Abstract
Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy.
Highlights
Lipids are major membrane components as well as the main source of cellular energy
Obesity and lipodystrophy are medical conditions characterized by excess body fat or too little body fat, respectively
In Drosophila Seipin (dSeipin) mutant flies, we found numerous lipid droplets in the salivary gland, a non-fat storage tissue, and reduced lipid storage in the fat body, an adipose tissue
Summary
Lipids are major membrane components as well as the main source of cellular energy. Cells have developed precise homeostatic mechanisms to tightly regulate lipid uptake, synthesis, storage, and usage [1,2]. White adipose tissue is the main lipid storage organ; ectopic lipid storage in non-adipose tissues such as muscle, pancreas, and liver, is often observed in disease states such as obesity and lipodystrophy. Lipotoxicity as a result of ectopic lipid storage in these diseases is thought to be a major cause of severe pathological conditions including insulin resistance, pancreatic b-cell failure, and hepatic steatosis [4,5,6]. Surgical implantation of normal adipose tissue back into lipoatrophic mice reversed ectopic lipid accumulation in the liver, suggesting a tissue-non-autonomous mechanism [9]. The contribution of extrinsic and intrinsic mechanisms to ectopic lipid storage in non-adipose tissues in various diseases conditions remains to be determined
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