Abstract:
Excessive consumption of sucrose, in the form of sugar-sweetenedbeverages, hasbeen implicated in the pathogenesis of metabolic dysfunction‐associated fatty liver disease (MAFLD)and other related metabolic syndromes. The c-JunN-terminalkinase (JNK) pathway plays a crucialrole in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathwaycould potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlyingthese interventions remain incompletely understood given their multifaceted effects across multipletissues. In this study, we challenged rats with sucrose-sweetenedwater and investigated the potentialeffects of JNK inhibition by employing network analysis based on the transcriptome profilingobtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletalmuscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5Aeffectively reduces thecirculating triglyceride accumulation and inflammation in rats subjected to sucrose consumption.Coexpression analysis and genome-scalemetabolic modeling reveal that sucrose overconsumptionprimarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in theliver 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 underwentsubstantial 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.
