in the serum of CORT-treated mice.