The lipoatrophic caveolin-1 deficient mouse model reveals autophagy in mature adipocytes

Abstract

Adipose tissue lipoatrophy caused by caveolin gene deletion in mice is not linked to defective adipocyte differentiation. We show that adipose tissue development cannot be rescued by endothelial specific caveolin-1 re-expression, indicating primordial role of caveolin in mature adipocytes. Partial or total caveolin deficiency in adipocytes induced broad protein expression defects, including but not limited to previously described downregulation of insulin receptor. Global alterations in protein turnover, and accelerated degradation of long-lived proteins were found in caveolin-deficient adipocytes. Lipidation of endogenous LC3 autophagy marker and distribution of GFP-LC3 into aggregates demonstrated activated autophagy in the absence of caveolin-1 in adipocytes. Furthermore, electron microscopy revealed autophagic vacuoles in caveolin-1 deficient but not control adipocytes. Surprisingly, significant levels of lipidated LC3-II were found around lipid droplets of normal adipocytes, maintained in nutrient-rich conditions or isolated from fed mice, which do not display autophagy. Altogether, these data indicate that caveolin deficiency induce autophagy in adipocytes, a feature that is not a physiological response to fasting in normal fat cells. This likely resulted from defective insulin and lipolytic responses that converge in chronic nutrient shortage in adipocytes lacking caveolin-1. This is the first report of a pathological situation with autophagy as an adaptative response to adipocyte failure.

Distinct Roles of Endothelial and Adipocyte Caveolin-1 in Macrophage Infiltration and Adipose Tissue Metabolic Activity

“…They might be linked to global reduction in adipocyte metabolic activity revealed here by gene expression defects in microarray analysis. Accordingly, autophagic degradation was recently reported in caveolin-deficient adipocytes (20), as well as compromised lipid droplet growth and maturation defects (21). …”

Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis

“…These results point to differential functions for cav-1 and cavin-1, and a potential role of cavin-1 in regulation of lipolysis, but fail to explain the lower LD size observed in the primary cav-1 deficient adipocytes. Finally, it was reported that cav-1 deficient adipocytes have increased autophagy but it remains to be experimentally demonstrated whether this mechanism contributes to decreased LD size by channeling LD lipids to lysosomal degradation [105]. …”

miR-29a Promotes Lipid Droplet and Triglyceride Formation in HCV Infection by Inducing Expression of SREBP-1c and CAV1

“…Since SREBP-1c is the predominant hepatic isoform among the SREBP family and CAV1 is regulated by SREBP-1 and is one of the LD proteins responsible for its stability, they were chosen to be the main focus of this study 11,44. In this context, this study aimed at uncovering the impact of miR-29a on SREBP-1c and its downstream target, CAV1, in order to better elucidate their roles in LD formation.…”

“…Many research groups have investigated the relation between CAV1 levels and LDs in different cell types, including adipocytes, fibroblasts and hepatocytes 11,22–28. In a study of hepatocytes, NAFLD was shown to be associated with up-regulation of the hepatic CAV1 gene and protein expression as well as an increase in its localization on LDs 29,30.…”