Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats
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eLife assessment
The authors present a valuable study exploring the interaction between JNK signaling and high sucrose feeding. The strength of evidence supporting these observations is solid, including multi-tissue transcriptomic and metabolic analyses, followed by network modeling approaches to define the organs and pathways involved. Reviewers provided several suggestions to improve the manuscript including clarifications of model and analyses, as well as explanations for within-group variations and confirming RNA-seq results at the level of metabolite processes highlighted.
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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 modelling 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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eLife assessment
The authors present a valuable study exploring the interaction between JNK signaling and high sucrose feeding. The strength of evidence supporting these observations is solid, including multi-tissue transcriptomic and metabolic analyses, followed by network modeling approaches to define the organs and pathways involved. Reviewers provided several suggestions to improve the manuscript including clarifications of model and analyses, as well as explanations for within-group variations and confirming RNA-seq results at the level of metabolite processes highlighted.
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Reviewer #1 (Public review):
Summary:
In this manuscript, authors have investigated the effects of JNK inhibition on sucrose-induced metabolic dysfunction in rats. They used multi-tissue network analysis to study the effects of the JNK inhibitor JNK-IN-5A on metabolic dysfunction associated with excessive sucrose consumption. Their results show that JNK inhibition reduces triglyceride accumulation and inflammation in the liver and adipose tissues while promoting metabolic adaptations in skeletal muscle. The study provides new insights into how JNK inhibition can potentially treat metabolic dysfunction-associated fatty liver disease (MAFLD) by modulating inter-tissue communication and metabolic processes.
Strengths:
The study has several notable strengths:
Comprehensive Multi-Tissue Analysis: The research provides a thorough multi-tissue …
Reviewer #1 (Public review):
Summary:
In this manuscript, authors have investigated the effects of JNK inhibition on sucrose-induced metabolic dysfunction in rats. They used multi-tissue network analysis to study the effects of the JNK inhibitor JNK-IN-5A on metabolic dysfunction associated with excessive sucrose consumption. Their results show that JNK inhibition reduces triglyceride accumulation and inflammation in the liver and adipose tissues while promoting metabolic adaptations in skeletal muscle. The study provides new insights into how JNK inhibition can potentially treat metabolic dysfunction-associated fatty liver disease (MAFLD) by modulating inter-tissue communication and metabolic processes.
Strengths:
The study has several notable strengths:
Comprehensive Multi-Tissue Analysis: The research provides a thorough multi-tissue evaluation, examining the effects of JNK inhibition across key metabolically active tissues, including the liver, visceral white adipose tissue, skeletal muscle, and brain. This comprehensive approach offers valuable insights into the systemic effects of JNK inhibition and its potential in treating MAFLD.
Robust Use of Systems Biology: The study employs advanced systems biology techniques, including transcriptomic analysis and genome-scale metabolic modeling, to uncover the molecular mechanisms underlying JNK inhibition. This integrative approach strengthens the evidence supporting the role of JNK inhibitors in modulating metabolic pathways linked to MAFLD.
Potential Therapeutic Insights: By demonstrating the effects of JNK inhibition on both hepatic and extrahepatic tissues, the study offers promising therapeutic insights into how JNK inhibitors could be used to mitigate metabolic dysfunction associated with excessive sucrose consumption, a key contributor to MAFLD.
Behavioral and Metabolic Correlation: The inclusion of behavioral tests alongside metabolic assessments provides a more holistic view of the treatment's effects, allowing for a better understanding of the broader physiological implications of JNK inhibition.
Weaknesses:
While the study provides a comprehensive evaluation of JNK inhibitors in mitigating MAFLD conditions, addressing the following points will enhance the manuscript's quality:
The authors should explicitly mention and provide a detailed list of metabolites affected by sucrose and JNK inhibition treatment that have been previously associated with MAFLD conditions. This will better contextualize the findings within the broader field of metabolic disease research.
The limitations of the study should be clearly stated, particularly the lack of evidence on the effects of chronic JNK inhibitor treatment and potential off-target effects. Addressing these concerns will offer a more balanced perspective on the therapeutic potential of JNK inhibition.
The potential risks of using JNK inhibitors in non-MAFLD conditions should be highlighted, with a clear distinction made between the preventive and curative effects of these therapies in mitigating MAFLD conditions. This will ensure the therapeutic implications are properly framed.
The statistical analysis section could be strengthened by providing a justification for the chosen statistical tests and discussing the study's power. Additionally, a more detailed breakdown of the behavioral test results and their implications would be beneficial for the overall conclusions of the study.
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Reviewer #2 (Public review):
Summary:
Excessive sucrose is a possible initial factor for the development of metabolic dysfunction-associated fatty liver disease (MAFLD). To investigate the possibility that intervention with JNK inhibitor could lead to the treatment of metabolic dysfunction caused by excessive sucrose intake, the authors performed multi-organ transcriptomics analysis (liver, visceral fat (vWAT), skeletal muscle, and brain) in a rat model of MAFLD induced by sucrose overtake (+ a selective JNK2 and JNK3 inhibitor (JNK-IN-5A) treatment). Their data suggested that changes in gene expression in the vWAT as well as in the liver contribute to the pathogenesis of their MAFLD model and revealed that the JNK inhibitor has a cross-organ therapeutic effect on it.
Strengths:
(1) It has been previously reported that inhibition of JNK …
Reviewer #2 (Public review):
Summary:
Excessive sucrose is a possible initial factor for the development of metabolic dysfunction-associated fatty liver disease (MAFLD). To investigate the possibility that intervention with JNK inhibitor could lead to the treatment of metabolic dysfunction caused by excessive sucrose intake, the authors performed multi-organ transcriptomics analysis (liver, visceral fat (vWAT), skeletal muscle, and brain) in a rat model of MAFLD induced by sucrose overtake (+ a selective JNK2 and JNK3 inhibitor (JNK-IN-5A) treatment). Their data suggested that changes in gene expression in the vWAT as well as in the liver contribute to the pathogenesis of their MAFLD model and revealed that the JNK inhibitor has a cross-organ therapeutic effect on it.
Strengths:
(1) It has been previously reported that inhibition of JNK signalling can contribute to the prevention of hepatic steatosis (HS) and related metabolic syndrome in other models, but the role of JNK signalling in the metabolic disruption caused by excessive intake of sucrose, a possible initial factor for the development of MAFLD, has not been well understood, and the authors have addressed this point.
(2) This study is also important because pharmacological therapy for MAFLD has not yet been established.
(3) By obtaining transcriptomic data in multiple organs and comprehensively analyzing the data using gene co-expression network (GCN) analysis and genome-scale metabolic models (GEM), the authors showed the multi-organ interaction in not only in the pathology of MAFLD caused by excessive sucrose intake but also in the treatment effects by JNK-IN-5A.
(4) Since JNK signalling has diverse physiological functions in many organs, the authors effectively assessed possible side effects with a view to the clinical application of JNK-IN-5A.
Weaknesses:
(1) The metabolic process activities were evaluated using RNA-seq results in Figure 7, but direct data such as metabolite measurements are lacking.
(2) There is a lack of consistency in the data between JNK-IN-5A_D1 and _D2, and there is no sufficient data-based explanation for why the effects observed in D1 were inconsistent in the D2 samples.
(3) Although it is valuable that the authors were able to suggest the possibility of JNK inhibitor as a therapeutic strategy for MAFLD, the evaluation of the therapeutic effect was limited to the evaluation of plasma TG, LDH, and gene expression changes. As there was no evaluation of liver tissue images, it is unclear what changes were brought about in the liver by the excessive sucrose intake and the treatment with JNK-IN-5A.
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