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Ketoprofen alleviates diet-induced obesity and promotes white fat browning in mice via the activation of COX-2 through mTORC1-p38 signaling pathway

  • Molecular and cellular mechanisms of disease
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Abstract

The nonsteroidal anti-inflammatory drug (NSAID) ketoprofen is commonly used as a pain reliever, but its role in mediating the energy metabolism in lipids is unclear. This paper reports for the first time the critical role of ketoprofen in ameliorating white fat browning and alleviating diet-induced obesity. The effects of ketoprofen were evaluated using C57BL/6 mice fed a high fat diet and the expression levels of the target genes and proteins in the lipid metabolisms were determined by quantitative real-time PCR, immunoblot analysis, histopathology study, immunofluorescence, and molecular docking techniques. Ketoprofen induced browning in cultured 3T3-L1 white adipocytes and inguinal white adipose tissue by increasing the expression of core fat browning marker proteins as well as beige-specific genes through COX-2 activation. Ketoprofen also led to the robust activation of brown adipocytes and enhanced brown fat adipogenesis. In addition, ketoprofen elevated lipolysis, thereby increasing mitochondrial biogenesis resulting in higher fat oxidation. Furthermore, the molecular docking and mechanistic study demonstrated the recruitment of beige fat by ketoprofen via mTORC1-p38-mediated activation of the COX-2 pathway. Overall, these results indicate the unique role of ketoprofen in body weight reduction by enhancing thermogenesis, suggesting its therapeutic potential in the treatment of obesity.

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Abbreviations

ACO:

Acyl-coenzyme A oxidase 1

β3-AR:

Beta 3 adrenergic receptor

ATGL:

Adipose triglyceride lipase

BAT:

Brown adipose tissue

Cd137 :

Gene encoding TNF Receptor Superfamily Member 9 protein

Cidea :

Gene encoding cell death-inducing DFFA-like effector a

Cited1 :

Gene encoding Cbp/p300-interacting transactivator 1 C/EBP/Cebp, CCAAT/enhancer-binding protein/encoding gene

COX-1/2/Cox1/2 :

Cyclooxygenase-1/2

COX-4/Cox4 :

Cytochrome C complex IV/encoding gene

CPT1:

Carnitine palmitoyltransferase 1

CYT-C:

Cytochrome C complex

HSL:

Hormone-sensitive lipase

Lhx8 :

Gene encoding LIM/homeobox protein Lhx8

iWAT:

Inguinal white adipose tissue

mTORC1:

Mammalian target of rapamycin complex 1

Nrf1 :

Gene encoding nuclear respiratory factor 1

p38:

p38 mitogen-activated protein kinase

p53/p53 :

Tumor protein/encoding gene

p38:

p38 mitogen-activated protein kinase

PG:

Prostaglandin

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

Tbx1 :

Gene encoding T-box protein 1

Tfam :

Gene encoding mitochondrial transcription factor A

Tmem26 :

Gene encoding transmembrane protein 26

UCP1/Ucp1 :

Uncoupling protein 1/encoding gene

Zic1 :

Gene encoding zinc finger protein ZIC1.

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Funding

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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Author notes

  1. Nam Hyeon Kang and Sulagna Mukherjee contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea

    Nam Hyeon Kang, Sulagna Mukherjee, Myeong Hwan Jang, Huong Giang Pham, MinJi Choi & Jong Won Yun

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  1. Nam Hyeon Kang
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  2. Sulagna Mukherjee
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  4. Huong Giang Pham
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Contributions

NH, JMH, and CMJ performed the in vivo animal experiments. NH, SM, and PHG carried out the experimental work. 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.

Ethics statement

All animal experiments were approved by the Committee for Laboratory Animal Care and Use of Daegu University.

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Kang, N.H., Mukherjee, S., Jang, M.H. et al. Ketoprofen alleviates diet-induced obesity and promotes white fat browning in mice via the activation of COX-2 through mTORC1-p38 signaling pathway. Pflugers Arch - Eur J Physiol 472, 583–596 (2020). https://doi.org/10.1007/s00424-020-02380-7

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