Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.

2021 ◽  
Author(s):  
Patricia Cristine Borck ◽  
Sarah Rickli ◽  
Jean Franciesco Vettorazzi ◽  
Thiago Martins Batista ◽  
Antonio Carlos Boschero ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glucose Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Metabolic Diseases ◽  
Light Exposure ◽  
Biological Rhythms ◽  
Fibroblast Growth Factor 21 ◽  
Low Protein ◽  
Nighttime Light ◽  
Fgf21 Expression

Disruption of biological rhythms due exposure to artificial light at night (ALAN) has been emerged as new risk factor for metabolic diseases. However, it remains largely unexplored the effects induced by exposure to ALAN on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance. Objective: Here we evaluate whether low-protein diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a low-protein (LP) diet and housed on 12h light/dark (L/D) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/dark cycle or exposed to ALAN for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN lead to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly the insulin resistance developed in mice exposed to ALAN was diet-dependent. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of Phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of Fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation on hepatic Fgf21 expression.

scholarly journals DPP-4 inhibitor induces FGF21 expression via sirtuin 1 signaling and improves myocardial energy metabolism

2020 ◽  
Vol 36 (1) ◽  
pp. 136-146
Author(s):  
Nozomi Furukawa ◽  
Norimichi Koitabashi ◽  
Hiroki Matsui ◽  
Hiroaki Sunaga ◽  
Yogi Umbarawan ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Sirtuin 1 ◽  
Fibroblast Growth Factor 21 ◽  
Mouse Heart ◽  
Acid Uptake ◽  
Dipeptidyl Peptidase 4 ◽  
Fgf21 Expression

AbstractDipeptidyl peptidase-4 (DPP-4) inhibitors are widely used incretin-based therapy for the treatment of type 2 diabetes. We investigated the cardioprotective effect of a DPP-4 inhibitor, vildagliptin (vilda), on myocardial metabolism and cardiac performance under pressure overload. Mice were treated with either vehicle or vilda, followed by transverse aortic constriction (TAC). After 3 weeks of TAC, cardiac hypertrophy and impairment of systolic function were attenuated in vilda-treated mice. Pressure–volume analysis showed that vilda treatment significantly improved left-ventricular contractile efficiency in TAC heart. Myocardial energy substrate analysis showed that vilda treatment significantly increased glucose uptake as well as fatty acid uptake. Fibroblast growth factor 21 (FGF21), a peptide involved in the regulation of energy metabolism, increased in TAC heart and was further increased by vilda treatment. FGF21 was strongly expressed in cardiac fibroblasts than in cardiomyocytes in mouse heart after TAC with vilda treatment. Vilda treatment markedly induced FGF21 expression in human cardiac fibroblasts through a sirtuin (Sirt) 1-mediated pathway, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism and exert vilda-mediated beneficial effects in stressed heart. Vilda induced a metabolic regulator, FGF21 expression in cardiac fibroblasts via Sirt1, and increased contractile efficiency in murine pressure-overloaded heart.

scholarly journals ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-shan Wan ◽  
Xiang-hong Lu ◽  
Ye-cheng Xiao ◽  
Yuan Lin ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

scholarly journals Leptin as a Potential Regulator of FGF21

2016 ◽  
Vol 38 (3) ◽  
pp. 1218-1225 ◽  
Author(s):  
Mohamed Asrih ◽  
Christelle Veyrat-Durebex ◽  
Anne-Laure Poher ◽  
Jacqueline Lyautey ◽  
Françoise Rohner-Jeanrenaud ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepg2 Cells ◽  
Wistar Rats ◽  
Metabolic Diseases ◽  
Fibroblast Growth Factor 21 ◽  
New Findings ◽  
Expression Site ◽  
Fgf21 Expression

Background/Aims: Fibroblast growth factor 21 (FGF21), a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. Methods: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. Results: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. Conclusion: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.

scholarly journals Effects of Lipid Overload on Heart in Metabolic Diseases

2021 ◽  
Vol 53 (12) ◽  
pp. 771-778
Author(s):  
An Yan ◽  
Guinan Xie ◽  
Xinya Ding ◽  
Yi Wang ◽  
Liping Guo
Keyword(s):  
Cardiovascular Disease ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Glucose Metabolism ◽  
Diabetic Cardiomyopathy ◽  
Metabolic Diseases ◽  
Metabolism Disorder ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
Energy Metabolism Disorder

AbstractMetabolic diseases are often associated with lipid and glucose metabolism abnormalities, which increase the risk of cardiovascular disease. Diabetic cardiomyopathy (DCM) is an important development of metabolic diseases and a major cause of death. Lipids are the main fuel for energy metabolism in the heart. The increase of circulating lipids affects the uptake and utilization of fatty acids and glucose in the heart, and also affects mitochondrial function. In this paper, the mechanism of lipid overload in metabolic diseases leading to cardiac energy metabolism disorder is discussed.

scholarly journals Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

2020 ◽  
Author(s):  
Minsoo Kang ◽  
Sun Kyoung Han ◽  
Suhyun Kim ◽  
Sungyeon Park ◽  
Yerin Jo ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Metabolic Disorder ◽  
Leucine Zipper ◽  
Metabolic Diseases ◽  
Adenosine Monophosphate ◽  
The Body ◽  
Hepatic Gluconeogenesis ◽  
Leucine Zipper Protein

Abstract Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

scholarly journals Lack of skeletal muscle IL-6 influences hepatic glucose metabolism in mice during prolonged exercise

2017 ◽  
Vol 312 (4) ◽  
pp. R626-R636 ◽  
Author(s):  
Lærke Bertholdt ◽  
Anders Gudiksen ◽  
Camilla L. Schwartz ◽  
Jakob G. Knudsen ◽  
Henriette Pilegaard
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Prolonged Exercise ◽  
Hepatic Glycogen ◽  
Glucose Content ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Single Bout ◽  
Substrate Choice

The liver is essential in maintaining and regulating glucose homeostasis during prolonged exercise. IL-6 has been shown to be secreted from skeletal muscle during exercise and has been suggested to signal to the liver. Therefore, the aim of this study was to investigate the role of skeletal muscle IL-6 on hepatic glucose regulation and substrate choice during prolonged exercise. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice (age, 12–14 wk) and littermate lox/lox (Control) mice were either rested (Rest) or completed a single bout of exercise for 10, 60, or 120 min, and the liver was quickly obtained. Hepatic IL-6 mRNA was higher at 60 min of exercise, and hepatic signal transducer and activator of transcription 3 was higher at 120 min of exercise than at rest in both genotypes. Hepatic glycogen was higher in IL-6 MKO mice than control mice at rest, but decreased similarly during exercise in the two genotypes, and hepatic glucose content was lower in IL-6 MKO than control mice at 120 min of exercise. Hepatic phosphoenolpyruvate carboxykinase mRNA and protein increased in both genotypes at 120 min of exercise, whereas hepatic glucose 6 phosphatase protein remained unchanged. Furthermore, IL-6 MKO mice had higher hepatic pyruvate dehydrogenase (PDH)Ser232 and PDHSer300 phosphorylation than control mice at rest. In conclusion, hepatic gluconeogenic capacity in mice is increased during prolonged exercise independent of muscle IL-6. Furthermore, Skeletal muscle IL-6 influences hepatic substrate regulation at rest and hepatic glucose metabolism during prolonged exercise, seemingly independent of IL-6 signaling in the liver.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

scholarly journals Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 136
Author(s):  
Miguel Rebollo-Hernanz ◽  
Yolanda Aguilera ◽  
Maria A. Martin-Cabrejas ◽  
Elvira Gonzalez de Gonzalez de Mejia
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Fatty Acid Synthase ◽  
Cell Model ◽  
Fibroblast Growth Factor 21 ◽  
Alcoholic Fatty Liver ◽  
Atp Production ◽  
Cocoa Shell

The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases

2021 ◽  
Vol 184 (5) ◽  
pp. R193-R205
Author(s):  
David P Sonne
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Gastrointestinal Tract ◽  
Glucose Metabolism ◽  
Metabolic Diseases ◽  
Farnesoid X Receptor ◽  
Optimal Size ◽  
Lipid Digestion ◽  
Alcoholic Fatty Liver

During the last decades, it has become clear that the gastrointestinal tract plays a pivotal role in the regulation of glucose homeostasis. More than 40 hormones originate from the gastrointestinal tract and several of these impact glucose metabolism and appetite regulation. An astonishing example of the gut’s integrative role in glucose metabolism originates from investigations into bile acid biology. From primary animal studies, it has become clear that bile acids should no longer be labelled as simple detergents necessary for lipid digestion and absorption but should also be recognised as metabolic regulators implicated in lipid, glucose and energy metabolism. The nuclear farnesoid X receptor (FXR) is a part of an exquisite bile acid-sensing system that among other things ensures the optimal size of the bile acid pool. In addition, intestinal and hepatic FXR also impact the regulation of several metabolic processes such as glucose and lipid metabolism. Accordingly, natural and synthetic FXR agonists and certain FXR-regulated factors (i.e. fibroblast growth factor 19 (FGF19)) are increasingly being evaluated as treatments for metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease (and its inflammatory version, non-alcoholic steatohepatitis). Interestingly, decreased FXR activation also benefits glucose metabolism. This can be obtained by reducing bile acid absorption using bile acid sequestering agents (approved for the treatment of type 2 diabetes) or inhibitors of intestinal bile acid transporters,that is the apical sodium-dependent bile acid transporter (ASBT). This article discusses recent clinical trials that provide insights about the role of FXR-FGF19-targetted therapy for the treatment of metabolic diseases.

scholarly journals High Sugar Intake and Development of Skeletal Muscle Insulin Resistance and Inflammation in Mice: A Protective Role for PPAR-δAgonism

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Elisa Benetti ◽  
Raffaella Mastrocola ◽  
Mara Rogazzo ◽  
Fausto Chiazza ◽  
Manuela Aragno ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathways ◽  
Gastrocnemius Muscle ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Intercellular Adhesion Molecule ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Intercellular Adhesion Molecule 1 ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome Proliferator Activated Receptor (PPAR)-δagonists may serve for treating metabolic diseases. However, the effects of PPAR-δagonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR-δagonist, GW0742 (1 mg/kg/day for 16 weeks), in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS), the major sweetener in foods and soft-drinks (15% wt/vol in drinking water). Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR-δupregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR-δactivation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

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