Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Sarah C. Huen ◽  
Andrew Wang ◽  
Kyle Feola ◽  
Reina Desrouleaux ◽  
Harding H. Luan ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Cold Adaptation ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Bacterial Sepsis ◽  
Acute Infections ◽  
Evolutionarily Conserved ◽  
Sickness Behaviors ◽  
Deficient Mice ◽  
Glucose Supplementation

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.

scholarly journals Hepatic FGF21 mediates tissue tolerance during bacterial inflammation by preserving cardiac function

2020 ◽  
Author(s):  
Sarah C. Huen ◽  
Andrew Wang ◽  
Kyle Feola ◽  
Reina Desrouleaux ◽  
Harding H. Luan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Function ◽  
Fibroblast Growth Factor ◽  
Heart Function ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Fibroblast Growth ◽  
Adaptive Responses ◽  
Bacterial Peritonitis ◽  
Sickness Behaviors

AbstractSickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor-21 (FGF21), and decreases survival. Consistent with this observation, FGF21 deficient mice are more susceptible to mortality from endotoxemia and poly-bacterial peritonitis, but not viral infection. Here we report that increased circulating FGF21 during bacterial inflammation is hepatic-derived, promotes cardiac function, and is required for survival. FGF21 signaling downstream of its obligate co-receptor beta-Klotho (KLB) is required. However, mice with central nervous system or adipose-specific deletion of Klb do not demonstrate any difference in response to bacterial inflammation, suggesting that multiple tissues and/or a novel FGF21 target tissue are required for the full protective effect of FGF21. These data suggest that hepatic FGF21 is a novel cardioprotective factor in bacterial sepsis.eTOC SummaryIn response to bacterial inflammation, hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone that mediates adaptive responses to metabolic stresses such as starvation, promotes survival by supporting heart function.

scholarly journals Metabolism as Disease Tolerance: Implications for Sepsis-Associated Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
Sarah C. Huen
Keyword(s):  
Acute Kidney Injury ◽  
Metabolic Pathways ◽  
Host Response ◽  
Kidney Injury ◽  
Protective Role ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Disease Tolerance ◽  
Evolutionarily Conserved

Sepsis is a significant cause for mortality among critically ill patients. Metabolic derangements that develop in sepsis are often considered to be pathologic, contributing to sepsis morbidity and mortality. However, alterations in metabolism during sepsis are multifaceted and are incompletely understood. Acute anorexia during infection is an evolutionarily conserved response, suggesting a potential protective role of anorexia in the host response to infection. In animal models of bacterial inflammation, fasting metabolic programs associated with acute anorexia such as those regulated by fibroblast growth factor 21 and ketogenesis are associated with improved survival. Other fasting metabolic pathways such as fatty acid oxidation and autophagy are also implicated in preventing acute kidney injury (AKI). Global metabolic changes during sepsis and current clinical interventions can potentially affect disease tolerance mechanisms and modify the risk of AKI.

scholarly journals Metabolic Control of m6A RNA Modification

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 80
Author(s):  
Joohwan Kim ◽  
Gina Lee
Keyword(s):  
Cell Fate ◽  
Metabolic Pathways ◽  
Epigenetic Modification ◽  
Genetic Material ◽  
Rna Modification ◽  
Cell Fate Decisions ◽  
Disease States ◽  
Evolutionarily Conserved ◽  
Regulate Cell Growth ◽  
Epigenetic Processes

Nutrients and metabolic pathways regulate cell growth and cell fate decisions via epigenetic modification of DNA and histones. Another key genetic material, RNA, also contains diverse chemical modifications. Among these, N6-methyladenosine (m6A) is the most prevalent and evolutionarily conserved RNA modification. It functions in various aspects of developmental and disease states, by controlling RNA metabolism, such as stability and translation. Similar to other epigenetic processes, m6A modification is regulated by specific enzymes, including writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins). As this is a reversible enzymatic process, metabolites can directly influence the flux of this reaction by serving as substrates and/or allosteric regulators. In this review, we will discuss recent understanding of the regulation of m6A RNA modification by metabolites, nutrients, and cellular metabolic pathways.

scholarly journals Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions duringPlasmodium falciparumintraerythrocytic development

2013 ◽  
Vol 89 (4) ◽  
pp. 660-675 ◽  
Author(s):  
Jun Miao ◽  
Matthew Lawrence ◽  
Victoria Jeffers ◽  
Fangqing Zhao ◽  
Daniel Parker ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Lysine Acetylation ◽  
Evolutionarily Conserved

scholarly journals Ketogenesis Impact on Liver Metabolism Revealed by Proteomics of Lysine β-hydroxybutyrylation

2021 ◽  
Author(s):  
Kevin B. Koronowski ◽  
Carolina M. Greco ◽  
He Huang ◽  
Jin-Kwang Kim ◽  
Jennifer L. Fribourgh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Ketone Bodies ◽  
Hepatic Metabolism ◽  
Mass Spectrometry Analysis ◽  
Metabolic Enzyme ◽  
Spectrometry Analysis ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Rate Limiting

SUMMARYKetone bodies are evolutionarily conserved metabolites that function as energy substrates, signaling molecules and epigenetic regulators. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, which associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification and 1-carbon metabolic pathways. Kbhb of S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, results in inhibition of enzymatic activity. Our results illuminate the role of Kbhb on hepatic metabolism under ketogenic conditions and demonstrate the functional consequence of this modification on a central metabolic enzyme.

scholarly journals The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Redin A. Spann ◽  
Christopher D. Morrison ◽  
Laura J. den Hartigh
Keyword(s):  
Expression Patterns ◽  
Nutritional Stress ◽  
Receptor Expression ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Alcoholic Fatty Liver ◽  
Metabolic Functions ◽  
Brown Adipose ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.

scholarly journals Proinsulin misfolding is an early event in the progression to type 2 diabetes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anoop Arunagiri ◽  
Leena Haataja ◽  
Anita Pottekat ◽  
Fawnnie Pamenan ◽  
Soohyun Kim ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Leptin Receptor ◽  
Structural Basis ◽  
Early Event ◽  
Cell Dysfunction ◽  
Evolutionarily Conserved ◽  
Necessary And Sufficient ◽  
Type Two Diabetes ◽  
Deficient Mice

Biosynthesis of insulin – critical to metabolic homeostasis – begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.

scholarly journals PAS Kinase: A Nutrient and Energy Sensor “Master Key” in the Response to Fasting/Feeding Conditions

2020 ◽  
Vol 11 ◽  
Author(s):  
Verónica Hurtado-Carneiro ◽  
Ana Pérez-García ◽  
Elvira Alvarez ◽  
Carmen Sanz
Keyword(s):  
Transcription Factors ◽  
Metabolic Pathways ◽  
High Fat Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Metabolic Alterations ◽  
Multiple Organs ◽  
Pas Kinase ◽  
Energy Sensor ◽  
Deficient Mice

The protein kinase with PAS domains (PASK) is a nutrient and energy sensor located in the cells of multiple organs. Many of the recent findings for understanding PASK functions in mammals have been reported in studies involving PASK-deficient mice. This minireview summarizes the PASK role in the control of fasting and feeding responses, focusing especially on the hypothalamus and liver. In 2013, PASK was identified in the hypothalamic areas involved in feeding behavior, and its expression was regulated under fasting/refeeding conditions. Furthermore, it plays a role in coordinating the activation/inactivation of the hypothalamic energy sensors AMPK and mTOR/S6K1 pathways in response to fasting. On the other hand, PASK deficiency prevents the development of obesity and non-alcoholic fatty liver in mice fed with a high-fat diet. This protection is explained by the re-establishment of several high-fat diet metabolic alterations produced in the expression of hepatic transcription factors and key enzymes that control the main metabolic pathways involved in maintaining metabolic homeostasis in fasting/feeding responses. This minireview covers the effects of PASK inactivation in the expression of certain transcription factors and target enzymes in several metabolic pathways under situations such as fasting and feeding with either a standard or a high-fat diet.

Fibroblast growth factor-21 improves insulin action in non-lactating ewes

2022 ◽  
Author(s):  
Cassandra L Lamb ◽  
Sarah L. Giesy ◽  
Molly M McGuckin ◽  
James W. Perfield ◽  
Anthony Butterfield ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Insulin Action ◽  
Physiological State ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Fibroblast Growth ◽  
Entire Treatment Period ◽  
Set Point ◽  
Improve Insulin Action

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFa) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in non-lactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 ERK1/2 following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21 resistant state.

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