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.
Highlights
Type 2 diabetes (T2D) is characterized by the progressive deterioration of glycaemic control
We recently identified a long coiled‐coil protein, referred to as neuroendocrine long coiled‐coil protein‐2 (NECC2),[16,17] which associates with caveolae in neuroendocrine cells, wherein it colocalizes with the nerve growth factor (NGF) receptor, TrkA, and regulates TrkA‐mediated NGF signalling.[18]
Caveolae are composed of structural and cytoskeletal proteins, scaffolding factors, cholesterol and sphingolipids and a number of signalling molecules [eg insulin receptor (IR), MAPK cascade members, glucose transporter‐4 (GLUT‐4)], which are essential for caveolae formation, maintenance and functional organization.[9,34,35,36,37,38,39]
Summary
Type 2 diabetes (T2D) is characterized by the progressive deterioration of glycaemic control. Long alpha‐helical coiled‐coil proteins represent highly versatile molecules that have been proposed to act as molecular scaffolds and/or tethers that stabilize and organize membrane systems.[15] these proteins have been suggested to integrate signals and transduction pathways through their ability to interact with multiple signalling components.[15] We recently identified a long coiled‐coil protein, referred to as neuroendocrine long coiled‐coil protein‐2 (NECC2),[16,17] which associates with caveolae in neuroendocrine cells, wherein it colocalizes with the nerve growth factor (NGF) receptor, TrkA, and regulates TrkA‐mediated NGF signalling.[18] Remarkably, the presence and function of NECC2 in caveolae in adipocytes has not been yet documented. Our data indicate that NECC2 is a component of adipocyte caveolae that is regulated in response to obesity and associated metabolic complications, and support a role for this protein as a molecular scaffold modulating insulin signal transduction at these membrane microdomains
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