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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 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE282954 | GEO | 2025/02/04

REPOSITORIES: GEO

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Project description:The underlying mechanism of how the atopic lipids in skeletal muscle affect muscle growth remains elusive. Here we chose miniature Bama swine as our model to mimick human obesity and co-associated metabolic disorders by long time diet induction and study how the atopic fat accumulation in skeletal muscle influence muscle function. After 23 months high-fat high-sucrose diet (HFHSD) fed, the model minipig model of obesity accompanied with metabolic disorders like human, and they had increased body weight and extensive lipids deposition in adipose tissues (AT) and non-AT, especially in skeletal muscle. Further more, the mass of skeletal reduced greatly and the small area (0-2000μm2) muscle reduced after diet induced. The average fiber area of Gastroc reduced 25.2%, but no significant changes appeared in the other skeletal muscles. Antioxidant capacity of skeletal muscle also reduced. Microarray profiles showed genes related to fat deposition promotion (Peroxisome proliferator activated receptor γ, CCAAT/enhancer-binding protein α and apolipoprotein E), muscle growth inhibition (myostatin and p21) up regulated, and some other muscle cell differentiation related genes (myoD) down regulated. Meanwhile, adipokines like adiponectin and 11b-hydroxysteroid dehydrogenase type 1 (11βHSD1) which partake in the crosstalk between AT and skeletal muscles rose up. We draw a clear potential crosstalk pathway that, increased 11βHSD1 secreted by excess AT will promote the expression of the major inhibitor MSTN by activating corticosterone to cortisol, leading to the growth inhibition of skeletal muscle. Overall, this research announces how obesity affects skeletal muscle growth in a crosstalk sight. Male and female Bama minipigs, aged 6 months at the start of the study, were divided into the following two groups for 23 months of treatment. Bama minipigon control (CD group, N=3) were fed standard pig chow. The experimental group (N=6) were fed high-fat high-sucrose diet (53% basal diet, 37% sucrose, 10% lard, HFHSD).

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

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