Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice

Nomiyama, Takashi; Pérez-Tilve, Diego; Ogawa, Daisuke; Gizard, Florence; Zhao, Yue; Heywood, Elizabeth B.; Jones, Karrie L.; Kawamori, Ryuzo; Cassis, Lisa A.; Tschöp, Matthias H.; Bruemmer, Dennis

doi:10.1172/jci31986

Cited by 344 publications

(371 citation statements)

References 60 publications

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“…Previous studies have shown that expression of OPN is increased in diabetes, where it plays a key role in high-fat diet-induced macrophage recruitment to adipose tissue and the induction of insulin resistance (18). Moreover, OPN is upregulated in many forms of heart failure in which both gain-and loss-of-function experiments have shown that it plays a pathologic role in cardiac dysfunction (22,27,31).…”

Section: Discussionmentioning

confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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Section: Discussionmentioning

confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent studies have indicated that obese adipose tissue is hallmarked with chronic, lowgrade inflammation, and that inflammation plays a central role in the development of insulin resistance (1,2). Although the contributions of the CD44 encoded protein to the molecular pathogenesis of T2D have not yet been reported, SPP1 was reported as a link between adipose tissue inflammation (stromal infiltration by inflammatory cells) and the development of insulin resistance in a murine model of diet-induced obesity (25). Furthermore, the expression profile of CD44 and SPP1 are coordinately dysregulated, especially in adipose tissue ( Fig.…”

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confidence: 99%

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

Kodama

Horikoshi²,

Toda

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

152

162

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Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.bioinformatics | meta-analysis | integration | obesity | hyperglycemia

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“…6 Beside tubular cell EMT induction, MMP-9 is known to be capable of cleaving osteopontin (OPN), 22 a macrophage chemoattractant and macrophages are well known to have a role in renal fibrosis. [23][24][25] However, whether a protection in renal fibrosis was due to a reduction of macrophage infiltration in MMP-9 KO model is unclear. Furthermore, MMPs including MMP-9 has been shown to exhibit an opposing role at different stages of disease progression including renal disease.…”

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confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

132

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice

Cited by 344 publications

References 60 publications

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

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