Vol.:(0123456789) 1 3 European Journal of Nutrition https://doi.org/10.1007/s00394-020-02184-6 ORIGINAL CONTRIBUTION Theobromine alleviates diet‑induced obesity in mice via phosphodiesterase‑4 inhibition Myeong Hwan Jang 1  · Sulagna Mukherjee 1  · Min Ji Choi 1  · Nam Hyeon Kang 1  · Huong Giang Pham 1  · Jong Won Yun 1 Received: 3 October 2019 / Accepted: 10 January 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Purpose 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 identifed theobromine, a derivative of cocoa, as a potent natural component actively browning white fat cells. Here, we aimed to deduce the anti-obesity efect of theobromine involv- ing phosphodiesterase (PDE) dependent-regulatory pathway in obese animal models. Methods 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, immunofuorescence and molecular docking approaches. Results Theobromine alleviated diet-induced obesity in mice by browning of iWAT and activating BAT. Further, theobro- mine 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. Conclusion Altogether, the current results signifes 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. Keywords Adipose tissue · Anti-obesity · Theobromine · Phosphodiesterase · Fat browning Abbreviations ACOX1 Acyl-coenzyme A oxidase 1 AR Adrenergic receptor ATGL Adipose triglyceride lipase BAT Brown adipose tissue Cd137 Gene encoding tumor necrosis factor receptor superfamily member 9 Cidea Gene encoding cell death-inducing DFFA-like efector a Cited1 Gene encoding Cbp/p300-interacting transactivator 1 CPT1 Carnitine palmitoyltransferase 1 Eva1 Gene coding myelin protein zero like 2 HSL Hormone-sensitive lipase Lhx8 Gene encoding LIM/homeobox pro- tein Lhx8 PDE-3/4 Phosphodiesterase isoform ¾ PGC-1α/Ppargc1α Peroxisome proliferator-activated receptor gamma co-activator 1-alpha/ encoding gene PKA Protein kinase A PRDM16/Prdm16 PR domain-containing 16/encoding gene TB Theobromine Tbx1 Gene encoding T-box protein 1 Tmem26 Gene encoding transmembrane pro- tein 26 UCP1/Ucp1 Uncoupling protein 1/encoding gene Zic1 Gene encoding zinc fnger protein ZIC1 Myeong Hwan Jang and Sulagna Mukherjee equally contributed to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00394-020-02184-6) contains supplementary material, which is available to authorized users. * Jong Won Yun jwyun@daegu.ac.kr 1 Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea