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-␣ (TNF-␣) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-␣)-like effector A (CIDEA) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDEA is unknown, but CIDEA-null mice are resistant to obesity and diabetes. We investigated CIDEA 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 CIDEA in mice was not influenced by obesity. However, CIDEA expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDEA expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDEA by RNA interference stimulated lipolysis and increased TNF-␣ secretion by a posttranscriptional effect. Conversely, TNF-␣ treatment decreased adipocyte CIDEA expression via the mitogen-activated protein kinase c-Jun NH 2 -terminal kinase. We propose an important and human-specific role for CIDEA in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDEA and TNF-␣. Diabetes 54:1726 -1734, 2005
Aims/hypothesis Recent studies suggest a link between insulin resistance and mitochondrial function in white fat cells. The aim of this study was to evaluate adipocyte mitochondrial DNA (mtDNA) copy number in relation to adipocyte and clinical variables that are related to insulin sensitivity. Methods We studied a group of 148 healthy volunteers with a large inter-individual variation in BMI. Relative amounts of mtDNA and nuclear DNA were determined by quantitative RT-PCR. The mtDNA:nuclear DNA ratio reflects the tissue concentration of mtDNA per cell. Results The mtDNA copy number was enriched in adipocytes of adipose tissue and decreased slightly by ageing (p= 0.015) and increasing BMI (p=0.004); however, it was not influenced by sex, energy-restricted diets or marked longterm weight reduction. Adipose mtDNA copy number was not independently related to resting energy expenditure, overall insulin sensitivity or adipocyte lipolysis. However, it showed a strong positive correlation with basal (p=0.0012) and insulin-stimulated lipogenesis (p<0.0001) in fat cells, independently of age and BMI, and a weak positive correlation with levels of mRNA from several genes involved in mitochondrial oxidative capacity (r=0.2-0.3). Conclusions/interpretationThe mtDNA copy number in human white fat cells is fairly stable within healthy individuals. It is not influenced by sex or weight loss and is not important for overall insulin sensitivity or energy expenditure at rest. However, it is strongly related to adipocyte lipogenesis and weakly to mitochondrial oxidative capacity, suggesting that adipocyte mitochondria are, above all, local regulators.
Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.
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