Adipose tissue plays a key role in energy homeostasis both as an energy store and as an endocrine organ. Dysfunction of adipose tissue fat storage leads to fat deposition in other organs as ectopic fat and results in disadvantageous metabolic consequences as most apparent in subjects with familial lipodystrophy (19
). The cause of impaired adipose tissue storage capacity is unclear and SPARC that influences matricellular composition could contribute to its development by inhibition of adipocyte differentiation. Disturbance of the 3D extracellular matrix (ECM), for example, increased rigidity by increased collagen 1 content and has previously been shown to compromise in vitro adipocyte differentiation (20
), and collagen dysregulation has recently been attributed to metabolic dysregulation (3
The following attributes make SPARC a likely candidate to limit fat deposition in adipose tissue itself. Although it is an evolutionarily conserved collagen-binding glycoprotein, it does not contribute to the structure of the ECM, but it was recently shown to be a ligand of the integrin receptor α5-β1–integrin (21
) and inhibit adipogenesis through stimulation of β-catenin signaling (8
), which is part of the Wnt pathway that enhances osteoblastogenesis alongside the inhibition of adipogenesis (22
). SPARC null mice have a phenotype marked by an increased subcutaneous fat deposition, reduction in collagen 1 in SPARC-null fat, adipocytes of higher diameters, and fat pads with an increase in adipocyte number (23
The results of our study showed an increase of SPARC expression with increased fat mass that is consistent with previous reports showing a higher expression of SPARC in rodent obesity (24
) and elevated SPARC levels in obese subjects (25
). In addition, this is the first study to highlight the depot-specific expression of SPARC in humans. SPARC/osteonectin is expressed in various human tissues with particularly high expression in subcutaneous abdominal fat where is appears to be secreted primarily by adipocytes in comparison to the adipose tissue stromal fraction that is consistent with previous findings (2
). Subjects with familial lipodystrophy lack SCAT, and the metabolic consequences could be attributed to the limitation of subcutaneous tissue expansion to which SPARC as an inhibitor of adipogenesis (8
) with higher expression in SCAT may contribute.
This is the first study to assess metabolic parameters in combination with adipose tissue SPARC expression. We found a positive correlation with fasting insulin, fasting glucose, and HOMA-IR and waist circumference as well as hsCRP for subcutaneous and visceral depots. However, we did not find a correlation of SPARC with fasting lipids or blood pressure, which may in part be masked by treatment of subjects with hypercholesterolemia and hypertension (not shown).
Higami et al. (26
) examined genes downregulated by energy restriction in epididymal fat in mice, and SPARC was one of the prominently affected genes lowered by long-term energy restriction. Consistent with this we have found a strong downregulation of SPARC with weight loss after 8 weeks of a VLCD and an increment of SPARC with weight gain. Although HOMA-IR improved with weight loss in our VLCD study population, and SCAT-SPARC expression correlated with fasting insulin and HOMA-IR, the SPARC expression was no different in the BMI-matched groups with and without the metabolic syndrome, which is explained and consistent with the lack of correlation of SPARC with blood pressure and lipids. Leptin is a strong predictor of SPARC in the depot study as well as the VLCD study in which it is independent of the BMI at baseline. SPARC remains correlated with leptin expression but loses its association with weight loss after 8 weeks, after which subjects continued to lose weight. The strong correlation with insulin, glucose, and leptin in the depot and the VLCD study prompted us to study and confirm their regulation by further in vitro studies, while adiponectin showed an inverse correlation with SPARC expression in SCAT but not VAT and thus appeared less likely to be because of a direct effect.
Culture of visceral explants showed that glucose lowered and insulin and leptin increased SPARC expression that apart from the glucose correlation is consistent with the findings in the clinical studies. However, circulating glucose in vivo showed a positive correlation with SPARC-AT expression that contradicts the in vitro study in which supraphysiological glucose levels lower SPARC. The lack of influence of circulating glucose levels may be explained by the insulin resistance of adipocytes for glucose transport in obese individuals. In diabetic subjects, we would expect the glucose levels required to lower SPARC to be supraphysiological as found in marked hyperglycemia that is usually avoided by antidiabetic treatment. Although we show that SPARC is regulated by leptin, SPARC in turn suppresses leptin gene expression in mouse preadipocytes (21
), which may explain the high leptin levels observed in SPARC knockout mice (23
It was suggested that SPARC may be involved in inflammatory processes (27
), but data from our study show only a correlation of adipose tissue SPARC expression with the local expression of the MMIF-1—a proinflammatory adipocytokine (29
). An association of SPARC with MMIF was to our knowledge only reported in connection with malignant melanoma cells that showed overexpression of both (30
). Thus, the interaction of SPARC and MMIF remains to be confirmed but may explain a potential association of SPARC with diabetes with MMIF being associated with the pathogenesis of type 1 and type 2 diabetes and latter among others through a decrease in insulin signal transduction (31
Much pathology related to diabetes and obesity has been linked with SPARC. An increased SPARC expression was found in rodent models of diabetic nephropathy (32
), and SPARC null mice were shown to be protected from renal fibrosis (27
). Increased circulating levels of SPARC have been observed in subjects with cardiovascular disease (25
). SPARC is also expressed in human retinal endothelial cells (33
), and with its close interaction with VEGF and PAI-1 (34
) it may further the progression of diabetic retinopathy. Furthermore, SPARC is linked with tumorigenesis and appears to favor certain tumors (36
), although its exact role in tumor development is controversial (37
) and it remains to be shown whether SPARC could contribute to the association of obesity and some cancers (38
Apart from focusing on the potential advantages of lowering SPARC levels, the inducers of SPARC excess such as hyperleptinemia in subjects with leptin resistance and hyperinsulinemia in type 2 diabetes require similar attention. Leptin is a proinflammatory molecule, and it has been suggested that leptin is permissive in the pathogenesis of liver fibrosis as shown by protection of leptin-deficient mice from fibrosis during steatohepatitis or in response to chronic toxic liver injury (39
). As such, hyperleptinemia in adipose tissue may through upregulation of SPARC also induce adipose tissue fibrosis that requires further study.
In summary, our study showed that SPARC-AT expression is related to human metabolism and SPARC expression that is predominant in SCAT is upregulated by insulin and leptin. Together with the previous reported consequences of SPARC in other tissues, a role for SPARC in the development of obesity- and diabetes-related complications is likely. Further research is required to show whether increased adipose tissue SPARC limits the expansion of normal adipose tissue in response to energy excess and promotes ectopic fat deposition and associated metabolic dysfunction.