Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression

Abstract

Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+/-3.54 microm) and large cells (mean 100.1+/-3.94 microm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

“…PPARG and sterol regulatory element binding transcription factor 1, has been shown to be related to insulin resistance [38] and treatment with thiazolidinediones improves insulin sensitivity in parallel with enhancing the differentiation of new, small adipocytes [11,39]. Other suggested mechanisms linking fat cell size and insulin resistance are alterations in the expression pattern of immune-related genes and an altered cholesterol balance in cellular membranes of enlarged adipocytes [40,41]. Furthermore, a combined excess in energy intake and impaired adipogenesis could be manifested as enlarged fat cells and NEFA spill-over from adipose tissue to muscle and liver, where they accumulate as ectopic triacylglycerols.…”

Amelioration of insulin resistance by rosiglitazone is associated with increased adipose cell size in obese type 2 diabetic patients

“…Previous modeling and statistical studies have shown that the tail of small cells changes in a systematic and reproducible way with animal growth and changes in diet. We previously demonstrated that the adipose cell size distributions of fat biopsies as measured by the Multisizer 3 were similar to those of isolated adipose cells from the same biopsies; 13 the advantages of this method over the traditional microscopic techniques for measurement of adipose cell size 36,37 were also discussed previously. 13 Combining the experimental finding by other groups of cell-size distributions with the same character as reported here 13,21,22,26,28 and the results of the dynamic mathematical model gives us confidence that the small cells are real and not artifactual.…”

The effect of serum and follicular fluid amyloid-associated protein levels on in vitro fertilization outcome in patients with polycystic ovary syndrome

“…Serum AA protein is produced by the liver in response to inflammatory stimuli [24]. However, in the non-acute phase, adipose tissue may be the major source of serum AA protein [25], and serum AA messenger RNA (mRNA) expression is markedly higher in hypertrophic adipocytes [26]. Serum AA protein has been implicated in inflammation, insulin resistance, and atherosclerosis [4].…”