Potential role of increased matrix metalloproteinase-2 (MMP2) transcription in impaired adipogenesis in type 2 diabetes mellitus

Abstract

We measured gene expression of paracrine regulators involved in adipocyte differentiation within the stromovascular fraction of abdominal subcutaneous adipose tissue from obese individuals with (n = 30) and without (n = 18) type 2 diabetes mellitus (T2DM). Despite similar adiposity by design, subjects with T2DM had larger adipocytes (0.92 ± 0.28 vs. 0.75 ± 0.17 μl, p < 0.05) than controls. Gene expression of the adipogenic marker aP2 was lower (0.35 ± 0.16 vs. 0.58 ± 0.27 arbitrary units, p < 0.05) whereas the expression of matricellular peptidase, MMP2 was higher (1.65 ± 0.17 vs. 1.27 ± 0.21, p = 0.02) in T2DM vs. controls. The gene expression levels between the aP2 and MMP2 were inversely correlated (r = −0.32, p = 0.03). We conclude that early steps of adipogenesis may be impaired in T2DM independently of obesity due, in part, to an upregulation of the MMP2 transcription. KeywordsObesity; Type 2 diabetes; Adipocyte; Fatty acid binding protein aP2; Matrix metalloproteinase Obesity is associated with an extensive reorganization of adipose tissue including changes in adipogenesis, angiogenesis, extracellular matrix composition, and macrophage content. More specifically, the adipocyte differentiation in subcutaneous adipose tissue decreases with obesity [1]. Based on gene expression data, we suggest that obese individuals with type 2 diabetes (T2DM) have inhibited adipocyte differentiation when compared to obese non-diabetic controls [2]. However, the molecular mechanism of the impaired preadipocyte differentiation in T2DM is not known. It is well established that pro-inflammatory cytokines, chemokines, and proteolytic factors modulate adipocyte differentiation by paracrine mechanisms. Such factors are produced primarily by distinct cellular populations that comprise the stromovascular fraction (SVF) of adipose tissue (preadipocytes, mesenchymal stem cells, endothelial cells, smooth muscle cells, and infiltrating macrophages) and, to a lesser extent, by adipocytes [3,4]. Modified sensitivity of preadipocytes to adipogenic growth factors or hormones seems to also play a role [5]. In the present study, we asked whether the genes of selected pro- inflammatory and matricellular proteins, hormones, and/or molecules from selected signaling pathways are differentially expressed in the SVF of subcutaneous abdominal adipose tissue in obese diabetic vs. obese non-diabetic individuals. The selected genes were interleukin-6 (IL-6); tumor necrosis factor α (TNFα); CD68 (a member of the scavenger receptor superfamily expressed in macrophages and mast cells); monocyte chemotactic protein-1 (MCP1); macrophage migration inhibitory factor (MIF); macrophage inflammatory protein-1-α (MIP1A); stress-activated protein kinase JNK-1; IKKβ (an IκB kinase that activates the nuclear factor NFκB, a regulator of cytokine and chemokine gene transcription); matrix metalloproteinase-2 (MMP2, a gelatinase A or a type IV collagenase); and 11 β-hydroxysteroid dehydrogenase type 1 (11β-HSD1; enzyme that converts cortisone to cortisol). Furt...

Lower Total Adipocyte Number but No Evidence for Small Adipocyte Depletion in Patients With Type 2 Diabetes

“…This hypothesis is in accordance with recent data showing that insulin resistance per se causes impairment in adipogenesis (8,9). Future studies should test this novel hypothesis, i.e., that there might be a defect in the complete maturation of small adipocytes in patients with type 2 diabetes (supplemental Figure 4).…”

Gender-specific genetic associations of polymorphisms in ACE, AKR1C2, FTO and MMP2 with weight gain over a 10-year period

“…MMP2 is an endopeptidase that degrades the basement membrane surrounding adipocytes and thus may facilitate hypertrophic development of adipocytes and formation of adipocyte clusters (Brown et al 1997). An induction of the MMP2 transcription in adipose tissue of obese mice and during human adipocyte differentiation has been reported (Chavey et al 2003;Dubois et al 2008). In this study, we found that the C-allele of MMP2 in women is associated with weight gain over a 10-year period, which is in line with a study of Han et al (2008) who showed that the C-allele is associated with obesity.…”

Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue

“…An administration of a broad‐spectrum MMP inhibitor impairs AT growth, suggesting a functional role of MMPs on AT development in rodents (28). Nevertheless, only minor effects of partial MMP inhibition were observed on AT development and cellularity (29) while the deficiency of MMP‐2 impairs fat mass expansion and is associated with adipocyte hypotrophy (30). In marked contrast, MMP‐3 and MMP‐11 deficient mice consuming a high‐fat diet developed more AT than their wild type counterparts (31)(32).…”