The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)–activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)–generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging. Editor’s summary Under conditions of food scarcity, metabolic flexibility was historically important for humans to optimize storage and access to energy when food was not readily available. By contrast, the constant access to high-calorie foods in modern societies has become a liability, contributing to the rise in obesity and metabolic diseases. Reactive oxygen species are thought to contribute to the metabolic dysregulation associated with obesity and aging, but the underlying process was not well understood. Snieckute et al. have now identified a mechanism linking reactive oxygen species, a protein called ZAKα, and resulting changes in ribosome function, which then contribute to the observed metabolic changes across multiple model animal species. —Yevgeniya Nusinovich Reactive oxygen species cause activation of ZAKα and changes in ribosomal dynamics, resulting in metabolic dysregulation. INTRODUCTION When ribosomes stall and/or collide during mRNA translation, ribosomal surveillance mechanisms are activated. These pathways signal the presence of ribotoxic stress and coordinate the resolution of nonproductive ribosomes. The ribosome-binding and stress-sensing MAP3 kinase ZAKα is at the nexus of the ribotoxic stress response (RSR) that culminates in the activation of and signaling through the stress-associated MAP kinases p38 and JNK. The RSR pathway is nonessential, and little is known about the in vivo conditions in which translational problems occur and the contexts in which the RSR is physiologically important. RATIONALE Reactive oxygen species (ROS) activate p38 and JNK and impair ribosomal translation. We rationalized that these responses may be coupled, and that ROS, which is associated with a range of physiological and pathological biological transitions, is a source of RSR activation in vivo. ZAK knockout (KO) mice display a mild metabolic phenotype with leanness and decreased adiposity, suggesting that the RSR is involved in metabolic regulation. Further, p38 and JNK are involved in metabolic transitions such as the emergence of insulin resistance and liver steatosis in obesity. In the context of obesity and metabolic regulation, activation of these kinases is driven by elusive metabolic stress signals that could be mediated by any of the 21 known p38- and JNK-directed MAP3 kinases. We thus sought to investigate the potential links among ROS, RSR signaling, and metabolic regulation using cellular, zebrafish, and mouse models. RESULTS We confirmed that ROS activates the RSR in cellular models, associated with both stalling and collision of ribosomes. In vitro translation reactions highlighted that these effects are primarily mediated by effects on soluble translation factors, including transfer RNAs. When exposed to a pathological burst of ROS, developing zebrafish larvae deficient for the zakα gene were strongly protected against early lethality, likely due to prevention of RSR-induced programmed cell death. ZAK KO mice fed a high-fat high-sugar (HFHS) diet, which is associated with rapid weight gain and ROS-driven pathology in rodents, were protected against early manifestations of metabolic maladaptation, including blood glucose intolerance and liver steatosis. These phenotypes were accompanied by deregulated RSR signaling in ZAK KO mouse livers. In HFHS-fed mice, highly translated liver mRNAs displayed increased stalling and queuing of ribosomes, indicating the presence of known ZAKα-activating structures. Finally, aging in male mice is also associated with increased ROS production and metabolic deterioration manifested as impaired blood glucose intolerance, stochastic liver steatosis, and whitening of brown adipose tissue. ZAK KO mice were protected against all of these hallmarks of metabolic aging. CONCLUSION Our study uncovers ROS as a physiologically relevant source of translational aberrations and RSR activation. Furthermore, impaired ribosomes constitute at least a portion of the metabolic stress signals that drive unwanted metabolic maladaptation in obesity and aging. The strong protection against these reactions offered by Zak gene deletion in mice warrants investigation of the ZAKα kinase as a potential drug target for metabolic conditions such as nonalcoholic steatohepatitis, hypertension, and dyslipidemia. Additional work will be needed to unravel the tissue-specific contributions of RSR signaling to the above phenotypes and to identify other physiologically relevant sources of ribotoxic stress. The ribotoxic stress response drives metabolic maladaptation in obesity and aging. ROS are a physiologically relevant source of translational impairment and activation of the stress kinases ZAKα, p38, and JNK. In obese and aging mice, this RSR drives metabolic maladaptation manifested by blood glucose intolerance, liver steatosis, and whitening of brown adipose tissue (BAT). [Figure created with BioRender.]

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

As an endocrine hormone, fibroblast growth factor 21 (FGF21) plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle. Intervention with FGF21 in rodents or non-human primates has shown significant pharmacological effects on a range of metabolic dysfunctions, including weight loss and improvement of hyperglycemia, hyperlipidemia, insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the poor pharmacokinetic and biophysical characteristics of native FGF21, long-acting FGF21 analogs and FGF21 receptor agonists have been developed for the treatment of metabolic dysfunction. Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. Here we review the actions of FGF21 and summarize the associated clinical trials in obesity, type 2 diabetes mellitus (T2DM), and NAFLD, to help understand and promote the development of efficient treatment for metabolic diseases via targeting FGF21.

https://www.frontiersin.org/articles/10.3389/fphar.2022.1089214/pdf

The potential function and clinical application of FGF21 in metabolic diseases

Significance The cJUN NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and plays a key role during the development of metabolic syndrome. JNK2 acts in the liver by suppressing the expression of the hepatokine fibroblast growth factor 21 (FGF21). We show that the alternatively spliced JNK2α isoform mediates the effects of metabolic stress. Quantitative phosphoproteomics analysis and functional testing using genetic complementation analysis demonstrated that JNK2α-mediated phosphorylation of retinoid X receptor α (RXRα) inhibits FGF21 expression. These observations define a JNK/RXRα/FGF21 signaling axis that contributes to obesity-associated metabolic syndrome.

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome

The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear "hormone" receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they are either post-translationally modified by phosphorylation or directly interact with components of the MAPK pathways, events that govern their transcriptional activity towards target genes involved in cell differentiation, proliferation, metabolism and host immunity. This molecular crosstalk takes place not only in normal epithelial or tumor cells, but also in a plethora of immune cells from the adaptive and innate immune system in the tumor-stroma tissue microenvironment. Thus, the drugability of both the MAPK and the NHRSF pathways suggests potential for intervention therapies, especially for cancer immunotherapy. This review summarizes the existing literature covering the expression and function of NHRSF subclasses in human tumors, both solid and leukemias, and their effects in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy.

Endothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB antagonism has been demonstrated to favorably influence insulin resistance. Our study explored the role of ETB in metabolic syndrome. Wild type (etb+/+) and rescued ETB-deficient (etb-/-) mice were fed a high-fat diet, and energy, glucose, and insulin metabolism were analyzed, and hormones and lipids measured in serum and tissues. Cell culture experiments were performed in HepG2 cells. Compared to etb+/+ mice, etb-/- mice exhibited better glucose tolerance and insulin sensitivity, less WAT accumulation, lower serum triglycerides, and higher energy expenditure. Protection from metabolic syndrome was paralleled by higher hepatic production of fibroblast growth factor 21 (FGF21) and higher serum levels of free thyroxine (fT4), stimulators of energy expenditure. In conclusion, ETB deficiency confers protection from metabolic syndrome by counteracting glucose intolerance, dyslipidemia, and WAT accumulation due to enhanced energy expenditure, effects at least in part dependent on enhanced production of thyroid hormone/FGF21. ETB antagonism may therefore be a novel therapeutic approach in metabolic syndrome. 

Endothelin receptor B-deficient mice are protected from high-fat diet-induced metabolic syndrome.

Popular Tasks used by Researchers

How can I help with your research?

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

We encountered an error while loading the panel. Please try refreshing the page.

Something went wrong

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

Anyone with the link can view this chat. You can switch it back to private anytime.

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Armanda Roy

Author Tools

Chat about Author

Papers

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome