Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice

doi:10.1016/j.bbrc.2018.02.185

Biochemical and Biophysical Research Communications

Volume 497, Issue 4, 18 March 2018, Pages 1097-1103

https://doi.org/10.1016/j.bbrc.2018.02.185 Get rights and content

Highlights

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Transplantation of BAT, but not WAT, reduces the plaque size in apoE^−/− mice.
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Serum levels of noradrenalin, FGF-21, and adiponectin are increased in BAT-transplanted mice.
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β3-AR blocker abrogates the atheroprotective effect of BAT transplantation.
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β3-AR blocker abrogates the elevations of serum FGF-21 and adiponectin.
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Adiponectin levels show a significant inverse correlation with plaque size in BAT-transplanted mice.

Abstract

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE^−/− mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE^−/− mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Introduction

Brown adipose tissue (BAT) plays a crucial role in adaptive thermogenesis in small mammals and newborn infants, and has long been considered to have no physiological relevance in adult humans [1]. However, recent study using positron emission tomography and computed tomography (PET/CT) have revealed that BAT is active in adulthood during cold acclimation [2]. BAT is inversely correlated with BMI in humans, in contrast to white adipose tissue (WAT) [3]. These findings have led to the notion that activation of BAT is a potential therapeutic strategy to prevent the development of obesity and metabolic disease [[4], [5], [6]].

The effects of BAT activation on atherosclerosis have recently been investigated; however, experimental findings remain controversial [[7], [8], [9]]. Although BAT activation by cold acclimation significantly decreased plasma triglyceride, it increased the plasma levels of small low-density lipoprotein (LDL) remnants, leading to atherosclerotic plaque growth in apolipoprotein E deficient (apoE^−/−) mice accompanied by marked reduction of plasma adiponectin levels [7]. In contrast, BAT activation by β3-adrenergic receptor (AR) stimulation inhibits the development of atherosclerosis in APOE*3-Leiden.CETP mice, but not in hyperlipidemic apoE^−/− mice or LDL receptor deficient (LDLR^−/−) mice [8].

Previous studies have investigated the atheroprotective effects of activated BAT by focusing on augmented energy expenditure, with a consequent improvement in lipid homeostasis; however, BAT, as well as WAT, has recently been found as an endocrine organ that regulates metabolic homeostasis [10]. BAT produces and releases various kinds of adipokines, termed “batokines”, which have different actions from those in WAT [4,5]. Gunawardana et al. [4]. showed that adiponectin, leptin, and insulin growth factor-1 (IGF-1) was significantly increased in BAT-transplanted mice, which corrected glucose homeostasis in type 1 diabetic rats. A recent study by Stanford et al. [5]. showed that BAT transplantation stimulated the production and release of fibroblast growth factor 21 (FGF-21) in endogenous BAT, leading to improvement in glucose homeostasis and insulin sensitivity. However, it remains to be determined whether activated BAT could function as an endocrine organ to inhibit atherosclerosis development.

Here, we showed, for the first time, that BAT transplantation exerts atheroprotective effects, accompanied by enhanced expression of FGF-21 in endogenous BAT. Serum FGF-21 levels were also increased in BAT-transplanted mice along with a higher concentrations of serum adiponectin, which was inversely correlated with atherosclerotic lesions. Our findings suggest that BAT could function as an endocrine organ to inhibit atherosclerosis and its activation could be a potential therapeutic strategy to prevent cardiovascular diseases, as well as obesity and metabolic diseases, in adults.

Section snippets

Materials and methods

For detailed experimental procedures, see Supplementary material online.

Atherosclerotic lesion development is reduced in BAT-transplanted apoE^−/− mice accompanied by augmented activation of endogenous BAT

We first transplanted interscapular BAT from C57BL/6-Tg (CAG-EGFP) mice into the visceral cavity of age-matched apoE^−/− mice. Histochemical analysis of the grafted BAT after 12 weeks of transplantation revealed the successful engraftment of transplanted BAT (Supplementary Fig. S1). We then examined the impact of BAT transplantation on atherosclerosis in apoE^−/− mice. Atherosclerotic lesions in whole aortas was markedly reduced in BAT-transplanted mice compared with control mice (Fig. 1A and B).

Discussion

In this study, we showed for the first time that transplantation of interscapular BAT significantly inhibited atherosclerosis development in whole aortas of apoE^−/− mice without affecting serum cholesterol levels. An increase in serum FGF-21, which was produced and released from activated endogenous BAT, could contribute to atheroprotective action with simultaneous elevation of serum adiponectin released from iWAT. Treatment with the β3-AR blocker completely abrogated the atheroprotective

Funding

This work was supported by the grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan [grant number C: KAKENHI-24591120, 15K09162 to H.Y.].

Conflicts of interest

None declared.

Acknowledgments

We thank Dr. Yuji Naito and Dr. Wataru Aoi for providing equipment and technical advice on oxygen consumption measurements.

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Adiponectin (ADPN) and fibroblast growth factor 9 (FGF9) has been reported as anti-depressive and pro-depressive factor, respectively. However, it is unknown whether there is directly interaction between ADPN and FGF9 in depression. The present study aims to investigate the correlation between ADPN and FGF9 in depression disorder. Firstly, the decreased level of ADPN and the increased level of FGF9 in plasma of depressive patients compared with non-depressive subjects were observed. Furthermore, these is a significant negative correlation between the ratio of ADPN to FGF9 and the total score of Hamilton Depression Scale in total investigated subjects. The similar changes of ADPN and FGF9 were also observed in elder adiponectin gene knockout (Adipo^−/−) mice with an increasing trend to depressive-like behaviors. Secondly, the decreasing level of ADPN and increasing level of FGF9 in plasma and hippocampus tissues were observed in chronic unpredictable mild stress (CUMS)-induced depression in ICR mice with significant depressive-like behaviors and hippocampus damage, which attenuated by injection of recombinant ADPN or FGF9 antibody into lateral ventricle. In Adipo^−/− mice, injection of FGF9 antibody into lateral ventricle also attenuated CUMS-induced depressivelike behaviors. The protein expression of FGF receptor 3 (FGFR3), the main receptor of FGF9, was significantly down-regulated in hippocampus tissues of CUMS-treated mice, which could be attenuated by treatment with either recombinant ADPN or anti-FGF9. In summary, the present results suggest that ADPN maybe a key negative regulator of FGF9/FGFR3 in depressive disorder and the dysfunction of ADPN-FGF9 pathway plays a key role in stress-induced depression.
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View full text

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Atherosclerotic lesion development is reduced in BAT-transplanted apoE−/− mice accompanied by augmented activation of endogenous BAT

Discussion

Funding

Conflicts of interest

Acknowledgments

Cell Metab.

Trends Endocrinol. Metabol.

Cell Metab

Cell Metab.

Biochimie

Biochim. Biophys. Acta

Cell Metab.

Cell Metab.

Cell Metab.

Cell Metab.

Physiol. Behav.

Neuroscience

Am. J. Pathol.

Brown adipose tissue: function and physiological significance

Physiol. Rev.

Cold-activated brown adipose tissue in healthy men

N. Engl. J. Med.

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE^−/− mice

Atherosclerotic lesion development is reduced in BAT-transplanted apoE^−/− mice accompanied by augmented activation of endogenous BAT