Nebivolol induces, via β3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes

Bordicchia, Marica; Pocognoli, Antonella; D'Anzeo, Marco; Siquini, Walter; Minardi, Daniele; Muzzonigro, Giovanni; Dessı̀-Fulgheri, Paolo; Sarzani, Riccardo

doi:10.1097/hjh.0000000000000024

Cited by 32 publications

(30 citation statements)

References 45 publications

(57 reference statements)

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“…iv)human adipocytes differentiated in the presence of NT3 exhibit decreased size and increased UCP-1 expression; v) mice with reduced expression of NT3 (NT3 +/-), or with prevented endothelial NT3 expression (eNT3-), exhibit larger adipocytes, in WAT and BAT, and lower UCP-1 expression in BAT. Collectively, these observations support the notion that activation, is the principal initiator of lipolysis [38][39][40][41]. In BAT, β-adrenergic activation leads to increased expression and activation of UCP1 in the inner mitochondrial membrane, which collapses the proton gradient that would normally drive ATP synthesis and energy storage, increasing mitochondrial respiration and thermogenesis [28].…”

Section: Discussionsupporting

confidence: 63%

“…It is well known that β-adrenoceptors, and specially the β3 subtype, control the transcription of nuclear factors that increase mitochondrial biogenesis and UCP-1 expression [37,41,42,48,49]. However, the generation of β3 knockouts has not resulted remarkable changes in AT [50] by functional redundancy between the three βadrenoceptor subtypes co-expressed in adipocytes [42,51].…”

Section: Nt3 Stimulates Lipolysis Decreases Adipocyte Size and Incrementioning

confidence: 99%

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NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue

Bové

Montó

Guillem-Llobat

et al. 2020

Preprint

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NT3, through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (specially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.ConclusionsNT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1

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Section: Discussionsupporting

confidence: 63%

Section: Nt3 Stimulates Lipolysis Decreases Adipocyte Size and Incrementioning

confidence: 99%

NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue

Bové

Montó

Guillem-Llobat

et al. 2020

Preprint

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“…Our results showed that aortas with intact PVAT contracted more to KCl than PVAT denuded aortas in DOCA-salt-induced hypertensive mice. Meanwhile, several studies have revealed that in adipose tissue stimulation of ADRB3 induces UCP1 expression, reduction in lipid droplets size and adipose [14][15][16]. In the present study, we found that DOCA-salt treatment induced PVAT structure remodeling, accompanied by increased protein levels of ADRB3 and UCP1 in the PVAT.…”

Section: Discussionsupporting

confidence: 62%

Beta3 adrenergic receptor is involved in vascular injury in deoxycorticosterone acetate‐salt hypertensive mice

Lijuan

Ruan

et al. 2016

FEBS Letters

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Edited by Laszlo NagyBeta3 adrenergic receptor (ADRB3) mediates vessel relaxation in the endothelium while it modulates lipolysis in the adipose tissue. However, the function and regulation mechanism of ADRB3 in the perivascular adipose tissue (PVAT), especially in hypertension, is still unclear. We show that ADRB3 protein is upregulated in the PVAT of deoxycorticosterone acetatesalt (DOCA-salt) hypertensive mice, with the characteristics of PVAT browning and increased uncoupling protein 1 (UCP1) expression. Inhibition of ADRB3 with selective antagonist SR59230A caused serious vascular injury in vivo, even though UCP1 expression was downregulated. ADRB3 protein was regulated by let-7b, which was decreased in the PVAT of the DOCA-salt group. These data reveal that ADRB3 in PVAT contributes to vascular function in the progression of hypertension.

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“…All essentially lead to enhanced activity of endothelial nitric oxide synthase (eNOS) and thereby an increased NO release. In addition, nebivolol was shown to induce lipolysis and promote thermogenic and mitochondrial genes through β 3 ‐AR So far, the β 3 ‐ARs are poorly investigated, but first studies indicated that they can activate different signalling pathways involved in heart protection. Thus, targeting of β 3 ‐ARs could represent a novel potential strategy to improve cardiac function and metabolism …”

Section: Methodsmentioning

confidence: 99%

Nebivolol in the treatment of arterial hypertension

Olawi

Krüger

Grimm

et al. 2019

Basic Clin Pharma Tox

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This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third‐generation beta‐adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta‐adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β1/β2‐selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first‐ and second‐generation BAAs and cannot be translated directly into third‐generation drugs. The third‐generation BAA nebivolol has the highest β1‐selectivity seen so far, together with additional vasodilating and anti‐oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure‐lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long‐term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future.

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Nebivolol induces, via β3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes

Cited by 32 publications

References 45 publications

NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue

NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue

Beta3 adrenergic receptor is involved in vascular injury in deoxycorticosterone acetate‐salt hypertensive mice

Nebivolol in the treatment of arterial hypertension

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