Globular Adiponectin as a Complete Mesoangioblast Regulator: Role in Proliferation, Survival, Motility, and Skeletal Muscle Differentiation
15 Mar 2010-Molecular Biology of the Cell (American Society for Cell Biology)-Vol. 21, Iss: 6, pp 848-859
TL;DR: In vivo experiments confirm that globular adiponectin increases the survival, engraftment, and localization to muscle of mesoangioblasts in α-sarcoglycan-null mice.
Abstract: Mesoangioblasts are progenitor endowed with multipotent mesoderm differentiation ability. Despite the promising results obtained with mesoangioblast transplantation in muscle dystrophy, an improvement of their efficient engrafting and survival within damaged muscles, as well as their ex vivo activation/expansion and commitment toward myogenic lineage, is highly needed and should greatly increase their therapeutic potential. We show that globular adiponectin, an adipokine endowed with metabolic and differentiating functions for muscles, regulates vital cues of mesoangioblast cell biology. The adipokine drives mesoangioblasts to entry cell cycle and strongly counteracts the apoptotic process triggered by growth factor withdrawal, thereby serving as an activating and prosurvival stem cell factor. In addition, adiponectin provides a specific protection against anoikis, the apoptotic death due to lack of anchorage to extracellular matrix, suggesting a key protective role for these nonresident stem cells after systemic injection. Finally, adiponectin behaves as a chemoattractive factor toward mature myotubes and stimulates their differentiation toward the skeletal muscle lineage, serving as a positive regulator in mesoangioblast homing to injured or diseased muscles. We conclude that adiponectin exerts several advantageous effects on mesoangioblasts, potentially valuable to improve their efficacy in cell based therapies of diseased muscles.
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TL;DR: It is demonstrated that exogenous replenishment of adiponectin reverses metabolic abnormalities observed in Col6a1−/− myoblasts and is induced by fasting, a condition that has been previously shown to lead to the amelioration of the dystrophic phenotype.
Abstract: The role of adiponectin has been particularly deepened in diabetic muscles while the study of adiponectin in hereditary myopathies has been marginally investigated. Here, we report the study about adiponectin effects in Col6a1-/- (collagen VI-null) mice. Col6a1-/- mice show myophatic phenotype closer to that of patients with Bethlem myopathy, thus representing an excellent animal model for the study of this hereditary disease. Our findings demonstrate that Col6a1-/- mice have decreased plasma adiponectin content and diseased myoblasts have an impaired autocrine secretion of the hormone. Moreover, Col6a1-/- myoblasts show decreased glucose uptake and mitochondria with depolarized membrane potential and impaired functionality, as supported by decreased oxygen consumption. Exogenous addition of globular adiponectin modifies the features of Col6a1-/- myoblasts, becoming closer to that of the healthy myoblasts. Indeed, globular adiponectin enhances glucose uptake in Col6a1-/- myoblasts, modifies mitochondrial membrane potential, and restores oxygen consumption, turning closer to those of wild-type myoblasts. Finally, increase of plasma adiponectin level in Col6a1-/- mice is induced by fasting, a condition that has been previously shown to lead to the amelioration of the dystrophic phenotype. Collectively, our results demonstrate that exogenous replenishment of adiponectin reverses metabolic abnormalities observed in Col6a1-/- myoblasts. KEY MESSAGES: Col6a1-/- mice have decreased level of plasma adiponectin. Myoblasts from Col6a1-/- muscles have impaired local adiponectin secretion. Col6a1-/- myoblasts reveal altered metabolic features. Addition of exogenous adiponectin ameliorates Col6a1-/- metabolic features.
5 citations
TL;DR: Experimental evidence that S1P signalling is modulated by globular Adn treatment being able to increase the phosphorylation of SK1/2 as well as the mRNA expression levels of S 1P4 in C2C12 myotubes is provided.
Abstract: Background: Adiponectin (Adn), released by adipocytes and other cell types such as skeletal muscle, has insulin-sensitizing and anti-inflammatory properties. Sphingosine 1-phosphate (S1P) is reported to act as effector of diverse biological actions of Adn in different tissues. S1P is a bioactive sphingolipid synthesized by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK) 1 and 2. Consolidated findings support the key role of S1P in the biology of skeletal muscle. Methods and Results: Here we provide experimental evidence that S1P signalling is modulated by globular Adn treatment being able to increase the phosphorylation of SK1/2 as well as the mRNA expression levels of S1P4 in C2C12 myotubes. These findings were confirmed by LC-MS/MS that showed an increase of S1P levels after Adn treatment. Notably, the involvement of S1P axis in Adn action was highlighted since, when SK1 and 2 were inhibited by PF543 and ABC294640 inhibitors, respectively, not only the electrophysiological changes but also the increase of oxygen consumption and of aminoacid levels induced by the hormone, were significantly inhibited. Conclusion: Altogether, these findings show that S1P biosynthesis is necessary for the electrophysiological properties and oxidative metabolism of Adn in skeletal muscle cells.
4 citations
TL;DR: In this article , the authors investigated potential biomarkers associated with appendicular lean mass in community-dwelling older women and found that higher adiponectin plasma levels explained 14% of the lower appendicular mass.
Abstract: Inflammation is a chronic, sterile, low-grade inflammation that develops with advanced age in the absence of overt infection and may contribute to the pathophysiology of sarcopenia, a progressive and generalized skeletal muscle disorder. Furthermore, a series of biomarkers linked to sarcopenia occurrence have emerged. To aid diagnostic and treatment strategies for low muscle mass in sarcopenia and other related conditions, the objective of this work was to investigate potential biomarkers associated with appendicular lean mass in community-dwelling older women. This is a cross-sectional study with 71 older women (75 ± 7 years). Dual-energy X-ray absorptiometry was used to assess body composition. Plasmatic blood levels of adipokines (i.e., adiponectin, leptin, and resistin), tumor necrosis factor (TNF) and soluble receptors (sTNFr1 and sTNFr2), interferon (INF), brain-derived neurotrophic factor (BDNF), and interleukins (IL-2, IL-4, IL-5, IL-6, IL-8, and IL-10) were determined by enzyme-linked immunosorbent assay. Older women with low muscle mass showed higher plasma levels of adiponectin, sTNFr1, and IL-8 compared to the regular muscle mass group. In addition, higher adiponectin plasma levels explained 14% of the lower appendicular lean mass. High adiponectin plasmatic blood levels can contribute to lower appendicular lean mass in older, community-dwelling women.
4 citations
TL;DR: Further aspects of a possible role of recombinant adiponectin and leptin in the in vitro growth of primary porcine skeletal muscle cells cultured in energetically balanced, growth factor-supplemented, serum-free medium are elucidated.
Abstract: Cross-talk between adipose tissue and skeletal muscle may be mediated in part by adipokines This study was conducted to elucidate further aspects of a possible role of recombinant adiponectin and leptin in the in vitro growth of primary porcine skeletal muscle cells cultured in energetically balanced, growth factor-supplemented, serum-free medium (GF-SFM) Therefore, the effects of these adipokines on cell number (DNA content), DNA synthesis rate, cell death and on key intracellular signalling molecules were investigated Short-term adiponectin and leptin treatment decreased DNA synthesis, measured as [3H]-thymidine incorporation, as early as after 4-h exposure (P
3 citations
Cites background or result from "Globular Adiponectin as a Complete ..."
...…by looking at inconsistent results of a few studies, most of them performed using rodent muscle, reporting about stimulating (Lamosova and Zeman 2001, Ramsay 2003, Yu et al. 2008, Fiaschi et al. 2010), inhibitory (Arita et al. 2002, Wang et al. 2005) or a lack of effects (Carbo et al. 2000)....
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...…(MAPK), known to be involved in growth-mediating intracellular signalling pathways, can be phosphorylated after adiponectin treatment of murine muscle cell lines (Yamauchi et al. 2001, Wang et al. 2007, Fiaschi et al. 2009, Fiaschi et al. 2010) or human embryonic kidney cells (Lee et al. 2008)....
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Dissertation•
23 Jan 2014
TL;DR: In this paper, the role of adiponectin in regulating cardiac remodeling with a particular focus on the extracellular matrix (ECM) from a physiological and mechanistic perspective was investigated.
Abstract: Cardiac remodelling, the reorganization of the heart which occurs in response to factors impacting its function, includes remodelling of the extracellular matrix (ECM) and hypertrophic cardiomyocyte growth. Pressure overload (PO) induced remodelling of the ECM is initially considered a compensatory mechanism to maintain myocardial integrity, but is also considered a progressive, negative event increasing myocardial stiffness. Adiponectin, an adipokine inversely correlated with type 2 diabetes and obesity, plays an important role in the adaptive response of the heart in various cardiomyopathies, however, adiponectin signalling leading to ECM regulation remains unclear. The studies presented here investigate the role of adiponectin in regulating cardiac remodelling with a particular focus on the ECM from a physiological and mechanistic perspective.
Studies using wild-type (WT) and adiponectin deficient (AdKO) mice showed that PO induced left ventricular (LV) cardiac remodelling is delayed by adiponectin deficiency. The appearance of thick collagen fibres and activation of pro-fibrotic genes (MMPs and TIMPs) is delayed in AdKO mice subjected to PO when compared to WT mice. Cardiac hypertrophy and dysfunction, measured by echocardiography, is similarly delayed in AdKO mice. Furthermore, MEF2 activation determined using MEF2-lacZ reporter mice, is decreased in AdKO mice compared to WT mice following PO.
Studies in primary neonatal cardiac fibroblasts identified the APPL1-AMPK signalling axis as the mediator of adiponectin stimulated ECM remodelling through membrane localization of APPL1 and subsequent phosphorylation of AMPK, leading to MT1-MMP re-localization, MMP2 activation, and fibroblast migration. Also, adiponectin pre-treatment inhibited angiotensin II induced fibroblast to myofibroblast differentiation. Furthermore, in primary neonatal cardiomyocytes we identify the hypertrophic regulators Myocyte Enhancing Factor-2 (MEF2) and Atrial Natriuretic Factor (ANF) as downstream targets of adiponectin signalling.
Lastly, using an in vivo model of reverse remodeling, we show that myocardial strain and cardiac hypertrophy are regressed following LV unloading. However, regression of cardiac fibrosis was incomplete leading to persistent small fibre fibrosis.
Together these studies establish adiponectin as an important regulator of cardiac remodelling via the APPL1-AMPK signalling axis and MEF2 activation. Furthermore, we show that adiponectin deficiency confers protection against PO induced remodelling.
2 citations
References
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TL;DR: The 2-Delta Delta C(T) method as mentioned in this paper was proposed to analyze the relative changes in gene expression from real-time quantitative PCR experiments, and it has been shown to be useful in the analysis of realtime, quantitative PCR data.
139,407 citations
TL;DR: It is concluded that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy and that the replenishment of adiponECTin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
Abstract: Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
4,845 citations
TL;DR: It is shown that phosphorylation and activation of the 5′-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full- lengths Ad in the liver, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK.
Abstract: Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
4,298 citations
TL;DR: It is confirmed that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to thedegree of insulin resistance and hyperinsulinemia than to the level of adiposity and glucose intolerance.
Abstract: Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.
3,529 citations
"Globular Adiponectin as a Complete ..." refers background in this paper
...The peculiarity of adiponectin compared with sphingosine 1-phosphate is that the adipokine is produced by adipose tissue in an inverse relationship with fat mass, and its level is strongly decreased in diabetic patients (Weyer et al., 2001; Rasouli and Kern, 2008)....
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TL;DR: The cloning of complementary DNAs encoding adiponectin receptors 1 and 2 by expression cloning supports the conclusion that they serve as receptors for globular and full-length adiponECTin, and that they mediate increased AMP kinase and PPAR-α ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectionin.
Abstract: Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
3,013 citations