Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue

Abstract

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.

Age-dependent obesity and mitochondrial dysfunction

“…Indeed, inflammatory mediators are associated with a decline in mitochondrial content 17,[19][20][21] and presumably this inflammatory process does not occur-or occurs to a lesser extent-in aging WAT. Significantly, our data are in line with previous data in humans suggesting that decline of white adipocyte mitochondrial content as well as a global mitochondrial dysfunction is not necessarily taking place-or to a mild extent-in obese patients, [22][23][24][25] but more associated with concomitant diabetes. 22 Moreover, our data in humans also show that the expression of mitochondrial CIV components such as COX5B, is specifically reduced during aging.…”

Paradoxical Effect of Mitochondrial Respiratory Chain Impairment on Insulin Signaling and Glucose Transport in Adipose Cells

“…A possible relationship between mitochondrial levels and adipose tissue function has been inferred from results in animals and humans indicating that alterations in mitochondrial levels correlate with changes in insulin sensitivity (9,10,(15)(16)(17)(18)(19)(20)(21)(22)(23). In this report we have turned to a simple model, 3T3-L1 adipocytes, to determine whether a direct relationship between mitochondrial function and insulin sensitivity might indeed exist.…”

“…Adipocyte differentiation is accompanied by an expansion of mitochondrial mass (9,10), but the functional role of the relatively high levels of mitochondria in white adipocytes compared with those in adipose stroma and other tissues is not clear. High mitochondria levels may be required for the support of adipocyte-specific ATP-requiring processes (11), or to support metabolic functions such as glyceroneogenesis, which is required for triglyceride deposition (12,13).…”

Lipolysis—Not inflammation, cell death, or lipogenesis—Is involved in adipose tissue loss in cancer cachexia

“…33 In brief, isolated fat cells were incubated for 2 hours at 378C in a buffer containing 3H-glucose without (basal) or with different concentrations of insulin. After incubation, lipids were extracted, and radioactive glucose incorporation into total lipid was used as an index of lipogenesis.…”