Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns

Abstract

Anatomically separate fat depots differ in size, function, and contribution to pathological states, such as the metabolic syndrome. We isolated preadipocytes from different human fat depots to determine whether the basis for this variation is partly attributable to differences in inherent properties of fat cell progenitors. We found that genome-wide expression profiles of primary preadipocytes cultured in parallel from abdominal subcutaneous, mesenteric, and omental fat depots were distinct. Interestingly, visceral fat was not homogeneous. Preadipocytes from one of the two main visceral depots, mesenteric fat, had an expression profile closer to that of subcutaneous than omental preadipocytes, the other main visceral depot. Expression of genes that regulate early development, including homeotic genes, differed extensively among undifferentiated preadipocytes isolated from different fat depots. These profiles were confirmed by real-time PCR analysis of preadipocytes from additional lean and obese male and female subjects. We made preadipocyte strains from single abdominal subcutaneous and omental preadipocytes by expressing telomerase. Depot-specific developmental gene expression profiles persisted for 40 population doublings in these strains. Thus, human fat cell progenitors from different regions are effectively distinct, consistent with different fat depots being separate mini-organs.

Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration

“…A growing body of evidence suggests that these depot-specific associations are due to intrinsic differences in the properties of adipocytes in each depot (27,28) and the consequence of a divergence in their developmental origin (1,(9)(10)(11)(12)29). Consistent with this hypothesis, we and others observed high differential expression of developmental genes between intraabdominal and s.c. adipose depots in both rodents and humans (11,12). Of these genes, Tbx15 expression in human intraabdominal adipose depots was the most tightly correlated with obesity and the pattern of fat distribution, suggesting a role for Tbx15 in the depot-specific control of adipose tissue development and function.…”

“…Indeed, intraabdominal/visceral fat accumulation is associated with a higher risk of diabetes and metabolic syndrome, whereas increased s.c. fat in the thighs and hips may even have a protective effect (4,8,26). A growing body of evidence suggests that these depot-specific associations are due to intrinsic differences in the properties of adipocytes in each depot (27,28) and the consequence of a divergence in their developmental origin (1,(9)(10)(11)(12)29). Consistent with this hypothesis, we and others observed high differential expression of developmental genes between intraabdominal and s.c. adipose depots in both rodents and humans (11,12).…”

“…Recently, we and others have shown that several developmental genes, including several Hox genes, Shox2, Engrailed-1, and Tbx15, are differentially expressed between intraabdominal and s.c. adipocytes and preadipocytes of rodents and humans, in many cases by several orders of magnitude (9)(10)(11)(12). We hypothesized that these genes may play a role in adipose depot development and ultimately in differential adipose depot function.…”

Hypertrophy and hyperplasia of abdominal adipose tissues in women

“…[28][29][30] Recent studies using microarray analysis have also shown that fat tissue or preadipocytes from omental and subcutaneous fat depots have distinct expression profiles. 30,31 Differences in the expression of adipogenic genes in fat cells from different depots could contribute to regional fat distribution.…”

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

“…To test whether BMP7 was able to promote brown adipogenesis in human adipogenic cells, we treated preadipocytes isolated from different white-fat depots with BMP7. These adipose progenitors are known to possess depot-specific patterns of gene expression and differentiation capacities (43)(44)(45). Unlike murine primary ScaPCs, human primary preadipocytes required continuous exposure to BMP7 to differentiate into lipid-containing cells, as demonstrated by the expression of adipocyte marker aP2 (FABP4) (Fig.…”