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

May combine two claims.

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.

“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).”

• cites [23] Marinou, 2011, Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men, Br J Nutr sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds influence metabolic flexibility.

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

May combine two claims.

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.

“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.”

• cites [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 sourceNot checked yet

  Not checked in the free run.

• cites [12] Vitkup, 2006, Influence of metabolic network structure and function on enzyme evolution, Genome Biol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

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

“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.”

Probably not a substantial claim: may not pass S4 (based).

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

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

Probably not a substantial claim: may not pass S4 (based).

Mitochondria play a crucial role in determining metabolic flexibility.

“Mitochondria play a crucial role in determining metabolic flexibility”

Probably not a substantial claim: may not pass S4 (based).

Disrupted metabolic flexibility (metabolic inflexibility) is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer.

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

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Molecular and signaling pathways drive metabolic flexibility and often serve as metabolic sensors.

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

Probably not a substantial claim: may not pass S4 (based).

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

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

May combine two claims.

Metabolic inflexibility is a hallmark of many age-related metabolic diseases and also plays a central role in cancer and immune metabolism.

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

May combine two claims.

Near continuous intake of calorically dense processed foods combined with physical inactivity reduces a predilection for, and directly impedes, metabolic flexibility.

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

• cites [3] López-Otín, 2016, Metabolic control of longevity, Cell sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The modern era is characterized by unprecedented levels of food supply.

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

• cites [2] Speakman, 2013, Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints, Annu Rev Nutr sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mitochondria adapt their morphology to nutrient availability and in doing so regulate OXPHOS activity and substrate preference.

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

• cites [90] Cogliati, 2013, Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency, Cell sourceNot checked yet

  Not checked in the free run.

• cites [91] Cogliati, 2016, Mitochondrial cristae: where beauty meets functionality, Trends Biochem Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Upon consumption of a high-fat diet, lean subjects with adequate metabolic flexibility are able to increase fatty acid oxidation at the expense of glucose, whereas obese individuals are not.

“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).”

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Insulin-resistant obese patients manifest a lesser reliance on fatty acid oxidation compared with lean individuals and do not show increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusion.

“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.”

• cites [8] Kelley, 1999, Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss, Am J PhysiolNot checked yet

  Not checked in the free run.

• cites [9] Kelley, 2000, Fuel selection in human skeletal muscle in insulin resistance: a reexamination, Diabetes sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Glucagon stimulates hepatic glycogenolysis and ketogenesis, and decreased insulin suppresses hepatocyte malonyl-CoA synthesis and lipogenesis, with concomitant activation of fatty acid oxidation.

“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).”

• cites [21] Ramnanan, 2011, Physiologic action of glucagon on liver glucose metabolism, Diabetes Obes Metab sourceNot checked yet

  Not checked in the free run.

• cites [22] McGarry, 1980, Regulation of hepatic fatty acid oxidation and ketone body production, Annu Rev Biochem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Under the influence of insulin, the liver absorbs glucose from the circulation and stops glycogenolysis and gluconeogenesis.

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

May combine two claims.

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 clearance of circulating triacylglycerol.

“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).”

• cites [19] Frayn, 2002, Adipose tissue as a buffer for daily lipid flux, Diabetologia sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Adipose tissue responds to insulin by decreasing lipolysis and stimulating fatty acid and triacylglycerol synthesis from lipids and glucose.

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

• cites [18] Dimitriadis, 2011, Insulin effects in muscle and adipose tissue, Diabetes Res Clin Pract sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

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.

“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).”

• cites [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) sourceNot checked yet

  Not checked in the free run.

• cites [14] van Ommen, 2009, Challenging homeostasis to define biomarkers for nutrition related health, Mol Nutr Food Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

During the postprandial period of a carbohydrate-rich meal, pancreatic β cells respond to the rise in nutrients by releasing insulin, increasing the insulin-glucagon ratio.

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The concept of metabolic flexibility is particularly linked to the capacity of mitochondria to select fuel in response to nutritional changes, placing mitochondrial function at its core.

“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).”

• cites [4] Muoio, 2014, Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock, Cell sourceNot checked yet

  Not checked in the free run.

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Ectopic fat deposition is related to metabolic abnormalities and defects in insulin sensitivity, T2DM, cardiovascular disease, and cancer.

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

• cites [143] Tahergorabi, 2016, From obesity to cancer: a review on proposed mechanisms, Cell Biochem Funct sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [110] Kumar, 2012, Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells, Biochem Biophys Res Commun sourceNot checked yet

  Not checked in the free run.

• cites [111] Vettorazzi, 2016, The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells, Metabolism sourceNot checked yet

  Not checked in the free run.

• cites [112] Thomas, 2009, TGR5-mediated bile acid sensing controls glucose homeostasis, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

• cites [113] Alamri, 2016, The role of ghrelin in the regulation of glucose homeostasis, Horm Mol Biol Clin Investig sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [24] Paniagua, 2016, Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome, World J Diabetes sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [136] Ozanne, 2007, Mechanisms of disease: the developmental origins of disease and the role of the epigenotype, Nat Clin Pract Endocrinol Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Adiponectin suppresses glucose production in the liver and enhances FAO in skeletal muscle.

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

• cites [117] Coles, 2016, Adipokines in healthy skeletal muscle and metabolic disease, Adv Exp Med Biol sourceNot checked yet

  Not checked in the free run.

• cites [118] Yamauchi, 2002, Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase, Nat Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

May combine two claims.

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

“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).”

• cites [169] Johnson, 2016, Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation, Mol Metab sourceNot checked yet

  Not checked in the free run.

• cites [170] Van den Bossche, 2016, Mitochondrial dysfunction prevents repolarization of inflammatory macrophages, Cell Reports sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mitochondrial respiration is not impaired in cancer cells; instead, cancer cells emphasize acquisition and generation of building blocks necessary for cell division by enhancing biosynthetic metabolism using glycolytic intermediates.

“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).”

• cites [209] Lunt, 2011, Aerobic glycolysis: meeting the metabolic requirements of cell proliferation, Annu Rev Cell Dev Biol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Metabolic syndrome is associated with a 33% elevated total cancer mortality.

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

• cites [184] Gathirua-Mwangi, 2017, Metabolic syndrome and total cancer mortality in the Third National Health and Nutrition Examination Survey, Cancer Causes Control sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Metabolic inflexibility drives sepsis-related innate immunoparalysis as the metabolism through glycolysis, β-oxidation, and OXPHOS pathways in leukocytes is downregulated.

“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).”

• cites [171] Cheng, 2016, Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis, Nat Immunol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

TCA cycle intermediates are not solely used to produce NADH for mitochondrial respiration; they can also be used to form nonessential amino acids and fatty acids, which facilitate protein synthesis, membrane construction, and cholesterol synthesis.

“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).”

• cites [206] Pavlova, 2016, The emerging hallmarks of cancer metabolism, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Obesity can cause metabolic inflexibility of the heart and alter substrate selection.

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

• cites [179] Pascual, 2016, Fuel availability and fate in cardiac metabolism: a tale of two substrates, Biochim Biophys Acta sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Increased glucose uptake and metabolism in cancer is very often mediated by the oncogenic signaling protein Ras, which activates the PI3K/Akt pathway; PI3K/Akt signaling increases GLUT1 expression and translocation to the cell surface and enhances HK and phosphofructokinase activity, capturing glucose and increasing glycolytic flux.

“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).”

• cites [196] Muñoz-Pinedo, 2012, Cancer metabolism: current perspectives and future directions, Cell Death Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Macrophages that rely on fatty acid metabolism secrete anti-inflammatory cytokines and thus preserve insulin sensitivity of liver and adipose tissue (type M2).

“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).”

• cites [167] Johnson, 2012, The inflammation highway: metabolism accelerates inflammatory traffic in obesity, Immunol Rev sourceNot checked yet

  Not checked in the free run.

• cites [168] Kang, 2008, Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Reducing metabolic flexibility in cancer cells may lead to potential treatment options, because metabolic interference can come at a substantial cost to oncogenic potential.

“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).”

• cites [1] Olson, 2016, Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies, Trends Biochem Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The failing heart becomes metabolically inflexible with a decreased capacity to use fatty acids and an increased dependence on glucose metabolism.

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

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

• cites [214] Sullivan, 2015, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Alternative glycolytic branching 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.

“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.”

• cites [196] Muñoz-Pinedo, 2012, Cancer metabolism: current perspectives and future directions, Cell Death Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tumor cells do not become metabolically hardwired but remain able to reroute metabolism to adapt to their phenotype and the newly acquired environment.

“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).”

• cites [200] Herst, 2013, Cell hierarchy, metabolic flexibility and systems approaches to cancer treatment, Curr Pharm Biotechnol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Lactate produced from glycolysis is excreted from the cell or used in biosynthetic reactions such as aspartate synthesis.

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

• cites [1] Olson, 2016, Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies, Trends Biochem Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Type II glycolytic muscle fiber density is higher in obese and insulin-resistant patients, although it is unknown whether this is due to inactivity or impaired glucose metabolism.

“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).”

• cites [226] da Silva Aragão, 2014, Maternal protein restriction impairs the transcriptional metabolic flexibility of skeletal muscle in adult rat offspring, Br J Nutr sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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.”

• cites [229] Sepa-Kishi, 2016, Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism, Exerc Sport Sci Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Acute AMPK activation reduces glycogen and protein synthesis while promoting glucose transport and FAO.

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

• cites [222] Egan, 2013, Exercise metabolism and the molecular regulation of skeletal muscle adaptation, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [206] Pavlova, 2016, The emerging hallmarks of cancer metabolism, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Particularly combined with weight loss, exercise training improves insulin sensitivity, mitochondrial content, and fasting FAO.

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

• cites [220] Bergouignan, 2013, Effect of contrasted levels of habitual physical activity on metabolic flexibility, J Appl Physiol (1985) sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the human heart, exercise reduces cardiometabolic risk factors by increasing insulin sensitivity, decreasing cardiac lipid content, and improving glucose tolerance.

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

• cites [232] Vettor, 2014, Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism, Am J Physiol Endocrinol Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Glutamine can be used as an anaplerotic substrate in the TCA cycle, a carbon and nitrogen donor, or for production of purine and pyrimidine nucleotides necessary for DNA replication.

“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).”

• cites [216] Tardito, 2015, Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma, Nat Cell Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Glutamine is an essential nutrient for cancer proliferation, and its dependency is referred to as glutamine addiction.

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

• cites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

“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.”

• cites [94] Wüst, 2013, On-off asymmetries in oxygen consumption kinetics of single Xenopus laevis skeletal muscle fibres suggest higher-order control, J Physiol sourceNot checked yet

  Not checked in the free run.

• cites [177] Wüst, 2017, Rapid frequency-dependent changes in free mitochondrial calcium concentration in rat cardiac myocytes, J Physiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A high-intensity exercise training program showed elevated citrate synthase and β-hydroxyacyl CoA dehydrogenase activity after 5 days and increased levels of mitochondrial complexes after 10 days.

“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).”

• cites [51] Perry, 2010, Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle, J Physiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both aerobic and anaerobic/glycolytic exercise promote considerable health benefits such as increased mitochondrial content and improvements in glycemic control.

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

• cites [222] Egan, 2013, Exercise metabolism and the molecular regulation of skeletal muscle adaptation, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [137] Kirchner, 2013, Epigenetic flexibility in metabolic regulation: disease cause and prevention, Trends Cell Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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.”

• cites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA sourceNot checked yet

  Not checked in the free run.

May combine two claims.

High-fat feeding in mice induced PGC1α hypermethylation that was transferable to the offspring; maternal exercise prevented high-fat feeding hypermethylation of PGC1α and mitigated epigenetic associated metabolic dysfunction in the offspring.

“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).”

• cites [138] Barrès, 2016, The role of diet and exercise in the transgenerational epigenetic landscape of T2DM, Nat Rev Endocrinol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Glutamine addiction is beneficial for the cancer cell because it maintains mitochondrial TCA cycle integrity and provides large quantities of NADPH needed to meet the demands of cell proliferation.

“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).”

• cites [215] Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci USA sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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 caloric restriction in obese subjects.

“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).”

• cites [253] Timmers, 2011, Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans, Cell Metab sourceNot checked yet

  Not checked in the free run.

• cites [254] Bhatt, 2012, Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus, Nutr Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

AICAR 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.

“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).”

• cites [255] Komen, 2014, Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models, Br J Pharmacol sourceNot checked yet

  Not checked in the free run.

• cites [256] Narkar, 2008, AMPK and PPARdelta agonists are exercise mimetics, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Caloric restriction without hunger- or disease-related malnutrition in animals and humans results in healthier aging through improved metabolic health, reduced obesity, and reduced risk of T2DM, cancer, and cardiovascular disease.

“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).”

• cites [236] Mattison, 2017, Caloric restriction improves health and survival of rhesus monkeys, Nat Commun sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Caloric restriction is considered the most robust intervention to increase longevity in animal model systems and ameliorate age-associated disease in primates and humans.

“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).”

• cites [38] Fontana, 2015, Promoting health and longevity through diet: from model organisms to humans, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [242] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J Biol Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

• cites [242] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J Biol Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

“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).”

• cites [214] Sullivan, 2015, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Resveratrol 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.

“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)].”

• cites [247] de Ligt, 2015, Resveratrol and obesity: can resveratrol relieve metabolic disturbances, Biochim Biophys Acta sourceNot checked yet

  Not checked in the free run.

May combine two claims.

AICAR improves skeletal muscle glucose uptake and transport, fatty acid uptake, mitochondrial protein content, and insulin sensitivity in mice.

“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).”

• cites [223] Kjøbsted, 2017, Enhanced muscle insulin sensitivity after contraction/exercise is mediated by AMPK, Diabetes sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Metformin is one of the first-line treatments of patients with T2DM, and has also been used to treat patients at risk for T2DM, such as those with metabolic syndrome.

“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).”

• cites [87] Fadini, 2011, At the crossroads of longevity and metabolism: the metabolic syndrome and lifespan determinant pathways, Aging Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Intermittent fasting in rodents improved insulin and leptin sensitivity, increased ketone body levels, and reduced adiposity and inflammation.

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

• cites [235] Mattson, 2017, Impact of intermittent fasting on health and disease processes, Ageing Res Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [37] Madeo, 2015, Essential role for autophagy in life span extension, J Clin Invest sourceNot checked yet

  Not checked in the free run.

• cites [249] Andreux, 2013, Pharmacological approaches to restore mitochondrial function, Nat Rev Drug Discov sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Resveratrol treatment increased physical endurance and protected from high-fat diet-induced muscle accumulation of diacylglyceride and ceramide, and related mitochondrial dysfunction.

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

• cites [248] Um, 2010, AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol, Diabetes sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In patients with T2DM, carnitine acetyltransferase expression is severely perturbed, and free carnitine concentrations in diabetic mice are decreased compared with controls.

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

• cites [243] Muoio, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab sourceNot checked yet

  Not checked in the free run.

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

“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).”

• cites [229] Sepa-Kishi, 2016, Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism, Exerc Sport Sci Rev sourceNot checked yet

  Not checked in the free run.

• cites [257] Russell, 1999, Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR, Am J PhysiolNot checked yet

  Not checked in the free run.

May combine two claims.

l-carnitine supplementation improves metabolic flexibility by decreasing plasma glucose and insulin levels and increasing PDH activity in muscle of insulin-resistant subjects.

“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).”

• cites [243] Muoio, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

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

• cites [240] Zarrinpar, 2016, Daily eating patterns and their impact on health and disease, Trends Endocrinol Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Metformin reduces hepatic glucose production and increases insulin sensitivity by activating AMPK, although several AMPK-independent mechanisms have been proposed.

“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)].”

• cites [246] Pryor, 2015, Repurposing metformin: an old drug with new tricks in its binding pockets, Biochem J sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Animal studies demonstrated that resveratrol could stimulate energy expenditure and protect against a high-fat diet-induced weight gain via induction of FAO and reduced lipogenesis, mediated by activation of the AMPK-SIRT1 axis.

“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).”

• cites [250] Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell sourceNot checked yet

  Not checked in the free run.

• cites [251] Baur, 2006, Resveratrol improves health and survival of mice on a high-calorie diet, Nature sourceNot checked yet

  Not checked in the free run.

• cites [252] Shang, 2008, Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase, Acta Pharmacol Sin sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Although weight loss is generally achieved in overweight and obese subjects, potential adverse effects exist for leaner subjects.

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

• cites [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) sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Thiazolidinediones, such as rosiglitazone, potently activate PPARγ and lower blood glucose levels in patients with T2DM.

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

• cites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol sourceNot checked yet

  Not checked in the free run.

• cites [273] Sugii, 2009, PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization, Proc Natl Acad Sci USA sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Thiazolidinediones improve skeletal muscle glucose disposal via upregulation of GLUT1, decrease liver glucose output, and improve the lipid-buffering capacity of WAT and hepatic steatosis.

“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).”

• cites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol sourceNot checked yet

  Not checked in the free run.

• cites [273] Sugii, 2009, PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization, Proc Natl Acad Sci USA sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

“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).”

• cites [264] Cantó, 2012, The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity, Cell Metab sourceNot checked yet

  Not checked in the free run.

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [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 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Rapamycin has earned great interest over the years to prolong lifespan, even when administered to aged animals.

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

• cites [195] Riera, 2015, Tipping the metabolic scales towards increased longevity in mammals, Nat Cell Biol sourceNot checked yet

  Not checked in the free run.

• cites [280] Kennedy, 2016, The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging, Cell Metab sourceNot checked yet

  Not checked in the free run.

• cites [281] Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [249] Andreux, 2013, Pharmacological approaches to restore mitochondrial function, Nat Rev Drug Discov sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

“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).”

• cites [279] Li, 2014, Rapamycin: one drug, many effects, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nicotinamide mononucleotide conversion to NAD+ activates SIRT1 and improves glucose homeostasis in mice.

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

• cites [42] Houtkooper, 2012, Sirtuins as regulators of metabolism and healthspan, Nat Rev Mol Cell Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

SIRT3 is localized in the mitochondrial matrix and targets many proteins involved in metabolic homeostasis, including OXPHOS subunits.

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

• cites [42] Houtkooper, 2012, Sirtuins as regulators of metabolism and healthspan, Nat Rev Mol Cell Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Acetylation of mitochondrial proteins propagates metabolic inflexibility and deacetylation promotes metabolic flexibility.

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

• cites [178] Griffin, 2016, Nutrient sensing and utilization: getting to the heart of metabolic flexibility, Biochimie sourceNot checked yet

  Not checked in the free run.

• cites [259] Bleeker, 2016, Sirtuin activation as a therapeutic approach against inborn errors of metabolism, J Inherit Metab Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

PPARs are lipid sensors that transcriptionally modulate metabolic programs in response to nutrition and are interesting drug targets to improve metabolic flexibility.

“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)].”

• cites [269] Bugge, 2017, PPAR agonists, - could tissue targeting pave the way, Biochimie sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [277] Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Poly (ADP-ribose) polymerase inhibition rescued mitochondrial respiration defects and increased FAO in myotubes from obese patients by augmenting mitochondrial function.

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

• cites [268] Pirinen, 2014, Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Pharmacological inhibition of poly (ADP-ribose) polymerase in mice activates SIRT1 and increases mitochondrial respiratory capacity, leading to augmented fitness and protection from diet-induced obesity.

“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).”

• cites [268] Pirinen, 2014, Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

mTOR signaling is dysregulated in cancer, T2DM and obesity, and is therefore actively pursued as a promising drug target.

“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)].”

• cites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell sourceNot checked yet

  Not checked in the free run.

• cites [278] Albert, 2015, mTOR signaling in cellular and organismal energetics, Curr Opin Cell Biol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There are three PPAR isotypes (PPARα, PPARβ/δ, and PPARγ), which differ in ligand affinity and tissue distribution.

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

• cites [270] Gross, 2017, PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD, Nat Rev Endocrinol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In insulin-deficient mice, bezafibrate improves impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity.

“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).”

• cites [255] Komen, 2014, Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models, Br J Pharmacol sourceNot checked yet

  Not checked in the free run.

• cites [271] Franko, 2016, Bezafibrate improves insulin sensitivity and metabolic flexibility in STZ-induced diabetic mice, Diabetes sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nicotinamide mononucleotide administration to mice enhances energy metabolism, promotes physical activity, improves lipid profiles, and ameliorates age-related pathophysiology.

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

• cites [267] Mills, 2016, Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice, Cell Metab sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

mTOR is a central regulator of growth and metabolism in all eukaryotes and its activity depends on the cell's energy and nutrient levels.

“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)].”

• cites [275] Laplante, 2012, mTOR signaling in growth control and disease, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Prolonged rapamycin treatment improves metabolic profiles, increases oxygen consumption and ketogenesis, and markedly enhances insulin sensitivity.

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