A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-α-like effector A (CIDEA) in adipocyte lipolysis and obesity

Elevated circulating fatty acid concentration is a hallmark of insulin resistance and is at least in part attributed to the action of adipose tissue-derived tumor necrosis factor-alpha (TNF-alpha) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDER) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDER is unknown, but CIDER-null mice are resistant to obesity and diabetes. We investigated CIDER in adipose tissue of obese and lean humans and mice. The mRNA was expressed in white human fat cells and in brown mouse adipocytes. The adipose mRNA expression of CIDER in mice was not influenced by obesity. However, CIDER expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDER expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDER by RNA interference stimulated lipolysis and increased TNF-alpha secretion by a posttranscriptional effect. Conversely, TNF-alpha treatment decreased adipocyte CIDER expression via the mitogen-activated protein kinase c-Jun NH2-terminal kinase. We propose an important and human-specific role for CIDER in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDER and TNF-alpha.