Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue

Stephenson, Erin J.; Stayton, Amanda S; Sethuraman, Aarti; Rao, Prahlad K.; Meyer, A.; Gomes, Charles; Mulcahy, Molly C.; McAllan, Liam; Puchowicz, Michelle A.; Pierre, Joseph F.; Bridges, Dave; Han, Joan C.

doi:10.1038/s41467-022-33840-6

Cited by 6 publications

(9 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Principal component analysis (PCA) revealed that liquid sucrose ingestion resulted in the largest transcriptional changes in the liver and vWAT ( Fig. 3a ), which is consistent with previous results (Stephenson et al, 2022). Of note, we observed that JNK-IN-5A treatment, especially JNK_D1, corrected to a large extent of the gene expression profile in the liver and vWAT of treated-rats towards the profile of healthy controls on a principal components space ( Fig.…”

Section: Resultssupporting

confidence: 91%

Section: Jnk Inhibition Rewires Metabolic Perturbation In the Liver A...supporting

confidence: 90%

“…S5, Data S6 ). Taken together, these results suggest that JNK-IN-5A treatment reshapes sucrose-induced transcriptional changes in both the liver and vWAT, reinforcing their metabolic synergy in FA uptake and metabolism (Stephenson et al, 2022).…”

Section: Resultsmentioning

confidence: 73%

“…For instance, a previous study reported that rats subjected to a 12-week high-sucrose diet (25% w/v sucrose), developed a metabolic syndrome phenotype characterized by glucose intolerance, HS, and insulin resistance (IR) (Sousa et al, 2018). Recent research further reveals that the consumption of sucrose at a concentration of 10% w/v can disrupt energy balance and induce HS within 10-20 weeks (Jang et al, 2020; Stephenson et al, 2022). In this context, c-Jun-N-terminal Kinase (JNK), a mitogen-activated protein kinase family member, emerges as a critical player due to its known function in response to intra- and extracellular stress, including hypercaloric diet consumption (Nikolic et al, 2020; Sabio et al, 2009; Softic et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Yang,

Zhang,

Kim

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Jnk Inhibition Rewires Metabolic Perturbation In the Liver A...supporting

confidence: 90%

Section: Resultsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Yang,

Zhang,

Kim

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…As others have observed ( 56 ), there were sex differences in the response to diet and colon cancer. Typically, male mice gain weight earlier compared with female mice while on a HFD.…”

Section: Discussionsupporting

confidence: 73%

High-fat diet plus HNF1A variant promotes polyps by activating β-catenin in early-onset colorectal cancer

Song¹,

Sontz²,

Vance³

et al. 2023

JCI Insight

View full text Add to dashboard Cite

The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1A A98V , rs1800574). The HNF1A A98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/β-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1A A98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1A A98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1A A98V variant plus a HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.

show abstract

Mulberry and Hippophae‐based solid beverage attenuate hyperlipidemia and hepatic steatosis via adipose tissue–liver axis

Zhu,

Luo,

Sun

et al. 2024

Food Science & Nutrition

View full text Add to dashboard Cite

Dyslipidemia and hepatic steatosis are the characteristics of the initial stage of nonalcohol fatty liver disease (NAFLD), which can be reversed by lifestyle intervention, including dietary supplementation. However, such commercial dietary supplements with solid scientific evidence and in particular clear mechanistic elucidation are scarce. Here, the health benefits of MHP, a commercial mulberry and Hippophae‐based solid beverage, were evaluated in NAFLD rat model and the underlying molecular mechanisms were investigated. Histopathologic examination of liver and white adipose tissue found that MHP supplementation reduced hepatic lipid accumulation and adipocyte hypertrophy. Serum biochemical results confirmed that MHP effectively ameliorated dyslipidemia and decreased circulation‐free fatty acid level. RNA‐Seq‐based transcriptomic analysis showed that MHP‐regulated genes are involved in the inhibition of lipolysis of adipose tissue and thus may contribute to the reduction of hepatic ectopic lipid deposition. Furthermore, MHP upregulated ACSL1–CPT1a–CPT2 pathway, a canonical pathway that regulated mitochondrial fatty acid metabolism, and promoted liver and adipose tissue fatty acid β‐oxidation. These results suggest that adipose tissue–liver crosstalk may play a key role in maintaining glucose and lipid metabolic hemostasis. In addition, MHP can also ameliorate chronic inflammation through regulating the secretion of adipokines. Our study demonstrates that MHP is able to improve dyslipidemia and hepatic steatosis through crosstalk between adipose tissue and liver and also presents transcriptomic evidence to support the underlying mechanisms of action, providing solid evidence for its health claims.

show abstract

Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue

Cited by 6 publications

References 89 publications

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

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

High-fat diet plus HNF1A variant promotes polyps by activating β-catenin in early-onset colorectal cancer

Mulberry and Hippophae‐based solid beverage attenuate hyperlipidemia and hepatic steatosis via adipose tissue–liver axis

Contact Info

Product

Resources

About