The prevalence of obesity has increased dramatically in the last decades and is now considered a major health problem. In fact, the current epidemic of obesity has been suggested as the leading cause for the decreased life expectancy forecast for the next generation. Obesity is very often accompanied by other diseases, the most common being type 2 diabetes mellitus (T2DM) and cardiovascular complications [1–3].
T2DM and obesity both involve genetic and environmental factors. However, progression to overt diabetes in patients with obesity is not clearly predicted. Likewise, while some obese individuals progress to T2DM, others only have mild metabolic abnormalities suggesting that the absolute amount of fat stored may not be the most important factor in determining the relationship between obesity and T2DM [4–7].
Adipose tissue expandability in response to positive energy balance has traditionally been considered an adaptive passive process. However, recent evidence suggests that the expandability of adipose tissue is not an unlimited process. In fact, adipose tissue expandability may be an important factor determining the appearance of obesity-associated co-morbidities [7–9]. Several studies have shown the prevalence of a negative IR status and no complications in patients with severe morbid obesity (Metabolically healthy, but obese individuals) [10–12].
Adipose tissue expansion is well known to be linked to the development of its vasculature . Furthermore, it has been described that obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and proteolysis . However, until now, no studies have established the relationship between adipose tissue angiogenic capacity, obesity and IR.
It is generally well known that the vascular endothelial growth factor (VEGF) system accounts for most of the angiogenic activity in adipose tissue . VEGF-A (17-23 kDa) is a major angiogenic factor that stimulates proliferation and migration of ECs . VEGF-B (21 kDa) is 43% identical to VEGF-A; it also promotes angiogenesis and is implicated in extracellular matrix (ECM) degradation via the regulation of plasminogen activation . VEGF-C displays a 30% homology with VEGF-A, and plays an important role in both angiogenesis and lymphangiogenesis [18, 19]. VEGF-D is 48% identical to VEGF-C and also promotes the growth of lymphatic vessels . Matrix metalloproteinases (MMPs) are essential for proper ECM remodeling, a process that takes place during obesity-mediated adipose tissue formation. The development of obesity is associated with coordinated cellular processes, including adipocyte hypertrophy followed by recruitment of adipocyte precursors, and new fat cell differentiation [21, 22]. These processes are also accompanied by neovascularization, essential for the generation and proper function of adipose tissue . It is generally accepted that such multiple events include dynamic changes of cell-matrix interactions and extensive ECM remodeling, and that modifications in proteolytic activities within the adipose microenvironment might occur during the development of the fat depot. Among enzymes implicated in the degradation of matrix molecules and in the generation of bioactive factors, the matrix metalloproteinase family is considered to be primarily responsible for these processes . These subgroups are collagenases, gelatinases, stromelysins, membrane-type MMPs (MT-MMPs), and other MMPs [25, 26]. MMPs participate in many physiological and pathological processes such as embryonic development, angiogenesis, wound repair, reproductive cycling, and metastasis [24, 25]. Also, they can mediate the release and/or activation of sequestered growth factors, including VEGFs, and the cleavage of cell surface adhesion receptors .
On the basis of all these antecedents our aim was to analyze angiogenic factor and metalloproteinases expression levels in adipose tissue from control and obese subjects with or without IR, to study the relationship between adipose tissue-angiogenic factors/metalloproteinase, obesity and IR.