Little caves ameliorate hepatic insulin signaling. Focus on “Caveolin gene transfer improves glucose metabolism in diabetic mice”

Abstract

CAVEOLAE, DISCOVERED BY ELECTRON microscopy in 1950s, are membrane invaginations that accommodate various molecules involved in cellular signaling. Caveolin, a major component of caveolae, has been shown to inhibit the function of multiple caveolar proteins, including kinases, involved in cell differentiation and proliferation. Interestingly, insulin signal seems exempted from this inhibition and would rather require caveolin for proper signaling. In this issue of American Journal of Physiology-Cell Physiology, Otsu and coworkers (16) show that the insulin resistance state of obese and diabetic mice can be reversed upon caveolin-3 overexpression in liver. These interesting findings point to a novel role of caveolin in controlling whole insulin sensitivity and glucose homeostasis in mice. Caveolae, or “little caves,” first identified approximately 50 years ago when electron microscopy started, were described as morphologically distinct flasks, suggested to function as endocytic vesicles (17). In 1992, a major finding was the discovery of caveolin (now called caveolin-1) as a protein marker of caveolae. Caveolin is a small protein of 22 kDa with a hydrophobic region near the COOH terminus which anchors the protein to the membrane (10, 22). When caveolin is overexpressed in cells devoid of caveolae, the typical caveolar pattern is formed, implying that caveolin is the principal structural component of caveolae. In subsequent years, two other caveolin isoforms were identified, caveolin-2 and caveolin-3, which are the products of different genes. While the amino acid sequence homology is high between caveolin-1 and -3, their tissue distribution is quite different. Caveolin-1 is widely expressed in adipocytes, endothelial cells, and epithelial cells, whereas caveolin-3 is expressed in cardiac and in skeletal myocytes. Caveolin-2 is mostly coexpressed with caveolin-1, and the two subtypes may form functional hetero-oligomeric complexes. Because caveolin expression was thought, until recently, to be necessary and sufficient to form caveolae, the discovery of caveolins paved the way for functional studies that sought to define the role of caveolae. Indirect approaches to manipulate caveolin function first involved the introduction into cells of a small stretch of a peptide derived from the caveolin scaffolding domain. This revealed a role for caveolins in a number of signaling pathways and led to the conclusion that caveolae orchestrate signaling by organizing protein interactions at the plasma membrane (for review see Ref. 14). Further confirmation came by other experiments, such as by ablation of caveolae by altering the composition of the plasma membrane. Indeed, caveolar membranes closely resemble lipid rafts, enriched with particular lipid species such as sphingolipids and cholesterol. Thus, agents that destroy lipid rafts cause the disappearance of caveolae. From the use of such approaches, it also appeared that signaling was not the only membraneassociated event modified by alterations in caveolae. The endocytic delivery of a number of molecules was also altered by disruption of caveolae, thus emphasizing their function as endocytic portals (see Ref. 18 for review). Considering caveolins from a “trafficking” point of view also suggested that the function of caveolins and caveolae might be linked to cellular lipid transport and homeostasis. Caveolin can directly bind lipids, such as cholesterol or fatty acids, and can dynamically associate with cytoplasmic lipid droplets that provide intracellular lipid stores (11).