Abstract
FADD, a classical apoptotic signaling adaptor, was recently reported to have non‐apoptotic functions. Here, we report the discovery that FADD regulates lipid metabolism. PPAR‐α is a dietary lipid sensor, whose activation results in hypolipidemic effects. We show that FADD interacts with RIP140, which is a corepressor for PPAR‐α, and FADD phosphorylation‐mimic mutation (FADD‐D) or FADD deficiency abolishes RIP140‐mediated transcriptional repression, leading to the activation of PPAR‐α. FADD‐D‐mutant mice exhibit significantly decreased adipose tissue mass and triglyceride accumulation. Also, they exhibit increased energy expenditure with enhanced fatty acid oxidation in adipocytes due to the activation of PPAR‐α. Similar metabolic phenotypes, such as reduced fat formation, insulin resistance, and resistance to HFD‐induced obesity, are shown in adipose‐specific FADD knockout mice. Additionally, FADD‐D mutation can reverse the severe genetic obesity phenotype of ob/ob mice, with elevated fatty acid oxidation and oxygen consumption in adipose tissue, improved insulin resistance, and decreased triglyceride storage. We conclude that FADD is a master regulator of glucose and fat metabolism with potential applications for treatment of insulin resistance and obesity.
Highlights
Metabolic syndrome is an epidemic affecting a large percentage of the population of the world
Proteins involved in mitochondrial fatty acid oxidation systems were found to be strongly increased in both Fas-associated death domain-containing protein (FADD)-D and FADD KO MEFs as compared to wild-type (WT) MEFs, including very long-chain acyl-CoA dehydrogenases (VLCAD), long-chain acyl-CoA dehydrogenases (LCAD), and medium-chain acyl-CoA dehydrogenases (MCAD) (Appendix Fig S1C), indicating transcriptional activation of PPAR-a-regulated genes involved in fatty acid oxidation
Consistent with the data obtained from MEFs, both gene expression and protein level of PPAR-a were increased in white adipose tissue (WAT) of FADD-D mice (Fig 1A–C)
Summary
Metabolic syndrome is an epidemic affecting a large percentage of the population of the world. The increasing prevalence of the metabolic syndrome and obesity calls for new approaches for the prevention and management of these diseases. Unburned energy is stored at TGs in adipose tissues and subsequently in other organs such as the liver, when the energy consumption exceeds the calories combustion, leading to the development of obesity over time (Duncan et al, 2007). When TG synthesis exceeds lipolysis, it will lead to elevated TG storage, resulting in adipocyte hypertrophy and subsequently obesity. Most of the enzymes that regulate TG metabolism have been identified; signaling pathway controlling this process is still not well understood. Because of the high prevalence of dyslipidemia in the general population (Ginsberg et al, 2006), it is important to identify signaling factors regulating metabolic and regulatory aspects of the TG metabolism
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