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TNF-alpha is required for the attraction of mesenchymal precursors to white adipose tissue in Ob/ob mice.

ABSTRACT: Most adult tissues harbour a stem cell subpopulation (Mesenchymal Precursors or MPs) that represent a small proportion of the total cell number and have the potential to differentiate into several cell types within the mesenchymal lineage. In adipose tissue, adipocytes account for two-thirds of the total cell number. The remaining cells include blood and endothelial cells, along with adipocyte precursors (adipose MPs). Obesity is defined as an excess of body fat that frequently results in a significant impairment of health. The ob/ob mice bear a mutation in the ob gene that causes a deficiency in the hormone leptin and hence obesity. Here, we present evidence that ob/ob mice have a dramatic decrease in the resident MP pool of several tissues, including squeletal muscle, heart, lung and adipose tissue. Moreover, we show that that there is a migration of MP cells from distant organs, as well as homing of these cells to the adipose tissue mass of the ob/ob mice. We call this process adipotaxis. Once in the adipose tissue, migrant MPs undergoe adipose differentiation, giving rise to new differentiated adipocytes within the adipose mass. Finally, we provide evidence that adipotaxis is largely explained by the production of high levels of Tumor Necrosis Factor-alpha (TNF-alpha) within the ob/ob adipose tissue. The therapeutic implications for human obesity as well as for regenerative medicine are further discussed in this paper.

SUBMITTER: Galvez BG

PROVIDER: S-EPMC2635963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The ob gene encodes leptin, a hormone which induces satiety and increases energy expenditure. The peroxisome proliferator-activated receptor gamma 2 isoform (PPAR gamma 2) gene encodes a transcription factor which controls adipocyte differentiation and expression of fat-specific genes. We have studied the regulation of these two genes in white adipose tissue (WAT) during the suckling-weaning transition. Suckling rats ingest a high-fat diet (milk). Fat-pad weight barely varied during the last week of suckling. ob mRNA levels, which were very low in 15-day-old rats, rose approximately 6-fold until weaning at 21 days. When the rats were weaned on to a standard (high-carbohydrate) laboratory chow, epididymal WAT enlarged approximately 7-fold, and ob mRNA kept increasing progressively and doubled between 21 and 30 days. This evolution contrasted with that of fatty acid synthase (FAS) mRNA, which increased sharply, but only after weaning. To distinguish between the influence of developmental and nutritional factors on ob expression, a group of rats was weaned on to a high-fat diet. This prevented the rise in glycaemia and insulinaemia and the decrease in plasma non-esterified fatty acids which otherwise occurred at weaning. This also resulted in a slight (10-15%) decrease in food intake and body weight gain. Under this high-fat diet, the rise of ob mRNA in WAT was augmented (3.7-fold in 30- versus 21-day-old pups), whereas the normal rise in FAS mRNA levels was attenuated. Fat-pad weights and adipocyte cell size and number were roughly similar in high-carbohydrate- and high-fat-weaned pups. mRNA levels of PPAR gamma 2, like those of ob, were low in the WAT of 15-day-old suckling pups, doubled at 21 days, and reached a maximum as soon as 23 days. This evolution further differed from that of ob mRNA in not being influenced by diet composition. In conclusion, ob expression markedly increases during the suckling-weaning transition, and this effect is accentuated by a high-fat diet. Qualitative nutritional changes in ob mRNA were correlated with neither acute changes in adipose-tissue mass, nor cell size/number, nor variations in insulinaemia. PPAR gamma 2 also increased during suckling, but rapidly reached a plateau after weaning and no longer changed thereafter. Unlike ob, PPAR gamma 2 was not influenced by the diet composition.

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TNF-alpha is required for the attraction of mesenchymal precursors to white adipose tissue in Ob/ob mice.

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