Agné Kulyté

In obesity, white adipose tissue (WAT) inflammation is linked to insulin resistance. Increased adipocyte chemokine (C-C motif) ligand 2 (CCL2) secretion may initiate adipose inflammation by attracting the migration of inflammatory cells into the tissue. Using an unbiased approach, we identified adipose microRNAs (miRNAs) that are dysregulated in human obesity and assessed their possible role in controlling CCL2 production. In subcutaneous WAT obtained from 56 subjects, 11 miRNAs were present in all subjects and downregulated in obesity. Of these, 10 affected adipocyte CCL2 secretion in vitro and for 2 miRNAs (miR-126 and miR-193b), regulatory circuits were defined. While miR-126 bound directly to the 3'-untranslated region of CCL2 mRNA, miR-193b regulated CCL2 production indirectly through a network of transcription factors, many of which have been identified in other inflammatory conditions. In addition, overexpression of miR-193b and miR-126 in a human monocyte/macrophage cell line attenuated CCL2 production. The levels of the two miRNAs in subcutaneous WAT were significantly associated with CCL2 secretion (miR-193b) and expression of integrin, α-X, an inflammatory macrophage marker (miR-193b and miR-126). Taken together, our data suggest that miRNAs may be important regulators of adipose inflammation through their effects on CCL2 release from human adipocytes and macrophages.

CONTEXT: Large fat cell size is linked to type 2 diabetes risk and may involve an enhanced rate of adipocyte lipolysis causing elevated levels of fatty acids. OBJECTIVE: Our objective was to study the role of fat cell size in the regulation of lipolysis within a subject. DESIGN AND MAIN OUTCOME MEASURES: Subcutaneous adipose tissue was obtained from 16 healthy subjects. Large and small adipocytes were isolated for each sample. Hormonal regulation of lipolysis and expression of lipolysis-regulating proteins were investigated. RESULTS: No effect of cell size on the rate of lipolysis was observed when lipolysis was expressed per lipid weight of fat cells. However, when expressed per number of fat cells, the lipolysis was significantly higher in large as compared with small adipocytes. This was observed in both the unstimulated (basal) state and in the presence of the major lipolysis-regulating hormones such as catecholamines (stimulating), natriuretic peptides (stimulating), and insulin (inhibiting). The receptor properties (number, affinity, and coupling) for these hormones did not differ between large and small adipocytes. However, the expression of proteins regulating the final steps in hormone signaling to lipolysis (hormone-sensitive lipase, adipose triglyceride lipase, and perilipin) was increased in large adipocytes. CONCLUSION: Independently of the donor, sc fat cell size per se determines lipolysis rates. Large adipocytes have increased lipolytic capacity, probably due to the enrichment of regulatory proteins distal in the lipolytic cascade, to which all lipolytic signals converge (lipases and perilipin). Enhanced lipolytic capacity may link adipocyte hypertrophy to the risk of developing type 2 diabetes.

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.