A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21

Ruan, Chun; Kong, Lingrang; Chen, Xiaohui; Ma, Yu; Pan, Xiaoxia; Zhang, Ze-Bei; Gao, Pingjin

doi:10.1016/j.cmet.2018.06.013

Cited by 93 publications

(76 citation statements)

References 55 publications

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“…A study using hepatocyte-specific KO mice showed that liver is the major source of circulating FGF21 under physiologic conditions (Markan et al, 2014). Under certain pathophysiologic conditions, FGF21 is also ectopically expressed and released from nonhepatic tissues such as muscle (Izumiya et al, 2008;Kim et al, 2013) and BAT (Ruan et al, 2018). The molecular basis of the tissue-specific secretion of FGF21 has not been resolved.…”

Section: Fgf21mentioning

confidence: 99%

A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21

2019

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It has been more than a dozen years since FGF21 burst on the metabolism field in a paper showing that its pharmacologic administration caused weight loss and improved insulin sensitivity and lipoprotein profiles in obese rodents. Since then, FGF21 analogs have advanced all the way to clinical trials, and much progress has been made in understanding FGF21's pharmacology and physiology. In this Perspective, we highlight some of the interesting themes that have emerged from this first dozen years of FGF21 research, including its roles in autocrine/paracrine and endocrine responses to metabolic stress.

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Section: Fgf21mentioning

confidence: 99%

A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21

2019

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“…The heart is one of these potential target tissues, given the reports indicating a strong cardioprotective effect of FGF21 (Planavila et al 2013). However, direct evidence for this was lacking until the study by Ruan and his collaborators, who concluded, as a consequence of a study on the adenosine A2A receptor in BAT, that the FGF21 released by BAT targets the heart (Ruan et al 2018). Brown adipocytespecific FGF21 knockout impaired the previously observed effects of adenosine A2A receptor agonism in attenuating hypertensive cardiac remodelling.…”

Section: The Emerging Bat-to-heart Signalling Based On Fgf21mentioning

confidence: 99%

New insights into the secretory functions of brown adipose tissue

Villarroya

Cereijo

Gavaldà‐Navarro

et al. 2019

Journal of Endocrinology

144

114

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In recent years, an important secretory role of brown adipose tissue (BAT) has emerged, which is consistent, to some extent, with the earlier recognition of the important secretory role of white fat. The so-called brown adipokines or ‘batokines’ may play an autocrine role, which may either be positive or negative, in the thermogenic function of brown adipocytes. Additionally, there is a growing recognition of the signalling molecules released by brown adipocytes that target sympathetic nerve endings (such as neuregulin-4 and S100b protein), vascular cells (e.g., bone morphogenetic protein-8b), and immune cells (e.g., C-X-C motif chemokine ligand-14) to promote the tissue remodelling associated with the adaptive BAT recruitment in response to thermogenic stimuli. Moreover, existing indications of an endocrine role of BAT are being confirmed through the release of brown adipokines acting on other distant tissues and organs; a recent example is the recognition that BAT-secreted fibroblast growth factor-21 and myostatin target the heart and skeletal muscle, respectively. The application of proteomics technologies is aiding the identification of new members of the brown adipocyte secretome, such as the extracellular matrix or complement system components. In summary, BAT can no longer be considered a mere producer of heat in response to environment or dietary challenges; it is also an active secretory tissue releasing brown adipokines with a relevant local and systemic action. The identification of the major brown adipokines and their roles is highly important for the discovery of novel candidates useful in formulating intervention strategies for metabolic diseases.

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“…Although it is well documented that BAs are derived from distinct developmental origins, such as PDGFRα + ASCs located in WAT that express the common stem cell markers Sca1 and are shown to differentiate into BAs in vitro and in vivo [10]. BAs play a key role in the endocrine protection of hypertensive cardiac remodeling by activating A2AR/FGF21 pathway [5]. In the present study, we revealed that S-MSCs isolated in the dermis of mouse skin which expressed PDGFRα and readily differentiated into BAs regulated by mitochondrial activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic ablation of BAT is associated with not only obesity but also systemic hypertension and cardiac brosis as shown in transgenic mice with reduced brown fat [3,4]. Fibroblast growth factor 21 (FGF21) derived from BAT plays an endocrine protective role against hypertensive cardiac remodeling in mice [5]. BAs are the major component of BAT and arise from distinct developmental origins, including adipogenic progenitors, myogenic factor 5 (Myf5) + progenitors and neuronal cell differentiation [6,7].…”

mentioning

confidence: 99%

Mitochondrial Activity Regulates Skin-derived Mesenchymal Stem Cell Differentiation Into Brown Adipocyte Contributing to Hypertension

Chen

Sun

et al. 2020

Preprint

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Background: Brown adipocytes (BAs) are the major component of brown adipose tissue (BAT) that is closely related to systemic hypertension. BAs are derived from multiple progenitors including PDGFRα+ adipose-derived stem cells (ASCs). Skin-derived Mesenchymal Stem Cells (S-MSCs) have the capacity to differentiate into adipocytes. However, the differentiation of S-MSCs into BAs remains unexplored. We aim to study the ability and regulation mechanism of S-MSCs differentiation into BAs, and the direct role of BAT in blood pressure regulation. Methods: Protein expression was measured by Flow Cytometry or Western blotting, and gene mRNA levels were detected by real-time quantitative PCR (RT-PCR). For the BA differentiation of S-MSCs, S-MSCs were stimulated with a brown adipogenic cocktail containing insulin, IBMX, dexamethasone, triiodothyronine (T3), and rosiglitazone for the indicated periods. The oxygen consumption rate (OCR) was measured with an XF24 Extracellular Flux Analyzer. Mitochondrial mass was checked by flow cytometry and fluorescence staining. Hypertensive mouse model was induced in WT mice by infusion with angiotensin II (Ang II) and measured SBP using tail-cuff. The interscapular brown adipose tissue (iBAT)-deficiency mice were gotten by surgically removing the iBAT depot and allowed to recover for 6 days. Aorta, iBAT or heart tissue sections were examined by hematoxylin and eosin (HE) staining. Results: We found that S-MSCs isolated from the mouse dermis expressed the stem cell markers CD90/105 and PDGFRα, and readily differentiated into BAs. Mitochondrial biogenesis and oxygen consumption were markedly increased during BA differentiation of S-MSCs in vitro. Another, Ang II-induced hypertensive mice carried the change of iBAT to white adipose tissue (WAT), the enhanced Ang II-induced blood pressure and vascular remodeling were observed in BAT-deficient mice generated by surgically removing iBAT comparing with C57BL/6 (wild type-WT) mice. Conclusions: S-MSCs represent a useful in vitro model for differentiation of BAs regulated by mitochondrial activity, and are progenitors of BAs. This study indicates that PDGFRα+ S-MSCs could differentiate into BAs, and BAT plays a direct role in Ang II-induced hypertension and target organ remodeling.

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A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21

Cited by 93 publications

References 55 publications

A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21

A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21

New insights into the secretory functions of brown adipose tissue

Mitochondrial Activity Regulates Skin-derived Mesenchymal Stem Cell Differentiation Into Brown Adipocyte Contributing to Hypertension

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