Regulation of the Fibrosis and Angiogenesis Promoter SPARC/Osteonectin in Human Adipose Tissue by Weight Change, Leptin, Insulin, and Glucose

Abstract

OBJECTIVEMatricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines.RESEARCH DESIGN AND METHODSSerum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 ± 3.7 kg). Another six lean subjects underwent fast-food–based hyperalimentation for 4 weeks (weight gain: 7.2 ± 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses.RESULTSSPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment–insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein.CONCLUSIONSOur data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.

Elevated plasma levels of SPARC in patients with newly diagnosed type 2 diabetes mellitus

“…Recent evidence suggests that SPARC could be a key player in the pathology of obesity and T2DM. The biological mechanisms involving SPARC in the pathogenesis of IR and T2DM remain poorly understood, although potential mechanisms have been postulated, including the interaction of SPARC and macrophage migration inhibitory factor (MMIF) involved in inflammatory processes (2). In this study, we observed that the fasting plasma SPARC levels were significantly higher in subjects with T2DM compared with IGR and control subjects.…”

“…To the best of our knowledge, this is the first study to describe plasma levels of SPARC in patients with different glucose regulatory conditions. Although SPARC levels have been demonstrated to be downregulated by glucose in vitro (2,13,14), other modulators, including insulin and leptin, which have been reported as positive modulators, may also result in the elevation of SPARC levels in diabetic subjects. Adipose tissue is known to be an active and dynamic organ expressing and secreting several cytokines and chemokines.…”

“…Evidence suggests that a higher level of SPARC appears to inhibit the expansion of abdominal subcutaneous adipose tissue (7), probably by increasing ectopic lipid stores in other tissues such as liver or skeletal muscle resulting in predisposition to insulin resistance (IR). Expression of SPARC is markedly elevated in the adipose tissue in both obese (OB) mice and human individuals (2,8), and is positively regulated by weight change, calorie intake, insulin, and leptin. There is an association between SPARC and IR in human individuals, independent of obesity (2).…”

“…Expression of SPARC is markedly elevated in the adipose tissue in both obese (OB) mice and human individuals (2,8), and is positively regulated by weight change, calorie intake, insulin, and leptin. There is an association between SPARC and IR in human individuals, independent of obesity (2). In addition, SPARC has been implicated in the pathogenesis of diabetes complications such as retinopathy and nephropathy (9)(10)(11)(12).…”

“…It is expressed in most tissues but, in obesity, adipose tissue cells are the major source of circulating SPARC (2). As a multifunctional glycoprotein binding calcium, collagen and hydroxyapatite (3), SPARC is an extracellular regulatory macromolecule involved in osteogenesis, angiogenesis, wound healing, tumorigenesis, hepatic and renal fibrosis (4)(5)(6).…”