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Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition



Modern science has given much attention to the treatment of obesity by activating brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Recent studies have identified theobromine, a derivative of cocoa, as a potent natural component actively browning white fat cells. Here, we aimed to deduce the anti-obesity effect of theobromine involving phosphodiesterase (PDE) dependent-regulatory pathway in obese animal models.


For examining activity of theobromine, C57BL/6 mice were fed with high fat diet and treated with theobromine to determine the expression levels of protein markers by immunoblot analysis and gene targets by quantitative real-time PCR. Other methods used include histopathological studies, immunofluorescence and molecular docking approaches.


Theobromine alleviated diet-induced obesity in mice by browning of iWAT and activating BAT. Further, theobromine actively interacted with PDE4D and inhibited its activity in adipose tissues and cells potentiating energy expenditure. Moreover, the regulatory action of theobromine via inhibition of PDE4D was mediated by β3-AR signaling pathway.


Altogether, the current results signifies critical role of theobromine in reducing obesity by regulation of lipid metabolism through inhibition of PDE4, indicating its potential as a major therapeutic medicinal compound.

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Acyl-coenzyme A oxidase 1


Adrenergic receptor


Adipose triglyceride lipase


Brown adipose tissue

Cd137 :

Gene encoding tumor necrosis factor receptor superfamily member 9

Cidea :

Gene encoding cell death-inducing DFFA-like effector a

Cited1 :

Gene encoding Cbp/p300-interacting transactivator 1


Carnitine palmitoyltransferase 1

Eva1 :

Gene coding myelin protein zero like 2


Hormone-sensitive lipase

Lhx8 :

Gene encoding LIM/homeobox protein Lhx8


Phosphodiesterase isoform ¾

PGC-1α/Ppargc1α :

Peroxisome proliferator-activated receptor gamma co-activator 1-alpha/encoding gene


Protein kinase A

PRDM16/Prdm16 :

PR domain-containing 16/encoding gene



Tbx1 :

Gene encoding T-box protein 1

Tmem26 :

Gene encoding transmembrane protein 26

UCP1/Ucp1 :

Uncoupling protein 1/encoding gene

Zic1 :

Gene encoding zinc finger protein ZIC1


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This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT, No. 2019R1A2C2002163).

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Authors and Affiliations



MHJ, MJC, NHK, and HGP performed the experiments. SM performed data analyses, interpretation and molecular docking studies. SM and JWY wrote the manuscript and JWY is the guarantor for the integrity and accuracy of the data and is responsible for planning and designing this study.

Corresponding author

Correspondence to Jong Won Yun.

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None declared.

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Jang, M.H., Mukherjee, S., Choi, M.J. et al. Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition. Eur J Nutr 59, 3503–3516 (2020).

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  • Adipose tissue
  • Anti-obesity
  • Theobromine
  • Phosphodiesterase
  • Fat browning