Adipose tissue pathways involved in weight loss of cancer cachexia.

BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.

Effects of pain controlling neuropeptides on human fat cell lipolysis.

OBJECTIVE: Neuropeptides NPFF and NPSF are involved in pain control, acting through the G-protein coupled receptors (GPR)74 (high affinity for NPFF) and GPR147 (equal affinity for NPFF and NPSF). GPR74 also inhibits catecholamine-induced adipocyte lipolysis and regulates fat mass in humans. The aim of this study was to compare the effects of NPFF and NPSF on noradrenaline-induced lipolysis and to determine the expression of their receptors in human fat cells. DESIGN: Adipose tissue was obtained during surgery. Adipocytes were prepared and kept in primary culture. Lipolysis, protein expression and gene expression were determined. RESULTS: NPFF counteracted noradrenaline-induced lipolysis, which was more marked after 48 h than after 4 h exposure and was solely attributed to inhibition of beta-adrenoceptor signalling. NPSF counteracted noradrenaline-induced lipolysis maximally after 4 h of exposure, which was attributed to a combination of inhibition of beta-adrenoceptor signalling and decreased activation of the protein kinase-A hormone sensitive lipase complex by cyclic AMP. Both neuropeptides were effective in nanomolar concentrations. NPFF and NPSF had no effects on the expression of genes involved in catecholamine signal transduction. Both GPR74 and GPR147 were expressed at the protein level in fat cells from various adipose regions. GPR74 mRNA levels were higher in adipose tissue from obese as compared with non-obese subjects. High gene expression of either receptor correlated with low noradrenaline-induced lipolysis (P<0.05). CONCLUSIONS: Pain controlling neuropeptides NPFF and NPSF may be important for the regulation of lipolysis in man probably acting through GPR74 and GPR147. At low concentrations they inhibit catecholamine-induced lipolysis through rapid and long-term post-transcriptional effects at several steps in adrenoceptor signalling in fat cells.

Role of fat cell size for plasma leptin in a large population based sample.

Earlier studies suggest that fat mass is the only important factor predicting the circulating leptin level in humans. In this population based cross sectional study on 447 women and 158 men total fasting plasma leptin was related to adipose tissue mass and fat cell size to investigate the importance of adipose tissue cellularity. An abdominal subcutaneous fat biopsy was obtained and mean fat cell volume and mean fat cell weight and size were determined. Fasting serum Leptin and Leptin secretion in vitro was also measured. Body fat mass was measured by bioimpedance. Adipose tissue mass and fat cell size independently associated with leptin levels. Partial correlation coefficients were 0.6 (p<0.001) and 0.3 (p<0.01) for fat mass and fat cell size, respectively. Together they explained 2/3 of leptin variance (i. e., adjusted r (2)). Fat mass was a stronger regressor than fat cell volume. The relationship was independent of age, gender and adipocyte secretion of leptin (the latter determined in a subgroup of 391 individuals). In conclusion, although total fat mass is the strongest predictor of circulating leptin, adipose tissue cellularity play an additional independent and important role.

The influence of preadipocyte differentiation capacity on lipolysis in human mature adipocytes.

The ability of catecholamines to maximally stimulate adipocyte lipolysis (lipolytic capacity) is decreased in obesity. It is not known whether the lipolytic capacity is determined by the ability of adipocytes to differentiate. The aim of the study was to investigate if lipolytic capacity is related to preadipocyte differentiation and if the latter can predict lipolysis in mature adipocytes. IN VITRO experiments were performed on differentiating preadipocytes and isolated mature adipocytes from human subcutaneous adipose tissue. In preadipocytes, noradrenaline-induced lipolysis increased significantly until terminal differentiation (day 12). However, changes in the expression of genes involved in lipolysis (hormone sensitive lipase, adipocyte triglyceride lipase, the alpha2-and beta1-adrenoceptors, perilipin, and fatty acid binding protein) reached a plateau much earlier during differentiation (day 8). A significant positive correlation between lipolysis in differentiated preadipocytes and mature adipocytes was observed for noradrenaline (r=0.5, p<0.01). The late differentiation capacity of preadipocytes measured as glycerol-3-phosphate dehydrogenase activity was positively correlated with noradrenaline-induced lipolysis in preadipocytes (r=0.51, p<0.005) and mature fat cells (r=0.35, p<0.05). In conclusion, intrinsic properties related to terminal differentiation determine the ability of catecholamines to maximally stimulate lipolysis in fat cells. The inability to undergo full differentiation might in part explain the low lipolytic capacity of fat cells among the obese.

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

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 long-term 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/INTERPRETATION: The 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.