The effects of dietary methionine restriction on the function and metabolic reprogramming in the liver and brain – implications for longevity

2019 ◽  
Vol 30 (6) ◽  
pp. 581-593 ◽  
Author(s):  
Dušan Mladenović ◽  
Tatjana Radosavljević ◽  
Dragan Hrnčić ◽  
Aleksandra Rasic-Markovic ◽  
Olivera Stanojlović
Keyword(s):  
Growth Factor ◽  
Life Span ◽  
De Novo ◽  
Regulatory Element ◽  
Adenosine Monophosphate ◽  
Metabolic Reprogramming ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Methionine Restriction

Abstract Methionine is an essential sulphur-containing amino acid involved in protein synthesis, regulation of protein function and methylation reactions. Dietary methionine restriction (0.12–0.17% methionine in food) extends the life span of various animal species and delays the onset of aging-associated diseases and cancers. In the liver, methionine restriction attenuates steatosis and delays the development of non-alcoholic steatohepatitis due to antioxidative action and metabolic reprogramming. The limited intake of methionine stimulates the fatty acid oxidation in the liver and the export of lipoproteins as well as inhibits de novo lipogenesis. These effects are mediated by various signaling pathways and effector molecules, including sirtuins, growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding proteins, adenosine monophosphate-dependent kinase and general control nonderepressible 2 pathway. Additionally, methionine restriction stimulates the synthesis of fibroblast growth factor-21 in the liver, which increases the insulin sensitivity of peripheral tissues. In the brain, methionine restriction delays the onset of neurodegenerative diseases and increases the resistance to various forms of stress through antioxidative effects and alterations in lipid composition. This review aimed to summarize the morphological, functional and molecular changes in the liver and brain caused by the methionine restriction, with possible implications in the prolongation of maximal life span.

scholarly journals Dietary Essential Amino Acid Restriction Promotes Hyperdipsia via Hepatic FGF21

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1469
Author(s):  
Patricia M. Rusu ◽  
Andrea Y. Chan ◽  
Mathias Heikenwalder ◽  
Oliver J. Müller ◽  
Adam J. Rose
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Dietary Protein ◽  
Essential Amino Acid ◽  
De Novo ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
De Novo Biosynthesis ◽  
Dietary Requirements ◽  
Dietary Amino Acid

Prior studies have reported that dietary protein dilution (DPD) or amino acid dilution promotes heightened water intake (i.e., hyperdipsia) however, the exact dietary requirements and the mechanism responsible for this effect are still unknown. Here, we show that dietary amino acid (AA) restriction is sufficient and required to drive hyperdipsia during DPD. Our studies demonstrate that particularly dietary essential AA (EAA) restriction, but not non-EAA, is responsible for the hyperdipsic effect of total dietary AA restriction (DAR). Additionally, by using diets with varying amounts of individual EAA under constant total AA supply, we demonstrate that restriction of threonine (Thr) or tryptophan (Trp) is mandatory and sufficient for the effects of DAR on hyperdipsia and that liver-derived fibroblast growth factor 21 (FGF21) is required for this hyperdipsic effect. Strikingly, artificially introducing Thr de novo biosynthesis in hepatocytes reversed hyperdipsia during DAR. In summary, our results show that the DPD effects on hyperdipsia are induced by the deprivation of Thr and Trp, and in turn, via liver/hepatocyte-derived FGF21.

scholarly journals Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance

2018 ◽  
Vol 19 (11) ◽  
pp. 3552 ◽  
Author(s):  
Baile Wang ◽  
Kenneth Cheng
Keyword(s):  
Energy Balance ◽  
Hormonal Regulation ◽  
Energy Homeostasis ◽  
Adenosine Monophosphate ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Adaptive Thermogenesis ◽  
Increase Food Intake ◽  
Regulatory Effects ◽  
Underlying Mechanisms

As a cellular energy sensor and regulator, adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite to increase food intake and diminishing adaptive thermogenesis in adipose tissues to reduce energy expenditure in response to food deprivation. Numerous metabolic hormones, such as leptin, adiponectin, ghrelin and insulin, exert their energy regulatory effects through hypothalamic AMPK via integration with the neural circuits. Although activation of AMPK in peripheral tissues is able to promote fatty acid oxidation and insulin sensitivity, its chronic activation in the hypothalamus causes obesity by inducing hyperphagia in both humans and rodents. In this review, we discuss the role of hypothalamic AMPK in mediating hormonal regulation of feeding and adaptive thermogenesis, and summarize the diverse underlying mechanisms by which central AMPK maintains energy homeostasis.

scholarly journals Development of a fibroblast growth factor 21 assay

2017 ◽  
Author(s):  
◽  
Gabriela V. Tamassia
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Dynamic Range ◽  
Metabolic Stress ◽  
High Sensitivity ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Fibroblast Growth ◽  
Obesity And Diabetes ◽  
Hepatic Fatty Acid Oxidation

Obesity and diabetes play a major role in many diseases prevalent in our current society. Fibroblast Growth Factor 21 (FGF21) is a recently discovered hormone that has potential for therapeutic treatment of obesity and diabetes. It acts as a hormone in times of metabolic stress and is shown to stimulate hepatic fatty acid oxidation, ketogenesis, induce weight loss, allow for sustained decrease in plasma glucose and triglycrides, and decrease the growth hormone response. Obese or diabetic individuals often have higher than normal amounts of circulating FGF21; consequently, they may be considered FGF21 resistant. It is then advantageous to have an assay to measure FGF21 that will allow us to study FGF21 further. It is also important to study FGF21 in various livestock species for potential biomarkers, or as indicators of carcass quality that could prove to advance further research. We have developed a working FGF21 assay using an amplified luminescent proximity homogeneous assay (AlphaLISA). It is a homogeneous, no-wash immunoassay with high sensitivity and wide dynamic range. It is a bead based technology that brings two antibodies near each other allowing for an unstable singlet oxygen to trigger a downstream cascade of chemical events leading to a sharp intense chemiluminescent emission that can be read on an EnVision machine. The assay was set up using a 'sandwich' design with guinea pig or rabbit anti-bovine FGF21 antibodies attached to the acceptor beads and biotinylated rabbit anti-bovine FGF21 antibodies x attached to a streptavidin coated donor bead. The assay has a working range from 0.2-200 ng/ml. Standard curves in serum from bovine, porcine, rabbit, rat, ewe, fetal bovine has been conducted and assay conditions were optimized for each. Manipulations of the sera were necessary in order to get functional curves. These included diluting it 2 fold or more, depending on the species, and increasing incubation temperatures. The assay can function using both serum and plasma.

Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice

2008 ◽  
Vol 295 (2) ◽  
pp. E436-E445 ◽  
Author(s):  
Xing Xian Yu ◽  
Susan F. Murray ◽  
Lynnetta Watts ◽  
Sheri L. Booten ◽  
Justin Tokorcheck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Antisense Oligonucleotide ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Liver Steatosis ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Obese Mice ◽  
Peripheral Tissues

To investigate the role of JNK1 in metabolism, male ob/ ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65–95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1) increased mRNA levels of AR-β3 and UCP1 by >60% in BAT, 2) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30–60% in WAT, and 3) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKCε by 40–70% and increased levels of UCP2 and PPARα by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser302 and pIRS-1 Ser307 and increased levels of pAkt Ser473 in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities.

scholarly journals Fibroblast Growth Factor 21 Corrects Obesity in Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6018-6027 ◽  
Author(s):  
Tamer Coskun ◽  
Holly A. Bina ◽  
Michael A. Schneider ◽  
James D. Dunbar ◽  
Charlie C. Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
De Novo ◽  
Caloric Intake ◽  
De Novo Lipogenesis ◽  
Leptin Resistance ◽  
Health Concern ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Lipid Control

Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.

Metabolic Remodeling Induced by Adipocytes: A New Achilles' Heel in Invasive Breast Cancer?

2020 ◽  
Vol 27 (24) ◽  
pp. 3984-4001 ◽  
Author(s):  
Camille Attané ◽  
Delphine Milhas ◽  
Andrew J. Hoy ◽  
Catherine Muller
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Fatty Acid Oxidation ◽  
De Novo ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Oxidation Inhibitors ◽  
Metabolic Remodeling

Metabolic reprogramming represents an important hallmark of cancer cells. Besides de novo fatty acid synthesis, it is now clear that cancer cells can acquire Fatty Acids (FA) from tumor-surrounding adipocytes to increase their invasive capacities. Indeed, adipocytes release FA in response to tumor secreted factors that are transferred to tumor cells to be either stored as triglycerides and other complex lipids or oxidized in mitochondria. Like all cells, FA can be released over time from triglyceride stores through lipolysis and then oxidized in mitochondria in cancer cells. This metabolic interaction results in specific metabolic remodeling in cancer cells, and underpins adipocyte stimulated tumor progression. Lipolysis and fatty acid oxidation therefore represent novel targets of interest in the treatment of cancer. In this review, we summarize the recent advances in our understanding of the metabolic reprogramming induced by adipocytes, with a focus on breast cancer. Then, we recapitulate recent reports studying the effect of lipolysis and fatty acid oxidation inhibitors on tumor cells and discuss the interest to target these metabolic pathways as new therapeutic approaches for cancer.

scholarly journals A role for PPARα in the control of SREBP activity and lipid synthesis in the liver

2005 ◽  
Vol 389 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Brian L. Knight ◽  
Abdel Hebbachi ◽  
David Hauton ◽  
Anna-Marie Brown ◽  
David Wiggins ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cholesterol Synthesis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
Active Form ◽  
Dietary Cholesterol ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Hepatic Expression

Inclusion of the PPARα (peroxisome-proliferator-activated receptor α) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARα expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARα-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.

scholarly journals Functional role of a novel cis-acting element (GAGA box) in human type-1 angiotensin II receptor gene transcription

2000 ◽  
Vol 25 (1) ◽  
pp. 97-108 ◽  
Author(s):  
BD Wyse ◽  
SL Linas ◽  
TJ Thekkumkara
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
De Novo ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Receptor Expression ◽  
Cis Acting ◽  
Human Type

GH/growth factors have been shown to increase angiotensin type 1 receptor expression. In the present study we determined the cis-acting regulatory region controlling GH-induced transcription of the human type-1 angiotensin receptor (hAT(1)). In human proximal tubule cells transfected with a chloramphenicol acetyl transferase (CAT) reporter plasmid under the control of the hAT(1) promoter, GH induced CAT activity. Serial deletions of the hAT(1) promoter region indicated that an area between -314 bp and -70 bp upstream of the 5'-end of the cDNA sequence was essential for this activation to occur. Although sequence analysis identified putative multiple nuclear protein binding sites in this region, we determined that a 12 bp sequence (5'-GAGAGGGAGGAG-3', GAGA box) located between -161 bp and -149 bp was important for GH-mediated activation. Using mobility shift assays we demonstrated increased DNA binding activity to the labeled GAGA box in nuclear extracts treated with GH, suggesting this sequence is a GH response element. Southwestern analysis identified an 18 kDa GAGA box-binding protein (GAGA-BP). GH-induced activity of the GAGA-BP occurred within 2.5 min and reached a maximum at 5 min. Activation did not require de novo protein synthesis. Removal of the GAGA box abolished GH-induced transcription as well as basal transcription of the hAT(1) gene. Additional studies demonstrated that epidermal growth factor, platelet-derived growth factor and insulin activate the GAGA-BP, suggesting these growth factors can also regulate the transcription of the hAT(1) gene through the GAGA box. Our data show that the GAGA-BP acts as a trans-acting factor binding to the cis-acting regulatory element in the hAT(1) promoter, which is necessary for the basal and growth factor(s)-mediated transcriptional activation of the hAT(1) gene.

scholarly journals Peripheral signalling involved in energy homeostasis control

2012 ◽  
Vol 25 (2) ◽  
pp. 223-248 ◽  
Author(s):  
Andoni Lancha ◽  
Gema Frühbeck ◽  
Javier Gómez-Ambrosi
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Weight Control ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Sex Hormone Binding Globulin ◽  
Fibroblast Growth Factor 21 ◽  
Peripheral Tissues ◽  
Body Weight Control

The alarming prevalence of obesity has led to a better understanding of the molecular mechanisms controlling energy homeostasis. Regulation of energy intake and expenditure is more complex than previously thought, being influenced by signals from many peripheral tissues. In this sense, a wide variety of peripheral signals derived from different organs contributes to the regulation of body weight and energy expenditure. Besides the well-known role of insulin and adipokines, such as leptin and adiponectin, in the regulation of energy homeostasis, signals from other tissues not previously thought to play a role in body weight regulation have emerged in recent years. The role of fibroblast growth factor 21 (FGF21), insulin-like growth factor 1 (IGF-I), and sex hormone-binding globulin (SHBG) produced by the liver in the regulation of body weight and insulin sensitivity has been recently described. Moreover, molecules expressed by skeletal muscle such as myostatin have also been involved in adipose tissue regulation. Better known is the involvement of ghrelin, cholecystokinin, glucagon-like peptide 1 (GLP-1) and PYY3–36, produced by the gut, in energy homeostasis. Even the kidney, through the production of renin, appears to regulate body weight, with mice lacking this hormone exhibiting resistance to diet-induced obesity. In addition, the skeleton has recently emerged as an endocrine organ, with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin. The comprehension of these signals will help in a better understanding of the aetiopathology of obesity, contributing to the potential development of new therapeutic targets aimed at tackling excess body fat accumulation.

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