Although evidence supports an impairment of adipocyte differentiation in obese individuals with T2DM independently of adiposity [2
], no mechanism has been proposed. The two major hypotheses to explain such impairment include: (1) reduced sensitivity of preadipocytes to adipogenic hormones (i.e. glucocorticoids) and (2) increased secretion of cytokines, chemokines, and ECM components by the SV cells of adipose tissue. In an attempt to identify factors that play a role in the impairment of adipogenesis in T2DM, we studied mRNA levels of selected proteins in the SVF of subcutaneous abdominal adipose tissue in obese diabetic and obese non-diabetic individuals.
We found lower levels of aP2 mRNA in subjects with T2DM as compared to obese controls. Using fluorescent staining of freshly isolated SV cells from adipose tissue for aP2, lipids, and the macrophage marker CD68, we have previously identified that aP2 is expressed in preadipocytes, immature adipocytes containing small amount of multi-locular lipid droplets, and in a small proportion of macrophages [8
]. However, in the present study, the quantification of these cellular types was not performed and thus definitive conclusion cannot be drawn. Since the gene expression of inflammatory markers TNFα and IL-6 as well as of molecules pertaining to their regulatory signaling pathways (JNK and NFκB) was similar between the groups, one cannot imply an increased amount of macrophages in the subcutaneous adipose tissue of obese T2DM vs. obese controls. Additional measurement of the expression of the preadipocyte-specific marker Pref-1 in adipose tissue showed similar levels in both groups suggesting a comparable number of preadipocytes. Together, the above observations foster the interpretation that the reduced levels of aP2 mRNA reflect either lower number of small adipocytes or decreased expression of aP2 per cell in the small adipocytes present in the SVF suggesting impaired preadipocyte differentiation. It is possible that the adipocyte hypertrophy found in T2DM may be linked to the impaired preadipocyte differentiation.
A second finding of this study is the higher MMP2 gene expression in T2DM. Recently, Derosa et al. [9
] reported higher plasma levels of MMP2 in T2DM compared to healthy controls reflecting generalized abnormality of the extracellular matrix metabolism. An induction of the MMP2 transcription in the adipose tissue of genetically obese mice has also been reported [10
] but our finding of higher expression in T2DM, compared to obese non-diabetic subjects, is novel. MMP2 is an endopeptidase that degrades the basement membrane surrounding adipocytes and thus may facilitate hypertrophic development of adipocytes and formation of adipocyte clusters [11
]. Recent studies demonstrate a direct but inconsistent effect of MMP2 on early phases of murine preadipocyte differentiation [4
]. The negative correlation between MMP2 and aP2 gene expression in SV cells from subcutaneous adipose tissue leads us to speculate that elevated MMP2 transcript may play an inhibitory role early in the differentiation program. Alternative hypothesis is that impaired adipocyte differentiation may lead to an upregulation of MMP2 transcription. As usual, it is however impossible to imply causality from correlation analyses. Additional testing using MMP2 and its blockers in primary human preadipocyte cultures will be required.
In conclusion, the present study suggests: (1) impaired adipogenesis in T2DM and (2) a potential role of increased MMP2 transcript level in the impaired adipogenesis in T2DM.