Identification of new adipokines that potentially link obesity to insulin resistance represents a major challenge. We have recently shown that NOV/CCN3, a multifunctional matricellular protein, is synthesized and secreted by adipose tissue, with plasma levels highly correlated with body mass index. NOV has been previously involved in tissue repair, fibrotic and inflammatory diseases, and cancer. 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 WT mice but only on a 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 a 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) and in marked decrease in adipose tissue expression of several proinflammatory cytokines and chemokines and to an enhanced insulin signaling. Conversely, treatment of adipocytes by NOV increased chemokine expression. Altogether, these results show that NOV is a new adipocytokine that could be involved in obesity-associated insulin-resistance.