SPARC: a key player in the pathologies associated with obesity and diabetes

SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin or BM-40) is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions. Notably, SPARC is linked to human obesity; SPARC derived from adipose tissue is associated with insulin resistance and secretion of SPARC by adipose tissue is increased by insulin and the adipokine leptin. Furthermore, SPARC is associated with diabetes complications such as diabetic retinopathy and nephropathy, conditions that are ameliorated in the Sparc-knockout mouse model. As a regulator of the extracellular matrix, SPARC also contributes to adipose-tissue fibrosis. Evidence suggests that adipose tissue becomes increasingly fibrotic in obesity. Fibrosis of subcutaneous adipose tissue may restrict accumulation of triglycerides in this type of tissue. These triglycerides are, therefore, diverted and deposited as ectopic lipids in other tissues such as the liver or as intramyocellular lipids in skeletal muscle, which predisposes to insulin resistance. Hence, SPARC may represent a novel and important link between obesity and diabetes mellitus. This Review is focused on whether SPARC could be a key player in the pathology of obesity and its related metabolic complications.

SPARC (secreted protein acidic and rich in cysteine, also known as Bm-40) was initially identified in bone, in 1981, and is thus also known as osteonectin. SPARC is a glycoprotein of the extracellular matrix (ECM) that binds calcium, collagen and hydroxyapatite. SPARC weighs 34 kDa, but owing to glycosylation the secreted form migrates to 43 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis. as a secreted protein, SPARC is an extracellular regulatory macro- molecule that does not contribute to the matrix structure, but regulates the cell–matrix interaction.

SPARC is the product of a single gene localized on chromosomal region 5q31-33, in the proximity of the genes encoding macrophage colony-stimulating factor 1 (CsF1), interleukin 3 (il-3), platelet-derived growth factor (PDGF) and the β2 adrenergic receptor. the sequences of the SPARC gene and the protein it encodes are highly conserved among species. the structure of the human protein consists of 286 residues and three domains. the N-terminal domain of SPARC is an acidic region that contains the major immuno- logical epitopes of the protein. the second domain is a cysteine-rich follistatin-like domain, which binds activin, inhibin, heparin and proteoglycans and may regulate pro- liferation of endothelial cells. the C-terminal domain is a calcium-binding extracellular domain, which includes a binding site that interacts with endothelial cells and binds fibril-forming collagens (the latter occurring with increased affinity after cleavage of a single-bond peptide by metalloproteinases).

SPARC is also highly expressed in several tumors, such as ovarian and colorectal tumors and melanomas. since these early studies SPARC was found to be ubiquitously expressed and was studied in various pathological conditions ranging from liver and kidney disease to alzheimer disease. SPARC was also found to be secreted by adipose cells and circulating SPARC levels positively correlate with Bmi in humans. these findings suggest that the secretion of SPARC from adipose tissue may account for the majority of circulating SPARC. Given the profibrotic qualities of SPARC and the evidence of fibrosis in adipose tissue of individuals with obesity, a finding reported in 2008,SPARC was proposed to contribute to the patho- genesis of obesity-associated disorders, in particular by promoting insulin resistance.

General function

SPARC is counteradhesive (disrupts cell adhesion), a modulator of cell-surface interaction and an inhibitor.of the cell cycle. this protein is expressed when tissues undergo events that require changes in cell–matrix and cell–cell contact, particularly tissue renewal, tissue remodeling, and embryonic development. SPARC modulates tissue physiology by altering the cell–ECM interaction, cell proliferation and cell migration. owing to these properties, SPARC participates in wound healing, angiogenesis, tumorigenesis and inflammation. these functions are facilitated by SPARC’s ability to influence the activity of cytokines and growth factors, such as vascular endothelial growth factor (VEGF), which is the most potent and widely distributed angio- genic mitogen for capillary endothelial cells, PDGF, heparin-binding growth factor 2 (HBGF2, also known as FGF2) and insulin-like growth factor 1 (IGF1). Box 1 provides more details about proteins that are known to influence or are influenced by SPARC.

In addition, several SPARC-like proteins with functional similarities to SPARC have been identified. of these, SPARC-like protein 1 (also known as hevin) is expressed in the human central nervous system, along with SPARC, but the extent to which they share functionality is not clear.

SPARC and obesity

obesity, defined as a Bmi of more than 30 kg/m2, is closely linked with an elevated risk of metabolic com- plications, particularly T2DM and the metabolic syndrome (which often precedes diabetes mellitus). Furthermore, individuals with obesity have an increased risk of developing cardiovascular disease, which is partly due to the metabolic consequences of obesity, such as T2DM. obesity is also linked to an increased risk of cancer and mortality caused by cancer, and is associated with various cancers, such as those in the gastrointestinal tract and endometrium. SPARC dysregulation has been associated with a wide range of obesity-related disorders, including T2DM and its complications, renal and liver,disease, cardiovascular disease and obesity-associated cancers.


obesity is characterized by a proinflammatory state, which may contribute to obesity-related complications. the circulating levels of markers of systemic inflammation are increased in obesity and this effect has been attrib- uted to the increased adipose tissue mass. these markers include adipokines (proteins secreted by adipocytes that have paracrine and endocrine function), such as leptin, and cytokines, such as tumor necrosis factor (TNF), C-reactive protein (CRP), plasminogen activator inhibitor 1 (PAI1) and interleukins. the latter are secreted by stromal cells such as macrophages, which infiltrate the adipose tissue in obesity, and by adipocytes.


Apart from inflammatory signals, hypoxia (reduced tissue oxygenation) has also been implicated in the induction of adipose tissue fibrosis. Hypoxia of adipose tissue has been observed in vivo in obese rodents and also in humans with obesity. reduced partial pressure of oxygen in subcutaneous abdominal adipose tissue was associated with changes in collagen expression and decreased VEGF expression, which suggests that capillary dropout is taking place. Capillary rarefaction in the adipose tissue may, therefore, contribute to hypoxia, as this type of tissue expands in obesity.
Hypoxia activates the expression of hypoxia-inducible factor 1α (HIF1α) and inflammatory cytokines in adipose tissue and induces macrophage infiltration, all of which increase inflammation, and can, therefore, lead to fibrosis. The expression of HIF1A (the gene that encodes HIF1α) in adipose tissue increases with weight gain and decreases with weight loss.