Keith Dadson

Bio: Keith Dadson is an academic researcher from York University. The author has contributed to research in topics: Adiponectin & Pressure overload. The author has an hindex of 8, co-authored 10 publications receiving 211 citations.

Adiponectin action: a combination of endocrine and autocrine/paracrine effects.

Abstract: The widespread physiological actions of adiponectin have now been well characterized as clinical studies and work in animal models have established strong correlations between circulating adiponectin levels and various disease-related outcomes. Thus, conventional thinking attributes many of adiponectins beneficial effects to endocrine actions of adipose-derived adiponectin. However, it is now clear that several tissues can themselves produce adiponectin and there is growing evidence that locally produced adiponectin can mediate functionally important autocrine or paracrine effects. In this review article we discuss regulation of adiponectin production, its mechanism of action via receptor isoforms and signaling pathways and its principal physiological effects (ie. metabolic and cardiovascular). The role of endocrine actions of adiponectin and changes in local production of adiponectin or its receptors in whole body physiology is discussed.

Adiponectin mediated APPL1-AMPK signaling induces cell migration, MMP activation, and collagen remodeling in cardiac fibroblasts.

Abstract: Defects in adiponectin action have been implicated in the development of cardiac dysfunction in obesity and diabetes. Cardiac fibroblasts play an important role in regulating extracellular matrix remodeling yet little is known regarding the direct effects of adiponectin on cardiac fibroblasts. In this study, we first demonstrated temporal relocalization of cellular APPL1 in response to adiponectin in primary cardiac fibroblasts and that siRNA-mediated knockdown of APPL1 attenuated stimulation of AMPK by adiponectin. The cell surface content of MT1-MMP and activation of MMP2 were induced by adiponectin and these responses were dependent on AMPK signaling. Enhanced MMP activity facilitated increased fibroblast migration in response to adiponectin which was also prevented by inhibition of AMPK, with no change in cell proliferation observed. Collagen and elastin immunofluorescence demonstrated reorganization of the extracellular matrix in accordance with increased MMP activity, whereas quantitative mRNA analysis, (3) H-proline incorporation and picrosirius red assays showed no change in intracellular or extracellular total collagen levels in response to adiponectin. In summary, these data are the first to report the adiponectin stimulated APPL1-AMPK signaling axis in cardiac fibroblasts and characterize MT1-MMP translocation, MMP2 activity and cell migration as functional outcomes. These effects may be of significance in heart failure associated with obesity and diabetes.

Pressure Overload-Induced Cardiac Dysfunction in Aged Male Adiponectin Knockout Mice Is Associated With Autophagy Deficiency.

Abstract: Heart failure is a leading cause of death, especially in the elderly or obese and diabetic populations. Various remodeling events have been characterized, which collectively contribute to the progression of heart failure. Of particular interest, autophagy has recently emerged as an important determinant of cardiac remodeling and function. Here, we used aged, 13-month-old, male adiponectin knockout (Ad-KO) or wild-type (wt) mice subjected to aortic banding to induce pressure overload (PO). Cardiac strain analysis using speckle tracking echocardiography indicated significant dysfunction at an earlier stage in Ad-KO than wt. Analysis of autophagy by Western blotting for Light Chain 3 or microtubule-associated proteins 1B and Sequestosome 1 together with transmission electron microscopy of left ventricular tissue indicated a lack of PO-induced cardiac autophagy in Ad-KO compared with wt mice. Associated with this was mitochondrial degeneration and evidence of enhanced endoplasmic reticulum stress. Western blotting for Light Chain 3 or microtubule-associated proteins 1B, examination of flux using tandem fluoresent tagged-Light Chain 3, and analysis of lysosomal activity in H9c2 cardiac myoblasts treated with adiponectin indicated that adiponectin enhanced autophagy flux. In conclusion, adiponectin directly stimulates autophagic flux and the lack of autophagy in response to PO in aged mice lacking adiponectin may contribute to cellular events which exacerbate the development of cardiac dysfunction.

Heart Failure and MEF2 Transcriptome Dynamics in Response to β-Blockers.

Abstract: Myocyte Enhancer Factor 2 (MEF2) mediates cardiac remodelling in heart failure (HF) and is also a target of β-adrenergic signalling, a front-line treatment for HF. We identified global gene transcription networks involved in HF with and without β-blocker treatment. Experimental HF by transverse aortic constriction (TAC) in a MEF2 "sensor" mouse model (6 weeks) was followed by four weeks of β-blockade with Atenolol (AT) or Solvent (Sol) treatment. Transcriptome analysis (RNA-seq) from left ventricular RNA samples and MEF2A depleted cardiomyocytes was performed. AT treatment resulted in an overall improvement in cardiac function of TAC mice and repression of MEF2 activity. RNA-seq identified 65 differentially expressed genes (DEGs) due to TAC treatment with enriched GO clusters including the inflammatory system, cell migration and apoptosis. These genes were mapped against DEGs in cardiomyocytes in which MEF2A expression was suppressed. Of the 65 TAC mediated DEGs, AT reversed the expression of 28 mRNAs. Rarres2 was identified as a novel MEF2 target gene that is upregulated with TAC in vivo and isoproterenol treatment in vitro which may have implications in cardiomyocyte apoptosis and hypertrophy. These studies identify a cohort of genes with vast potential for disease diagnosis and therapeutic intervention in heart failure.

Adiponectin, the past two decades

Abstract: Adiponectin is an adipocyte-specific factor, first described in 1995. Over the past two decades, numerous studies have elucidated the physiological functions of adiponectin in obesity, diabetes, inflammation, atherosclerosis, and cardiovascular disease. Adiponectin, elicited through cognate receptors, suppresses glucose production in the liver and enhances fatty acid oxidation in skeletal muscle, which together contribute to a beneficial metabolic action in whole body energy homeostasis. Beyond its role in metabolism, adiponectin also protects cells from apoptosis and reduces inflammation in various cell types via receptor-dependent mechanisms. Adiponectin, as a fat-derived hormone, therefore fulfills a critical role as an important messenger to communicate between adipose tissue and other organs. A better understanding of adiponectin actions, including the pros and cons, will advance our insights into basic mechanisms of metabolism and inflammation, and potentially pave the way toward novel means of pharmacological intervention to address pathophysiological changes associated with diabetes, atherosclerosis, and cardiometabolic disease.

Adiponectin Regulation and Function

Abstract: Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK), and increased peroxisome proliferator-activated receptor alpha (PPARα) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. © 2017 American Physiological Society. Compr Physiol 8:1031-1063, 2018.

Adiponectin, driver or passenger on the road to insulin sensitivity?

Abstract: Almost 20 years have passed since the first laboratory evidence emerged that an abundant message encoding a protein with homology to the C1q superfamily is highly specifically expressed in adipocytes. At this stage, we refer to this protein as adiponectin. Despite more than 10,000 reports in the literature since its initial description, we seem to have written only the first chapter in the textbook on adiponectin physiology. With every new aspect we learn about adiponectin, a host of new questions arise with respect to the underlying molecular mechanisms. Here, we aim to summarize recent findings in the field and bring the rodent studies that suggest a causal relationship between adiponectin levels in plasma and systemic insulin sensitivity in perspective with the currently available data on the clinical side.