The caveolae‐associated coiled‐coil protein, NECC2, regulates insulin signalling in Adipocytes

Abstract

Adipocyte dysfunction in obesity is commonly associated with impaired insulin signalling in adipocytes and insulin resistance. Insulin signalling has been associated with caveolae, which are coated by large complexes of caveolin and cavin proteins, along with proteins with membrane‐binding and remodelling properties. Here, we analysed the regulation and function of a component of caveolae involved in growth factor signalling in neuroendocrine cells, neuroendocrine long coiled‐coil protein‐2 (NECC2), in adipocytes. Studies in 3T3‐L1 cells showed that NECC2 expression increased during adipogenesis. Furthermore, NECC2 co‐immunoprecipitated with caveolin‐1 (CAV1) and exhibited a distribution pattern similar to that of the components of adipocyte caveolae, CAV1, Cavin1, the insulin receptor and cortical actin. Interestingly, NECC2 overexpression enhanced insulin‐activated Akt phosphorylation, whereas NECC2 downregulation impaired insulin‐induced phosphorylation of Akt and ERK2. Finally, an up‐regulation of NECC2 in subcutaneous and omental adipose tissue was found in association with human obesity and insulin resistance. This effect was also observed in 3T3‐L1 adipocytes exposed to hyperglycaemia/hyperinsulinemia. Overall, the present study identifies NECC2 as a component of adipocyte caveolae that is regulated in response to obesity and associated metabolic complications, and supports the contribution of this protein as a molecular scaffold modulating insulin signal transduction at these membrane microdomains.

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

“…Insulin signalling in preadipocytes and adipocytes depends on key signal molecules such as PI-3K and AKT [14,26,27]. Several studies showed that the factors of insulin/IGF-1 signal, such as PIK3R1, AKT3 and MAPK3, were down-regulated during the adipogenic differentiation of hMACs but were up-regulated after removing the adipogenic stimuli from the adipogenic differentiation medium [28,29].…”

Revising Endosomal Trafficking under Insulin Receptor Activation

“…The physiopathological relevance of caveolar endocytosis has been demonstrated in several studies. In adipocytes, NECC2, a caveolae component that is regulated in obesity, modulates insulin signal transduction at these membrane microdomains acting as a molecular scaffold [25]. Caveolin-1 has been also involved in the regulation of voltagedependent potassium channel Kv1.3, which participates in peripheral insulin sensitivity.…”

Caveolin-1 Regulates Cellular Metabolism: A Potential Therapeutic Target in Kidney Disease

“…Long-term high glucose stimulates adipocytes and reduces the sensitivity of Cav-1 to insulin and inhibits IR and PKB (AKT-2) phosphorylation, which affect the GLUT4 in the intracellular glucose storage vesicles to transport to the plasma membrane caveolae and bind to Cav-1 and subsequently mediate glucose uptake (Palacios-Ortega et al, 2016). In contrast, in a high-glucose environment, the caveolae-related coiled-coil protein (NECC2) is highly expressed on adipocytes, which is closely linked to insulin-related glucose uptake by triggering insulin induction of NECC2 transport to the cell surface and binding to Cav-1 (Trávez et al, 2018). At this point, the IR binds to the scaffold domain of Cav-1 and then activates the PI3K/Akt signaling pathway (Trávez et al, 2018).…”