Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats

Hong Yang; Cheng Zhang; Woonghee Kim; Mengnan Shi; Metin Kiliclioglu; Cemil Bayram; Ismail Bolar; Özlem Özdemir Tozlu; Cem Baba; Nursena Yuksel; Serkan Yildirim; Shazia Iqbal; Jihad Sebhaoui; Ahmet Hacımuftuoglu; Matthias Uhlen; Jan Boren; Hasan Turkez; Adil Mardinoglu

doi:10.7554/eLife.98427

Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats

Hong Yang, Cheng Zhang, Woonghee Kim, Mengnan Shi, Metin Kiliclioglu, Cemil Bayram, Ismail Bolar, Özlem Özdemir Tozlu, Cem Baba, Nursena Yuksel, Serkan Yildirim, Shazia Iqbal, Jihad Sebhaoui, Ahmet Hacımuftuoglu, Matthias Uhlen, Jan Boren, Hasan Turkez, Adil Mardinoglu

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Abstract

Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.

Original language	English
Journal	eLife
Volume	13
DOIs	https://doi.org/10.7554/eLife.98427
Publication status	Published - 11 Feb 2025

Keywords

Animals
Dietary Sucrose/adverse effects
Rats
Male
Muscle, Skeletal/metabolism
Gene Expression Profiling
Liver/metabolism
JNK Mitogen-Activated Protein Kinases/metabolism
Rats, Sprague-Dawley
Metabolic Diseases/metabolism

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10.7554/eLife.98427Licence: CC BY

Multi-tissue network analysis_YANG_Publishedonline11February2025_GOLD_VoR (CC BY)Final published version, 2.62 MBLicence: CC BY

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Yang, H., Zhang, C., Kim, W., Shi, M., Kiliclioglu, M., Bayram, C., Bolar, I., Tozlu, Ö. Ö., Baba, C., Yuksel, N., Yildirim, S., Iqbal, S., Sebhaoui, J., Hacımuftuoglu, A., Uhlen, M., Boren, J., Turkez, H., & Mardinoglu, A. (2025). Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats. eLife, 13. https://doi.org/10.7554/eLife.98427

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title = "Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats",

abstract = "Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.",

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author = "Hong Yang and Cheng Zhang and Woonghee Kim and Mengnan Shi and Metin Kiliclioglu and Cemil Bayram and Ismail Bolar and Tozlu, {{\"O}zlem {\"O}zdemir} and Cem Baba and Nursena Yuksel and Serkan Yildirim and Shazia Iqbal and Jihad Sebhaoui and Ahmet Hacımuftuoglu and Matthias Uhlen and Jan Boren and Hasan Turkez and Adil Mardinoglu",

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day = "11",

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Yang, H, Zhang, C, Kim, W, Shi, M, Kiliclioglu, M, Bayram, C, Bolar, I, Tozlu, ÖÖ, Baba, C, Yuksel, N, Yildirim, S, Iqbal, S, Sebhaoui, J, Hacımuftuoglu, A, Uhlen, M, Boren, J, Turkez, H & Mardinoglu, A 2025, 'Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats', eLife, vol. 13. https://doi.org/10.7554/eLife.98427

TY - JOUR

T1 - Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats

AU - Yang, Hong

AU - Zhang, Cheng

AU - Kim, Woonghee

AU - Shi, Mengnan

AU - Kiliclioglu, Metin

AU - Bayram, Cemil

AU - Bolar, Ismail

AU - Tozlu, Özlem Özdemir

AU - Baba, Cem

AU - Yuksel, Nursena

AU - Yildirim, Serkan

AU - Iqbal, Shazia

AU - Sebhaoui, Jihad

AU - Hacımuftuoglu, Ahmet

AU - Uhlen, Matthias

AU - Boren, Jan

AU - Turkez, Hasan

AU - Mardinoglu, Adil

PY - 2025/2/11

Y1 - 2025/2/11

N2 - Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.

AB - Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.

KW - Animals

KW - Dietary Sucrose/adverse effects

KW - Rats

KW - Male

KW - Muscle, Skeletal/metabolism

KW - Gene Expression Profiling

KW - Liver/metabolism

KW - JNK Mitogen-Activated Protein Kinases/metabolism

KW - Rats, Sprague-Dawley

KW - Metabolic Diseases/metabolism

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U2 - 10.7554/eLife.98427

DO - 10.7554/eLife.98427

M3 - Article

C2 - 39932177

AN - SCOPUS:85218435359

SN - 2050-084X

VL - 13

JO - eLife

JF - eLife

ER -

Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats

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Keywords

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