Role of cAMP and cGMP Signaling in Brown Fat

Reverte-Salisa, Laia; Sanyal, Abhishek; Pfeifer, Alexander

doi:10.1007/164_2018_117

Cited by 31 publications

(26 citation statements)

References 159 publications

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“…After 1 week of repeated D1-agonist administration—in spite of elevated cAMP in iBAT—neither Ucp1 nor iBAT temperature were increased. This is contrary to the well-known effect of an NE-induced cAMP increase 36 and suggests differences in the downstream signaling cascade that, in case of the D1-agonist, do not further promote thermogenesis. The lack of downstream signaling could be caused by the biased agonism of SKF38393, namely G-protein signaling in absence of β-arrestin recruitment 37 , which can prevent late signaling and therefore avert sustained thermogenesis 38 , 39 .…”

Section: Discussioncontrasting

confidence: 94%

Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

Raffaelli

Resch

Oelkrug

et al. 2020

Sci Rep

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Brown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

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Section: Discussioncontrasting

confidence: 94%

Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

Raffaelli

Resch

Oelkrug

et al. 2020

Sci Rep

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“…Canonically, β3-AR signaling occurs via activation of Gsα-type G proteins, followed by the stimulation of adenylyl cyclase and an increased production of intracellular cAMP to regulate protein phosphorylation and gene transcription ( Cannon and Nedergaard, 2004 ; Collins, 2012 ; Li et al, 2016 ; Reverte-Salisa et al, 2019 ). To establish whether cAMP signaling is required for β3-AR-mediated activation of DNL gene expression in adipocytes, we used mice with the genetic deletion of Gsα selectively in adipocytes by crossing Gsα-Flox/Flox mice with adiponectin-Cre mice to generate Adipo-GsαKO (knockout) mice, as previously described ( Li et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration

et al. 2020

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SUMMARY Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo . We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.

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“…The cAMP-PKA pathway plays an outstanding role in adipocytes. Apart from lipolysis-the release of free fatty acids from adipocytes-cAMP signaling controls the metabolic phenotype and mitochondrial content of these cells 21,64 . Upon activation of cAMP signaling (e.g., via noradrenergic stimulation), white adipocytes change their phenotype from a fat storing to an energy expending cell, in a process known as "browning", and become so-called beige fat cells 22,23 .…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

et al. 2020

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Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a ‘fat-burning’ phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders.

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Role of cAMP and cGMP Signaling in Brown Fat

Cited by 31 publications

References 159 publications

Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration

Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

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