Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Blondin, Denis P.; Nielsen, Søren; Kuipers, Eline N.; Severinsen, Mai Charlotte Krogh; Jensen, Verena Hirschberg; Miard, Stéphanie; Jespersen, Naja Zenius; Kooijman, Sander; Boon, Mariëtte R.; Fortin, Mélanie; Phoenix, Serge; Frisch, Frédérique; Guérin, Brigitte; Turcotte, Éric; Haman, François; Richard, Denis; Picard, Frédéric; Rensen, Patrick C.N.; Schéele, Camilla; Carpentier, André C.

doi:10.1016/j.cmet.2020.07.005

Cited by 242 publications

(264 citation statements)

References 53 publications

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“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is human brown adipocytes (43). UCP1 mRNA expression in human adipocytes was also increased by PHDi-treatment (Figure 3d), suggesting that PHDi could induce a beiging-gene signature in human WAT.…”

Section: Pan-phd Inhibition Inducesmentioning

confidence: 84%

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Gómez

Cervera

Wang

et al. 2021

Preprint

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Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.

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Section: Pan-phd Inhibition Inducesmentioning

confidence: 84%

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Gómez

Cervera

Wang

et al. 2021

Preprint

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“…Therefore, we cannot exclude that β 3 ‐agonism in BAT cells 54,55 may stimulate tissue thermogenesis without necessarily affecting perfusion. Stimulation of blood flow and BAT in humans may also involve different receptors than for rats 56,57 …”

Section: Discussionmentioning

confidence: 99%

Contribution of perfusion to the ¹¹C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and ⁶⁸Ga‐DOTA PET in a rat model

Richard

Noll

Archambault

et al. 2020

Magnetic Resonance in Med

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Purpose: Determine if dynamic contrast enhanced (DCE)-MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N′, N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. Methods: Rats were split into three groups. In group 1 (N = 6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10 °C for 48 h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68 Ga-DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE-MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. Results: DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. Conclusion: Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

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“…Although there are many similarities between rodent and human BAT depots, notable differences also exist. Whereas the activation of murine BAT is mediated by b3-AR, a recent study revealed that b2-AR is the relevant adrenoceptor which activates human BAT (4). This underscores the need for caution when translating new advances generated by preclinical studies to humans.…”

Section: Perspectivesmentioning

confidence: 99%

Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity

et al. 2020

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Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Cited by 242 publications

References 53 publications

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Contribution of perfusion to the ¹¹C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and ⁶⁸Ga‐DOTA PET in a rat model

Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity

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Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Cited by 242 publications

References 53 publications

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Contribution of perfusion to the 11C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and 68Ga‐DOTA PET in a rat model

Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity

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Contribution of perfusion to the ¹¹C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and ⁶⁸Ga‐DOTA PET in a rat model