Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

In the paper

“After an overnight fast, ketone bodies are in the micromolar range (∼30 μM for women and ∼60 μM for men), which is not detected by most assays (23).”

What the sources say

• Not checked yetcites [23] Marinou, 2011, Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men, Br J Nutr source

In the paper

“Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here.”

In the paper

“At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria.”

• Also stated in: § Defining Metabolic Flexibility · plain

  “At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways that manage nutrient sensing, uptake, transport, storage, and utilization.”

What the sources say

• Not checked yetcites [11] Obre, 2015, Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy, Int J Biochem Cell Biol source
• Not checked yetcites [12] Vitkup, 2006, Influence of metabolic network structure and function on enzyme evolution, Genome Biol source

In the paper

“Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise.”

In the paper

“The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues.”

In the paper

“Mitochondria play a crucial role in determining metabolic flexibility”

In the paper

“Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer.”

In the paper

“Molecular and signaling pathways drive metabolic flexibility and often serve as metabolic sensors”

In the paper

“Metabolic flexibility pathways are therapeutic targets for age-related diseases, similar to caloric restriction or exercise”

In the paper

“Metabolic inflexibility is a hallmark of many age-related metabolic diseases but also plays a central role in, for instance, cancer and immune metabolism”

In the paper

“This near continuous intake of calorically dense processed foods, combined with physical inactivity, reduces a predilection for, and directly impedes, metabolic flexibility (3).”

What the sources say

• Not checked yetcites [3] López-Otín, 2016, Metabolic control of longevity, Cell source

In the paper

“The modern era, however, is characterized by unprecedented levels of food supply (2).”

What the sources say

• Not checked yetcites [2] Speakman, 2013, Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints, Annu Rev Nutr source

In the paper

“Mitochondria are pliable organelles, and they adapt their morphology to nutrient availability and in doing so regulate OXPHOS activity and substrate preference (90, 91).”

What the sources say

• Not checked yetcites [90] Cogliati, 2013, Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency, Cell source
• Not checked yetcites [91] Cogliati, 2016, Mitochondrial cristae: where beauty meets functionality, Trends Biochem Sci source

In the paper

“More recent work showed that, upon consumption of a high-fat diet, lean subjects with adequate metabolic flexibility were able to increase fatty acid oxidation (FAO) at the expense of glucose, whereas obese individuals were not (10).”

What the sources say

• Not checked yetcites [10] Battaglia, 2012, Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals, Am J Physiol Endocrinol Metab source

In the paper

“Insulin-resistant obese patients however manifested a lesser reliance on fatty acid oxidation compared with lean individuals and did not show increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusion.”

What the sources say

• Not checked yetcites [8] Kelley, 1999, Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss, Am J Physiol
• Not checked yetcites [9] Kelley, 2000, Fuel selection in human skeletal muscle in insulin resistance: a reexamination, Diabetes source

In the paper

“Glucagon stimulates hepatic glycogenolysis and ketogenesis, and the decrease in insulin suppresses hepatocyte malonyl-coenzyme A (CoA) synthesis and lipogenesis, with concomitant activation of FAO (21, 22).”

What the sources say

• Not checked yetcites [21] Ramnanan, 2011, Physiologic action of glucagon on liver glucose metabolism, Diabetes Obes Metab source
• Not checked yetcites [22] McGarry, 1980, Regulation of hepatic fatty acid oxidation and ketone body production, Annu Rev Biochem source

In the paper

“Under the influence of insulin, the liver is triggered to absorb glucose from the circulation and stop glycogenolysis and gluconeogenesis.”

In the paper

“Fatty acids derived from a meal trigger adipose tissue to reduce nonesterified fatty acid release and prompt hepatocytes to reduce endogenous triacylglycerol release, together stimulating the clearance of circulating triacylglycerol (19).”

What the sources say

• Not checked yetcites [19] Frayn, 2002, Adipose tissue as a buffer for daily lipid flux, Diabetologia source

In the paper

“Adipose tissue responds to insulin by decreasing the rate of lipolysis and stimulating fatty acid and triacylglycerol synthesis from lipids and glucose (18).”

What the sources say

• Not checked yetcites [18] Dimitriadis, 2011, Insulin effects in muscle and adipose tissue, Diabetes Res Clin Pract source

In the paper

“Taken together, metabolic flexibility can be understood as an adaptive response of an organism’s metabolism to maintain energy homeostasis by matching fuel availability and demand to periodic fasting, varying meal composition, physical activity, and environmental fluctuations (13, 14).”

What the sources say

• Not checked yetcites [13] Carstens, 2013, Fasting substrate oxidation in relation to habitual dietary fat intake and insulin resistance in non-diabetic women: a case for metabolic flexibility, Nutr Metab (Lond) source
• Not checked yetcites [14] van Ommen, 2009, Challenging homeostasis to define biomarkers for nutrition related health, Mol Nutr Food Res source

In the paper

“During the postprandial period of a carbohydrate-rich meal for instance, pancreatic β cells respond to the rise in nutrients by releasing insulin into the bloodstream, increasing the insulin-glucagon ratio (Fig. 1).”

In the paper

“The concept of metabolic flexibility was particularly linked to the capacity of mitochondria to select fuel in response to nutritional changes (4) and placed mitochondrial function at its core (11).”

What the sources say

• Not checked yetcites [4] Muoio, 2014, Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock, Cell source
• Not checked yetcites [11] Obre, 2015, Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy, Int J Biochem Cell Biol source

In the paper

“Ectopic fat deposition is related to metabolic abnormalities and defects in insulin sensitivity, T2DM, cardiovascular disease, and cancer (143).”

What the sources say

• Not checked yetcites [143] Tahergorabi, 2016, From obesity to cancer: a review on proposed mechanisms, Cell Biochem Funct source

In the paper

“Bile acids induce insulin secretion directly via the transmembrane bile acid receptor Takeda G protein–coupled receptor 5 (on β cells and indirectly via stimulation of l-cell derived GLP-1 and subsequent insulin release (110–112).”

What the sources say

• Not checked yetcites [110] Kumar, 2012, Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells, Biochem Biophys Res Commun source
• Not checked yetcites [111] Vettorazzi, 2016, The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells, Metabolism source
• Not checked yetcites [112] Thomas, 2009, TGR5-mediated bile acid sensing controls glucose homeostasis, Cell Metab source

In the paper

“The postprandial decrease in ghrelin lowers hepatic glucose production while increasing peripheral glucose-uptake in both skeletal muscle and adipose tissue (113).”

What the sources say

• Not checked yetcites [113] Alamri, 2016, The role of ghrelin in the regulation of glucose homeostasis, Horm Mol Biol Clin Investig source

In the paper

“Finally, obesity is associated with a state of chronic low-grade inflammation because ectopic fat depots release more inflammatory mediators than peripheral fat depots and infiltration of macrophages (24).”

What the sources say

• Not checked yetcites [24] Paniagua, 2016, Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome, World J Diabetes source

In the paper

“People with a family history for T2DM have an increased risk for developing metabolic inflexibility; the lower HK II activity and PGC1 expression play a role in this (136).”

What the sources say

• Not checked yetcites [136] Ozanne, 2007, Mechanisms of disease: the developmental origins of disease and the role of the epigenotype, Nat Clin Pract Endocrinol Metab source

In the paper

“Adiponectin suppresses glucose production in the liver and enhances FAO in skeletal muscle (117, 118).”

What the sources say

• Not checked yetcites [117] Coles, 2016, Adipokines in healthy skeletal muscle and metabolic disease, Adv Exp Med Biol source
• Not checked yetcites [118] Yamauchi, 2002, Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase, Nat Med source

In the paper

“Adipose tissue macrophages that have been activated and rely on glucose are proinflammatory (type M1) and contribute to adipose inflammation and insulin resistance.”

In the paper

“iNOS is an important metabolic regulator of the immune response because NO inhibits OXPHOS and oxidative metabolism, thus promoting the glycolytic and proinflammatory phenotype (169, 170).”

What the sources say

• Not checked yetcites [169] Johnson, 2016, Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation, Mol Metab source
• Not checked yetcites [170] Van den Bossche, 2016, Mitochondrial dysfunction prevents repolarization of inflammatory macrophages, Cell Reports source

In the paper

“Today, we understand that mitochondrial respiration is not impaired but that cancer cells place emphasis on acquisition and generation of building blocks necessary for cell division. They do so by enhancing biosynthetic metabolism using glycolytic intermediates (209).”

What the sources say

• Not checked yetcites [209] Lunt, 2011, Aerobic glycolysis: meeting the metabolic requirements of cell proliferation, Annu Rev Cell Dev Biol source

In the paper

“Metabolic syndrome is associated with a 33% elevated total cancer mortality (184).”

What the sources say

• Not checked yetcites [184] Gathirua-Mwangi, 2017, Metabolic syndrome and total cancer mortality in the Third National Health and Nutrition Examination Survey, Cancer Causes Control source

In the paper

“Metabolic inflexibility drives sepsis-related innate immunoparalysis as the metabolism through glycolysis, β-oxidation, and OXPHOS pathways in leukocytes is downregulated, resulting in their inability to mount any response whatsoever (171).”

What the sources say

• Not checked yetcites [171] Cheng, 2016, Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis, Nat Immunol source

In the paper

“Even TCA cycle intermediates are not solely used to produce NADH for mitochondrial respiration, but intermediates can also be used to form nonessential amino acids and fatty acids, which facilitate protein synthesis, membrane construction and cholesterol synthesis (206).”

What the sources say

• Not checked yetcites [206] Pavlova, 2016, The emerging hallmarks of cancer metabolism, Cell Metab source

In the paper

“Obesity can cause metabolic inflexibility of the heart and alter substrate selection (179).”

What the sources say

• Not checked yetcites [179] Pascual, 2016, Fuel availability and fate in cardiac metabolism: a tale of two substrates, Biochim Biophys Acta source

In the paper

“Increased glucose uptake and metabolism is very often mediated by the oncogenic signaling protein Ras, which activates the PI3K/Akt pathway. PI3K/Akt signaling increases the expression of GLUT1 and its translocation to the cell surface, and enhances HK and phosphofructokinase activity, thus capturing glucose and increasing glycolytic flux (196).”

What the sources say

• Not checked yetcites [196] Muñoz-Pinedo, 2012, Cancer metabolism: current perspectives and future directions, Cell Death Dis source

In the paper

“Conversely, macrophages that rely on fatty acid metabolism secrete anti-inflammatory cytokines and thus preserve insulin sensitivity of liver and adipose tissue (type M2) (167, 168).”

What the sources say

• Not checked yetcites [167] Johnson, 2012, The inflammation highway: metabolism accelerates inflammatory traffic in obesity, Immunol Rev source
• Not checked yetcites [168] Kang, 2008, Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity, Cell Metab source

In the paper

“Indeed, reducing metabolic flexibility in cancer cells may lead to potential treatment options, because metabolic interference can come at a substantial cost to oncogenic potential (1).”

What the sources say

• Not checked yetcites [1] Olson, 2016, Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies, Trends Biochem Sci source

In the paper

“Conversely, the failing heart becomes metabolically inflexible with a decreased capacity to use fatty acids and an increased dependence on glucose metabolism (175).”

What the sources say

• Not checked yetcites [175] Kaimoto, 2017, Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure, Am J Physiol Heart Circ Physiol source

In the paper

“Aspartate is used to support protein and nucleotide synthesis in proliferating cells and sustains proliferation in the face of OXPHOS impairment (214).”

What the sources say

• Not checked yetcites [214] Sullivan, 2015, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells, Cell source

In the paper

“These alternative pathways include the PPP using glucose-6-phosphate, hexosamine biosynthesis using fructose-6-phosphate, phospholipid biosynthesis using dihydroxyacetone phosphate, and glycine and serine biosynthesis using 3-phosphoglycerate.”

What the sources say

• Not checked yetcites [196] Muñoz-Pinedo, 2012, Cancer metabolism: current perspectives and future directions, Cell Death Dis source

In the paper

“Metabolic adaptations that underlie clonal evolution of tumor cells to a metastatic phenotype suggest that tumor cells do not become metabolically hardwired but remain able to reroute metabolism to adapt to their phenotype and the newly acquired environment (200).”

What the sources say

• Not checked yetcites [200] Herst, 2013, Cell hierarchy, metabolic flexibility and systems approaches to cancer treatment, Curr Pharm Biotechnol source

In the paper

“Lactate, produced from glycolysis, is excreted from the cell or used in biosynthetic reactions such as aspartate synthesis (1).”

What the sources say

• Not checked yetcites [1] Olson, 2016, Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies, Trends Biochem Sci source

In the paper

“FAO in skeletal muscle increases during physical exertion independent of body mass index, although regular exercise is likely needed to sustain a long-lasting impact on metabolic flexibility (10).”

What the sources say

• Not checked yetcites [10] Battaglia, 2012, Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals, Am J Physiol Endocrinol Metab source

In the paper

“Intriguingly, type II, glycolytic, muscle fiber density is higher in obese and insulin-resistant patients, although it is unknown whether these are due to inactivity or impaired glucose metabolism (226).”

What the sources say

• Not checked yetcites [226] da Silva Aragão, 2014, Maternal protein restriction impairs the transcriptional metabolic flexibility of skeletal muscle in adult rat offspring, Br J Nutr source

In the paper

“In rats, chronic endurance exercise induces browning in subcutaneous WAT concomitant with increased mobilization of energy stores, which were attenuated in animals fed high-fat diets.”

What the sources say

• Not checked yetcites [229] Sepa-Kishi, 2016, Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism, Exerc Sport Sci Rev source

In the paper

“Acute AMPK activation reduces glycogen and protein synthesis while promoting glucose transport and FAO (222).”

What the sources say

• Not checked yetcites [222] Egan, 2013, Exercise metabolism and the molecular regulation of skeletal muscle adaptation, Cell Metab source

In the paper

“However, not all tumors are glutamine dependent because some tumors and embryonic stem cells are capable of proliferation without an exogenous supply of glutamine, because they can synthesize it (206).”

What the sources say

• Not checked yetcites [206] Pavlova, 2016, The emerging hallmarks of cancer metabolism, Cell Metab source

In the paper

“Particularly combined with weight loss, exercise training improves insulin sensitivity, mitochondrial content, and fasting FAO (220).”

What the sources say

• Not checked yetcites [220] Bergouignan, 2013, Effect of contrasted levels of habitual physical activity on metabolic flexibility, J Appl Physiol (1985) source

In the paper

“Also, in the human heart, exercise reduces cardiometabolic risk factors by increasing insulin sensitivity, decreasing cardiac lipid content, and improving glucose tolerance (232).”

What the sources say

• Not checked yetcites [232] Vettor, 2014, Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism, Am J Physiol Endocrinol Metab source

In the paper

“Glutamine can either be used as an important anaplerotic substrate in the TCA cycle, a carbon and nitrogen donor, or for production of purine and pyrimidine nucleotides that are necessary for DNA replication (216).”

What the sources say

• Not checked yetcites [216] Tardito, 2015, Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma, Nat Cell Biol source

In the paper

“Glutamine is an essential nutrient for cancer proliferation and its dependency is also referred to as “glutamine addiction” (215).”

What the sources say

• Not checked yetcites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA source

In the paper

“Contraction-induced calcium uptake acutely increases OXPHOS (94, 177) and augments glucose transport and stimulates lipid uptake and oxidation through MEF2-induced expression of GLUT4 and PGC1α, respectively.”

What the sources say

• Not checked yetcites [94] Wüst, 2013, On-off asymmetries in oxygen consumption kinetics of single Xenopus laevis skeletal muscle fibres suggest higher-order control, J Physiol source
• Not checked yetcites [177] Wüst, 2017, Rapid frequency-dependent changes in free mitochondrial calcium concentration in rat cardiac myocytes, J Physiol source

In the paper

“A high-intensity exercise training program, however, showed elevated citrate synthase and β-hydroxyacyl CoA dehydrogenase activity after 5 days and increased levels of mitochondrial complexes after 10 days (51).”

What the sources say

• Not checked yetcites [51] Perry, 2010, Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle, J Physiol source

In the paper

“Both promote considerable health benefits such as increased mitochondrial content and improvements in glycemic control (222).”

What the sources say

• Not checked yetcites [222] Egan, 2013, Exercise metabolism and the molecular regulation of skeletal muscle adaptation, Cell Metab source

In the paper

“Short-term, high-intensity exercise decreases muscle promoter methylation of genes involved in mitochondrial function such as PGC1α, TFAM, MEF2A, and PDK4, whereas in patients with T2DM, these regions usually have higher methylation levels (137).”

What the sources say

• Not checked yetcites [137] Kirchner, 2013, Epigenetic flexibility in metabolic regulation: disease cause and prevention, Trends Cell Biol source

In the paper

“In proliferating cells, the transcription factor Myc is a major driver of glutamine utilization and is frequently targeted for upregulation in various tumors, despite the abundance of glucose.”

What the sources say

• Not checked yetcites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA source

In the paper

“High-fat feeding in mice induced PGC1α hypermethylation that was transferable to the offspring. Maternal exercise, on the other hand, prevented high-fat feeding hypermethylation of PGC1α and mitigated epigenetic associated metabolic dysfunction in the offspring (138).”

What the sources say

• Not checked yetcites [138] Barrès, 2016, The role of diet and exercise in the transgenerational epigenetic landscape of T2DM, Nat Rev Endocrinol source

In the paper

“This glutamine addiction is beneficial for the cancer cell because it maintains mitochondrial TCA cycle integrity and provides the cell with large quantities of NADPH needed to meet the demands of cell proliferation (215).”

What the sources say

• Not checked yetcites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA source

In the paper

“Clinical studies in humans suggest that resveratrol may improve insulin sensitivity and reduce plasma levels of glucose and insulin in patients with T2DM and mimic CR in obese subjects (253, 254).”

What the sources say

• Not checked yetcites [253] Timmers, 2011, Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans, Cell Metab source
• Not checked yetcites [254] Bhatt, 2012, Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus, Nutr Res source

In the paper

“AICAR also rescued mitochondrial function in mice deficient in cytochrome c oxidase and augmented exercise endurance in healthy animals in a PGC1α-dependent manner, even if they were untrained (255, 256).”

What the sources say

• Not checked yetcites [255] Komen, 2014, Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models, Br J Pharmacol source
• Not checked yetcites [256] Narkar, 2008, AMPK and PPARdelta agonists are exercise mimetics, Cell source

In the paper

“CR without hunger- or disease-related malnutrition in animals and humans results in healthier aging through improved metabolic health, reduced obesity, and the risk of T2DM, cancer, and cardiovascular disease (236).”

What the sources say

• Not checked yetcites [236] Mattison, 2017, Caloric restriction improves health and survival of rhesus monkeys, Nat Commun source

In the paper

“Additionally, CR is considered the most robust intervention to increase longevity in animal model systems and ameliorate age-associated disease in primates and humans (see “Prolonged fasting and caloric/dietary restriction” and “Aging”) (38).”

What the sources say

• Not checked yetcites [38] Fontana, 2015, Promoting health and longevity through diet: from model organisms to humans, Cell source

In the paper

“Carnitine plays a role in the import of long-chain fatty acids into the mitochondria for use in β-oxidation and in the mitochondrial efflux of excess carbons in the form of acyl-carnitines (242).”

What the sources say

• Not checked yetcites [242] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J Biol Chem source

In the paper

“In obese rats, free carnitine in skeletal muscle is decreased and supplementation of l-carnitine restored metabolic flexibility (242).”

What the sources say

• Not checked yetcites [242] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J Biol Chem source

In the paper

“Time-restricted feeding restores both cycling of metabolic regulators such as cAMP response element-binding protein, mTOR and AMPK, and circadian clock gene expression (214).”

What the sources say

• Not checked yetcites [214] Sullivan, 2015, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells, Cell source

In the paper

“Resveratrol (3,5,4′-trihydroxystilbene) is a plant-derived polyphenol that activates AMPK and, via SIRT1, increases PGC1α, PGC1α deacetylation, mitochondrial size and density, and mtDNA content in skeletal muscle [reviewed in de Ligt et al. (247)].”

What the sources say

• Not checked yetcites [247] de Ligt, 2015, Resveratrol and obesity: can resveratrol relieve metabolic disturbances, Biochim Biophys Acta source

In the paper

“The AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) improves skeletal muscle glucose uptake and transport, fatty acid uptake, mitochondrial protein content, and insulin sensitivity in mice (223).”

What the sources say

• Not checked yetcites [223] Kjøbsted, 2017, Enhanced muscle insulin sensitivity after contraction/exercise is mediated by AMPK, Diabetes source

In the paper

“Metformin is one of the first-line treatments of patients with T2DM, but it has also been used to treat patients at risk for T2DM, such as those with metabolic syndrome (87).”

What the sources say

• Not checked yetcites [87] Fadini, 2011, At the crossroads of longevity and metabolism: the metabolic syndrome and lifespan determinant pathways, Aging Cell source

In the paper

“Intermittent fasting in rodents improved insulin and leptin sensitivity increases ketone body levels and reduced adiposity and inflammation (235).”

What the sources say

• Not checked yetcites [235] Mattson, 2017, Impact of intermittent fasting on health and disease processes, Ageing Res Rev source

In the paper

“Because resveratrol activates mitochondrial biogenesis through the AMPK-SIRT1-PGC1α axis, it prompts mitochondrial biogenesis, the unfolded protein response, and autophagy machinery that are known to extend longevity in animals (37, 249).”

What the sources say

• Not checked yetcites [37] Madeo, 2015, Essential role for autophagy in life span extension, J Clin Invest source
• Not checked yetcites [249] Andreux, 2013, Pharmacological approaches to restore mitochondrial function, Nat Rev Drug Discov source

In the paper

“Resveratrol treatment also increased physical endurance and protected from high-fat diet-induced muscle accumulation of diacylglyceride and ceramide, and related mitochondrial dysfunction (248).”

What the sources say

• Not checked yetcites [248] Um, 2010, AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol, Diabetes source

In the paper

“In patients with T2DM, carnitine acetyltransferase expression is severely perturbed and free carnitine concentrations in diabetic mice are decreased compared with controls (243, 244).”

What the sources say

• Not checked yetcites [243] Muoio, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab source
• Not checked yetcites [244] Xia, 2011, L-carnitine ameliorated fatty liver in high-calorie diet/STZ-induced type 2 diabetic mice by improving mitochondrial function, Diabetol Metab Syndr source

In the paper

“Chronic exposure of AICAR reduced white adiposity and increased OXPHOS in rat hearts by increasing PGC1α expression and FAO (229), as well as glucose uptake (257).”

What the sources say

• Not checked yetcites [229] Sepa-Kishi, 2016, Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism, Exerc Sport Sci Rev source
• Not checked yetcites [257] Russell, 1999, Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR, Am J Physiol

In the paper

“Although not yet in clinical practice, l-carnitine supplementation improves metabolic flexibility by decreasing plasma glucose and insulin levels and increasing PDH activity in muscle of insulin-resistant subjects (243).”

What the sources say

• Not checked yetcites [243] Muoio, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab source

In the paper

“Energy-restricting dietary regimens have proven effective in augmenting metabolic flexibility in animal studies and hold promise for application in humans (234).”

What the sources say

• Not checked yetcites [234] Tay, 2018, Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low saturated fat diet versus a high-carbohydrate, low-fat diet in type 2 diabetes: a 2-year randomized clinical trial, Diabetes Obes Metab source

In the paper

“In rodents, food intake outside the active phase causes obesity, whereas time-restricted feeding protects against obesity and insulin resistance (240).”

What the sources say

• Not checked yetcites [240] Zarrinpar, 2016, Daily eating patterns and their impact on health and disease, Trends Endocrinol Metab source

In the paper

“Metformin is a biguanide and reduces hepatic glucose production and increases insulin sensitivity by activating AMPK, although several AMPK-independent mechanisms have been proposed [reviewed in Pryor and Cabreiro (246)].”

What the sources say

• Not checked yetcites [246] Pryor, 2015, Repurposing metformin: an old drug with new tricks in its binding pockets, Biochem J source

In the paper

“Animal studies have also demonstrated that resveratrol could stimulate energy expenditure and protect against a high-fat diet-induced weight gain (250), via induction of FAO and reduced lipogenesis, mediated by activation of the AMPK-SIRT1 axis (251, 252).”

What the sources say

• Not checked yetcites [250] Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell source
• Not checked yetcites [251] Baur, 2006, Resveratrol improves health and survival of mice on a high-calorie diet, Nature source
• Not checked yetcites [252] Shang, 2008, Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase, Acta Pharmacol Sin source

In the paper

“Although weight loss is generally achieved in overweight and obese subjects, potential adverse effects exist for leaner subjects (237).”

What the sources say

• Not checked yetcites [237] Harvie, 2017, Potential benefits and harms of intermittent energy restriction and intermittent fasting amongst obese, overweight and normal weight subjects-a narrative review of human and animal evidence, Behav Sci (Basel) source

In the paper

“Finally, thiazolidinediones, such as rosiglitazone, potently activate PPARγ and lower blood glucose levels in patients with T2DM.”

What the sources say

• Not checked yetcites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol source
• Not checked yetcites [273] Sugii, 2009, PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization, Proc Natl Acad Sci USA source

In the paper

“Thiazolidinediones improve skeletal muscle glucose disposal via upregulation of GLUT1, decrease liver glucose output, and, as a primary target, improve the lipid-buffering capacity of WAT and as such improve hepatic steatosis (270, 273).”

What the sources say

• Not checked yetcites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol source
• Not checked yetcites [273] Sugii, 2009, PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization, Proc Natl Acad Sci USA source

In the paper

“For instance, nicotinamide riboside, which is converted to nicotinamide mononucleotide via the NAD+ salvage pathway in eukaryote cells, can boost NAD+ synthesis and can enhance oxidative metabolism and protect mouse tissues from high-fat diet-induced metabolic abnormalities (264) by means of PPARγ and antioxidant gene upregulation (265).”

What the sources say

• Not checked yetcites [264] Cantó, 2012, The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity, Cell Metab source
• Not checked yetcites [265] Shi, 2017, Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet, Mol Nutr Food Res source

In the paper

“Tesaglitazar increases whole-body glucose metabolic insulin action in obese rats by reducing hepatic glucose output, restoring skeletal muscle glucose uptake, and suppressing free fatty acid release by adipocytes (272).”

What the sources say

• Not checked yetcites [272] Wallenius, 2013, The PPAR α/γhagonist, tesaglitazar, improves insulin mediated switching of tissue glucose and free fatty acid utilization in vivo in the obese Zucker rat, PPAR Res source

In the paper

“Additionally, rapamycin has earned great interest over the years to prolong lifespan (195, 280), even when administered to aged animals (281).”

What the sources say

• Not checked yetcites [195] Riera, 2015, Tipping the metabolic scales towards increased longevity in mammals, Nat Cell Biol source
• Not checked yetcites [280] Kennedy, 2016, The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging, Cell Metab source
• Not checked yetcites [281] Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature source

In the paper

“Similarly, synthetic PPARβ/δ agonists such as GW501516 or L-165041 reduce adiposity improve insulin sensitivity and hyperlipidemia in obese patients, through their ability to augment mitochondrial biogenesis and activity (249).”

What the sources say

• Not checked yetcites [249] Andreux, 2013, Pharmacological approaches to restore mitochondrial function, Nat Rev Drug Discov source

In the paper

“Rapamycin, however, has poor solubility and pharmacokinetics, which led to the production of rapamycin analogs (rapalogs), which are currently used in some cancer therapies (279).”

What the sources say

• Not checked yetcites [279] Li, 2014, Rapamycin: one drug, many effects, Cell Metab source

In the paper

“Nicotinamide mononucleotide conversion to NAD+ activates SIRT1 and improves glucose homeostasis in mice (42).”

What the sources say

• Not checked yetcites [42] Houtkooper, 2012, Sirtuins as regulators of metabolism and healthspan, Nat Rev Mol Cell Biol source

In the paper

“SIRT3, which is localized in the mitochondrial matrix, targets many proteins involved in metabolic homeostasis, including OXPHOS subunits (42).”

What the sources say

• Not checked yetcites [42] Houtkooper, 2012, Sirtuins as regulators of metabolism and healthspan, Nat Rev Mol Cell Biol source

In the paper

“Acetylation of mitochondrial proteins propagates metabolic inflexibility and deacetylation promotes metabolic flexibility (178, 259).”

What the sources say

• Not checked yetcites [178] Griffin, 2016, Nutrient sensing and utilization: getting to the heart of metabolic flexibility, Biochimie source
• Not checked yetcites [259] Bleeker, 2016, Sirtuin activation as a therapeutic approach against inborn errors of metabolism, J Inherit Metab Dis source

In the paper

“PPARs are lipid sensors that transcriptionally modulate metabolic programs in response to nutrition and are interesting drug targets to improve metabolic flexibility [reviewed in Bugge and Holst (269)].”

What the sources say

• Not checked yetcites [269] Bugge, 2017, PPAR agonists, - could tissue targeting pave the way, Biochimie source

In the paper

“A reduction in cellular energy charge, such as during glucose deprivation or fasting, inhibits mTORC1 by AMPK-dependent as well as AMPK-independent pathways, and is required for the generation of ketone bodies in the liver (277).”

What the sources say

• Not checked yetcites [277] Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature source

In the paper

“Moreover, poly (ADP-ribose) polymerase inhibition rescued mitochondrial respiration defects and increased FAO in myotubes from obese patients by augmenting mitochondrial function (268).”

What the sources say

• Not checked yetcites [268] Pirinen, 2014, Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle, Cell Metab source

In the paper

“Moreover, because mTOR controls many vital cellular processes, its complete inhibition by high doses of rapamycin may negatively affect the maintenance of tissue functions and provoke adverse events (275).”

What the sources say

• Not checked yetcites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell source

In the paper

“Alternatively, pharmacological inhibition of the NAD+ consuming enzyme poly (ADP-ribose) polymerase in mice activates SIRT1 and increases mitochondrial respiratory capacity leading to augmented fitness and protection from diet-induced obesity (268).”

What the sources say

• Not checked yetcites [268] Pirinen, 2014, Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle, Cell Metab source

In the paper

“Indeed, mTOR signaling is dysregulated in cancer, T2DM and obesity, and is therefore actively perused as a promising drug target [reviewed in Laplante and Sabatini (275 and Albert and Hall (278)].”

What the sources say

• Not checked yetcites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell source
• Not checked yetcites [278] Albert, 2015, mTOR signaling in cellular and organismal energetics, Curr Opin Cell Biol source

In the paper

“There are three PPAR isotypes (PARα, PPARβ/δ, and PPARγ), which differ in ligand affinity and tissue distribution [reviewed in Gross et al. (270)].”

What the sources say

• Not checked yetcites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol source

In the paper

“In insulin-deficient mice, bezafibrate improves impaired glucose metabolism by augmenting hepatic mitochondrial performance [reviewed in Komen and Thorburn (255)], suppressing hepatic inflammatory pathways, and improving insulin sensitivity (271).”

What the sources say

• Not checked yetcites [255] Komen, 2014, Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models, Br J Pharmacol source
• Not checked yetcites [271] Franko, 2016, Bezafibrate improves insulin sensitivity and metabolic flexibility in STZ-induced diabetic mice, Diabetes source

In the paper

“Nicotinamide mononucleotide administration to mice also enhances energy metabolism, promotes physical activity, improves lipid profiles, and ameliorates age-related pathophysiology (267).”

What the sources say

• Not checked yetcites [267] Mills, 2016, Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice, Cell Metab source

In the paper

“mTOR is a central regulator of growth and metabolism in all eukaryotes and its activity depends on the cells energy and nutrient levels [reviewed in Laplante and Sabatini (275)].”

What the sources say

• Not checked yetcites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell source

In the paper

“Prolonged treatment improves metabolic profiles, increases oxygen consumption and ketogenesis, and markedly enhances insulin sensitivity [reviewed in Li et al. (279)].”

What the sources say

• Not checked yetcites [279] Li, 2014, Rapamycin: one drug, many effects, Cell Metab source

In the paper

“Additionally, nicotinamide riboside treatment in aging mice increased skeletal muscle function by preventing stem cell senescence, improved mitochondrial function, and a higher expression of genes involved in the TCA cycle and OXPHOS (266).”

What the sources say

• Not checked yetcites [266] Zhang, 2016, NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice, Science source

In the paper

“mTORC1 facilitates cellular growth by a shift in glucose metabolism from OXPHOS to glycolysis, likely through an mTORC1-mediated increase in the translation of the transcription factor HIF1α and an increased flux through the PPP, which uses carbons from glucose to generate NADPH and other intermediary metabolites needed for proliferation and growth (276).”

What the sources say

• Not checked yetcites [276] Düvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol Cell source

In the paper

“For instance, 25% of the BXD strains, which were generated by crossing C57BL/6J and DBA/2J, have a hypersecretion of insulin in response to glucose (301).”

What the sources say

• Not checked yetcites [301] Wong, 2013, A novel mechanism regulating insulin secretion involving Herpud1 in mice, Diabetologia source

In the paper

“Moreover, important advances have been made in quantifying the metabolic spectrum in C. elegans (299).”

What the sources say

• Not checked yetcites [299] Gao, 2017, A sensitive mass spectrometry platform identifies metabolic changes of life history traits in C. elegans, Sci Rep source

In the paper

“For instance, genome-scale models of cancer metabolism can help us comprehend the complexity of human cancer heterogeneity in relation to substrate preference and therefore expedite the discovery of putative anticancer targets (285).”

What the sources say

• Not checked yetcites [285] Lewis, 2013, The evolution of genome-scale models of cancer metabolism, Front Physiol source

In the paper

“suggested that insulin resistance in one tissue created a knock-on effect in other tissues that tries to compensate for the reduced flexibility”

What the sources say

• Not checked yetcites [312] Pearson, 2016, The effects of insulin resistance on individual tissues: an application of a mathematical model of metabolism in humans, Bull Math Biol source

In the paper

“For instance, vitamin C and bile acid synthesis pathways are different in rats and humans (303).”

What the sources say

• Not checked yetcites [303] Blais, 2017, Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions, Nat Commun source

In the paper

“As such, systems biological approaches can represent, analyze, and predict the behavior of the whole system (158).”

What the sources say

• Not checked yetcites [158] Calçada, 2014, The role of low-grade inflammation and metabolic flexibility in aging and nutritional modulation thereof: a systems biology approach, Mech Ageing Dev source

In the paper

“A good example of this is the global human metabolic network, Recon 1, which was released in 1997 (308).”

What the sources say

• Not checked yetcites [308] Bordbar, 2012, Using the reconstructed genome-scale human metabolic network to study physiology and pathology, J Intern Med source

In the paper

“Among other topics, Recon is used to predict biomarkers for inborn errors of metabolism, to identify drug targets and possible side effects, and to study cancer metabolism and the interactions between microorganisms and their host (310).”

What the sources say

• Not checked yetcites [310] Swainston, 2016, Recon 2.2: from reconstruction to model of human metabolism, Metabolomics source

In the paper

“The round worm Caenorhabditis elegans, for instance, is used to investigate metabolic pathways and has been instrumental in elucidating key genetic regulators of metabolism in relation to lifespan (36, 293, 294).”

What the sources say

• Not checked yetcites [36] Kapahi, 2017, Dietary restriction and lifespan: lessons from invertebrate models, Ageing Res Rev source
• Not checked yetcites [293] Maglioni, 2016, C. elegans as a model organism for human mitochondrial associated disorders, Mitochondrion source
• Not checked yetcites [294] Lapierre, 2012, Lessons from C. elegans: signaling pathways for longevity, Trends Endocrinol Metab source

In the paper

“Finally, metabolic flexibility modeling can give us insight into the evolution of metabolic pathways (291), demonstrating that genes encoding enzymes with high connectivity and high metabolic flux have a greater chance of conservation (12) and are the most likely sites of metabolic regulation (292).”

What the sources say

• Not checked yetcites [291] Abedpour, 2015, Resource constrained flux balance analysis predicts selective pressure on the global structure of metabolic networks, BMC Syst Biol source
• Not checked yetcites [12] Vitkup, 2006, Influence of metabolic network structure and function on enzyme evolution, Genome Biol source
• Not checked yetcites [292] Kuehne, 2017, Metabolic network segmentation: a probabilistic graphical modeling approach to identify the sites and sequential order of metabolic regulation from non-targeted metabolomics data, PLOS Comput Biol source

In the paper

“Labeling with [1,2-13C]-glucose and [U-13C]-glutamine revealed considerable differences in metabolic pathway fluxes between the exponential growth and stationary phase of Chinese hamster ovary cells. Specifically, glycolytic flux and lactate production was high and PPP flux low in the exponential growth phase, which was collectively reversed in the stationary phase concomitant with lactate”

What the sources say

• Not checked yetcites [288] Ahn, 2013, Parallel labeling experiments with [1,2-(13)C]glucose and [U-(13)C]glutamine provide new insights into CHO cell metabolism, Metab Eng source

In the paper

“Inbred lines have been generated for C. elegans (295) and, recently, metabolic network models became available (296, 297).”

What the sources say

• Not checked yetcites [295] Doroszuk, 2009, A genome-wide library of CB4856/N2 introgression lines of Caenorhabditis elegans, Nucleic Acids Res source
• Not checked yetcites [296] Yilmaz, 2016, A Caenorhabditis elegans genome-scale metabolic network model, Cell Syst source
• Not checked yetcites [297] Gebauer, 2016, A genome-scale database and reconstruction of Caenorhabditis elegans metabolism, Cell Syst source

In the paper

“For example, mice have been the driving force behind research into CR (300), and the use of recombinant inbred lines such as the BXD mouse strains now offer insights into the role of genetic background effects and can help translate the differences between gene variants into meaningful data for human populations and disease.”

What the sources say

• Not checked yetcites [300] Demetrius, 2005, Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans, EMBO Rep source

In the paper

“The model also simulated that insulin resistance causes fatty liver regardless of the site of insulin resistance in the body”

What the sources say

• Not checked yetcites [312] Pearson, 2016, The effects of insulin resistance on individual tissues: an application of a mathematical model of metabolism in humans, Bull Math Biol source

In the paper

“Such a multilayered cross-omics approach can help elucidate complex traits associated with metabolic flexibility (302).”

What the sources say

• Not checked yetcites [302] Williams, 2016, Systems proteomics of liver mitochondria function, Science source

In the paper

“The natural variation in gene expression that is present in the human population is also recapitulated in these models and therefore more honestly reflect genotype-phenotype associations than artificial loss-of-function situations, such as gene knockouts or knock-down experiments (82).”

What the sources say

• Not checked yetcites [82] Houtkooper, 2010, Metabolic networks of longevity, Cell source

In the paper

“Methodological differences can severely impact interpretation of study data (106), advocating for a gold-standard application of available methods and technology.”

What the sources say

• Not checked yetcites [106] Dubé, 2014, Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance, Am J Physiol Endocrinol Metab source

In the paper

“A community-driven reconstruction, Recon 2, was released in 2013 and included 65 cell type–specific models (309).”

What the sources say

• Not checked yetcites [309] Thiele, 2013, A community-driven global reconstruction of human metabolism, Nat Biotechnol source

In the paper

“Genome-scale metabolic models can also be applied to investigate genetic variation in genotype-phenotype interactions and as such can be used to identify metabolic biomarkers and discover treatments based on genetic markers (311).”

What the sources say

• Not checked yetcites [311] McGarrity, 2016, Understanding the causes and implications of endothelial metabolic variation in cardiovascular disease through genome-scale metabolic modeling, Front Cardiovasc Med source

In the paper

“Recent advances in metabolite extraction from isolated mitochondria demonstrate that metabolic flux models can be built with increasing precision (289).”

What the sources say

• Not checked yetcites [289] Chen, 2016, Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism, Cell source

In the paper

“However, metabolic flexibility is likely best understood as a system of interacting components (282).”

What the sources say

• Not checked yetcites [282] van Ommen, 2014, Phenotypic flexibility as key factor in the human nutrition and health relationship, Genes Nutr source

In the paper

“Metabolic flux analysis, flux balance analysis, and metabolic pathway analysis are among the most popular tools in stoichiometric network analysis and are used extensively to study (cancer) metabolism (284, 285).”

What the sources say

• Not checked yetcites [284] Orman, 2011, Advanced stoichiometric analysis of metabolic networks of mammalian systems, Crit Rev Biomed Eng source
• Not checked yetcites [285] Lewis, 2013, The evolution of genome-scale models of cancer metabolism, Front Physiol source

In the paper

“To standardize and validate phenotyping in mice, standard operating procedures were developed by the Eumorphia program to ensure that test outcomes are comparable between different laboratories (307).”

What the sources say

• Not checked yetcites [307] Argmann, 2005, Mouse phenogenomics: the fast track to “systems metabolism, Cell Metab source

In the paper

“Metabolic flexibility is likely best understood as a system of interacting components to manage energy resources and requirements in health and disease”

What the sources say

• Not checked yetcites [289] Chen, 2016, Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism, Cell source

In the paper

“great progress has been made over the past few decades to understand its underpinnings”

What the sources say

• Not checked yetcites [107] Goodpaster, 2017, Metabolic flexibility in health and disease, Cell Metab source

In the paper

“because of the complexity of metabolic flexibility, many ends remain untied and solid translational steps are often missing”

In the paper

“The wealth of available preclinical data suggests that metabolic flexibility is the cornerstone of many (patho)biological processes.”

In the paper

“The use of isotope labeling to determine metabolic flux and substrate preference is a common practice”

What the sources say

• Not checked yetcites [319] Amoedo, 2017, Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy, Biochim Biophys Acta source

In the paper

“it is evident that metabolic flexibility can be placed in the broad context of health and disease”

In the paper

“It is this wealth, however, that hampers translation to applicable human interventions.”

In the paper

“the situation portrayed here does not necessarily reflect that of each individual”

In the paper

“Flux measurements can aptly portray the dynamics of metabolism, whereas protein and gene expression analyses are typically static snapshots in time.”

In the paper

“Besides abating metabolic inflexibility such strategies may even prolong health span and lifespan.”

In the paper

“Together with the endocrine system, mitochondria orchestrate the metabolic reprogramming necessary to sustain cell function in both healthy and pathological conditions.”