Ketone body metabolism and cardiometabolic implications for cognitive health
Okunogbe A., Nugent R., Spencer G., Ralston J., Wilding J. Economic impacts of overweight and obesity: current and future estimates for 161 countries. BMJ Glob. Health. 2022;7: ARTN e009773. https://doi.org/10.1136/bmjgh-2022-009773.
Huai P. C., Liu J., Ye X., Li W. Q. Association of central obesity with all cause and cause-specific mortality in US adults: A prospective cohort study. Front. Cardiovasc. Medicine. 2022;9: ARTN 816144. https://doi.org/10.3389/fcvm.2022.816144.
Michalsen V. L. et al Obesity measures, metabolic health and their association with 15-year all-cause and cardiovascular mortality in the SAMINOR 1 Survey: a population-based cohort study. BMC Cardiovasc. Disord. 2021;21. ARTN 510. https://doi.org/10.1186/s12872-021-02288-9.
Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).
Google Scholar
Ferrante, A. W. Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J. Intern. Med. 262, 408–414 (2007).
Google Scholar
Campbell, P., Rutten, F. H., Lee, M. M., Hawkins, N. M. & Petrie, M. C. Heart failure with preserved ejection fraction: everything the clinician needs to know. Lancet 403, 1083–1092 (2024).
Google Scholar
de la Monte, S. M., Longato, L., Tong, M. & Wands, J. R. Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr. Opin. Invest Dr 10, 1049–1060 (2009).
Dewidar, B. et al. Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases. EBioMedicine 94, 104714 (2023).
Google Scholar
Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).
Google Scholar
Fan, J., Krautkramer, K. A., Feldman, J. L. & Denu, J. M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10, 95–108 (2015).
Google Scholar
Zhu, J. J. & Thompson, C. B. Metabolic regulation of cell growth and proliferation. Nat. Rev. Mol. Cell Biol. 20, 436–450 (2019).
Google Scholar
Lee, I. H. & Finkel, T. Metabolic regulation of the cell cycle. Curr. Opin. Cell Biol. 25, 724–729 (2013).
Google Scholar
Hall, S. E., Wastney, M. E., Bolton, T. M., Braaten, J. T. & Berman, M. Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation. J. Lipid Res 25, 1184–1194 (1984).
Google Scholar
Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J. Clin. Investig. 106, 473–481 (2000).
Google Scholar
Dunn, L. et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol. Aging 35, 1111–1115 (2014).
Google Scholar
Kim, D. Y., Park, J. & Han, I. O. Hexosamine biosynthetic pathway and -GlcNAc cycling of glucose metabolism in brain function and disease. Am. J. Physiol.-Cell Physiol. 325, C981–C998 (2023).
Google Scholar
Wilder, R. The effect of ketonemia on the course of epilepsy. MAYO Clin. Proc. 2, 307–308 (1921).
Shippy, D. C., Wilhelm, C., Viharkumar, P. A., Raife, T. J. & Ulland, T. K. beta-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology. J. Neuroinflamm. 17, 280 (2020).
Google Scholar
Yin, J. X. et al. Ketones block amyloid entry and improve cognition in an Alzheimer’s model. Neurobiol. Aging 39, 25–37 (2016).
Google Scholar
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017). PMCID: PMC5313038.
Google Scholar
Kivimäki M. et al. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ-Brit Med J. 2019;365. ARTN l1495. https://doi.org/10.1136/bmj.l1495.
Taylor, M. K., Sullivan, D. K., Mahnken, J. D., Burns, J. M. & Swerdlow, R. H. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement (N. Y) 4, 28–36 (2017).
Google Scholar
Ota, M. et al. Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer’s disease. Neurosci. Lett. 690, 232–236 (2019).
Google Scholar
Hegardt, F. G. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem J. 338, 569–582 (1999).
Google Scholar
Quant, P. A., Tubbs, P. K. & Brand, M. D. Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme. Eur. J. Biochem 187, 169–174 (1990).
Google Scholar
von Meyenn, F. et al. Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell Metab. 17, 436–447 (2013).
Google Scholar
Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).
Google Scholar
Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).
Google Scholar
Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic Fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).
Google Scholar
Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. MAYO Clin. Proc. 55, 434–438 (1980).
Google Scholar
Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Investig. 114, 147–152 (2004).
Google Scholar
Lee, S. et al. Impaired ketogenesis is associated with metabolic-associated fatty liver disease in subjects with type 2 diabetes. Front Endocrinol. 14, 1124576 (2023).
Google Scholar
Mey J. T. et al. beta-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro. Am. J. Physiol. Endocrinol. Metab. (2020).
Hughey C. C., Puchalska P., Crawford P. A. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim. et Biophys. Acta (BBA) – Mol. Cell Biol. Lipids. 2022:159209. https://doi.org/10.1016/j.bbalip.2022.159209.
Fletcher, J. A. et al. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 5, e127737 (2019).
Google Scholar
Sunny, N. E., Parks, E. J., Browning, J. D. & Burgess, S. C. Excessive hepatic mitochondrial TCA Cycle and Gluconeogenesis in Humans with Nonalcoholic Fatty Liver Disease. Cell Metab. 14, 804–810 (2011).
Google Scholar
Reaven, G. M. Pathophysiology of insulin-resistance in human-disease. Physiol. Rev. 75, 473–486 (1995).
Google Scholar
Harrison, H. C. & Long, C. N. H. The distribution of ketone bodies in tissues. J. Biol. Chem. 133, 209–218 (1940).
Google Scholar
Halestrap, A. P. The monocarboxylate transporter family–Structure and functional characterization. IUBMB Life 64, 1–9 (2012).
Google Scholar
Balasse, E. O. & Fery, F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diab./Metab. Rev. 5, 247–270 (1989).
Google Scholar
Valente-Silva, P., Lemos, C., Köfalvi, A., Cunha, R. A. & Jones, J. G. Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices. NMR Biomed. 28, 1111–1116 (2015).
Google Scholar
Sato, K. et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9, 651–658 (1995).
Google Scholar
Endemann, G., Goetz, P. G., Edmond, J. & Brunengraber, H. Lipogenesis from ketone bodies in the isolated perfused rat liver. Evidence for the cytosolic activation of acetoacetate. J. Biol. Chem. 257, 3434–3440 (1982).
Google Scholar
Robinson, A. M. & Wlliamson, D. H. Utilization of D-3-hydroxy[3-14C]butyrate for lipogenesis in vivo in lactating rat mammary gland. Biochem. J. 176, 635–638 (1978).
Geelen, M. J., Lopes-Cardozo, M. & Edmond, J. Acetoacetate: a major substrate for the synthesis of cholesterol and fatty acids by isolated rat hepatocytes. FEBS Lett. 163, 269–273 (1983).
Google Scholar
Hasegawa, S. et al. Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels. Mol. Genet. Metab. 107, 553–560 (2012).
Google Scholar
Hasegawa, S. et al. Acetoacetyl-CoA synthetase is essential for normal neuronal development. Biochem. Biophys. Res Commun. 427, 398–403 (2012).
Google Scholar
Bergstrom, J. D. The lipogenic enzyme acetoacetyl-CoA synthetase and ketone body utilization for denovo lipid synthesis, a review. J. Lipid Res. 64, 100407 (2023).
Google Scholar
Taggart, A. K. et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005).
Google Scholar
Fu, S. P. et al. β-Hydroxybutyric acid inhibits growth hormone-releasing hormone synthesis and secretion through the GPR109A/extracellular signal-regulated 1/2 signalling pathway in the hypothalamus. J. Neuroendocrinol. 27, 212–222 (2015).
Google Scholar
Rahman, M. et al. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat. Commun. 5, 3944 (2014).
Google Scholar
Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl Acad. Sci. USA 108, 8030–8035 (2011).
Google Scholar
Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Google Scholar
Xie, Z. et al. Metabolic regulation of gene expression by Histone Lysine beta-Hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).
Google Scholar
Miyamoto, J. et al. Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proc. Natl Acad. Sci. USA 116, 23813–23821 (2019).
Google Scholar
Fenselau, A. & Wallis, K. 3-oxo acid coenzyme A-transferase in normal and diabetic rat muscle. Biochem. J. 158, 509–512 (1976).
Google Scholar
Grinblat, L., Pacheco Bolanos, L. F. & Stoppani, A. O. Decreased rate of ketone-body oxidation and decreased activity of D-3-hydroxybutyrate dehydrogenase and succinyl-CoA:3-oxo-acid CoA-transferase in heart mitochondria of diabetic rats. Biochem. J. 240, 49–56 (1986).
Google Scholar
Turko, I. V., Marcondes, S. & Murad, F. Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase. Am. J. Physiol. Heart Circ. Physiol. 281, H2289–H2294 (2001).
Google Scholar
Nyenwe, E. A. & Kitabchi, A. E. The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management. Metabolism 65, 507–521 (2016).
Google Scholar
Owen, O. E. et al. Brain metabolism during fasting. J. Clin. Invest 46, 1589–1595 (1967).
Google Scholar
Cotter, D. G., d’Avignon, D. A., Wentz, A. E., Weber, M. L. & Crawford, P. A. Obligate role for ketone body oxidation in neonatal metabolic homeostasis. J. Biol. Chem. 286, 6902–6910 (2011). PMCID: PMC3044945.
Google Scholar
Fukao, T. et al. A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency. Mol. Genet. Metab. 89, 280–282 (2006).
Google Scholar
Qiu, C. X., De Ronchi, D. & Fratiglioni, L. The epidemiology of the dementias: an update. Curr. Opin. Psychiatr. 20, 380–385 (2007).
Google Scholar
Xu, W. L. et al. Midlife overweight and obesity increase late-life dementia risk A population-based twin study. Neurology 76, 1568–1574 (2011).
Google Scholar
Whitmer, R. A., Gunderson, E. P., Barrett-Connor, E., Quesenberry, C. P. & Yaffe, K. Obesity in middle age and future risk of dementia: a 27-year longitudinal population-based study. BMJ-Brit. Med. J. 330, 1360–1362b (2005).
Google Scholar
Schubert, D. Glucose metabolism and Alzheimer’s disease. Ageing Res. Rev. 4, 240–257 (2005).
Google Scholar
Wang, Y., Chiu, E., Rosenberg, J. & Gambhir, S. S. Standardized uptake value atlas: characterization of physiological 2-deoxy-2-[18F]fluoro-D-glucose uptake in normal tissues. Mol. Imaging Biol. 9, 83–90 (2007).
Google Scholar
Boumezbeur, F. et al. The contribution of blood lactate to brain energy metabolism in humans measured by dynamic C nuclear magnetic resonance spectroscopy. J. Neurosci. 30, 13983–13991 (2010).
Google Scholar
Ebert, D., Haller, R. G. & Walton, M. E. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J. Neurosci. 23, 5928–5935 (2003).
Google Scholar
Hefner, M., Baliga, V., Amphay, K., Ramos, D. & Hegde, V. Cardiometabolic modification of amyloid beta in Alzheimer’s disease pathology. Front. Aging Neurosci. 13, 721858 (2021).
Google Scholar
Erion, J. R. et al. Obesity elicits Interleukin 1-mediated deficits in hippocampal synaptic plasticity. J. Neurosci. 34, 2618–2631 (2014).
Google Scholar
Guo, D. H. et al. Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1 cells. J. Clin. Investig. 130, 1961–1976 (2020).
Google Scholar
Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674 (2013).
Google Scholar
Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med 21, 263–269 (2015).
Google Scholar
Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Investig. 116, 1784–1792 (2006).
Google Scholar
Ng R. C. L. et al. Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol. Neurodegener. 2016;11. ARTN 71. https://doi.org/10.1186/s13024-016-0136-x.
Bloemer J. et al. Adiponectin knockout mice display cognitive and synaptic deficits. Front. Endocrinol. 2019;10. ARTN 819. https://doi.org/10.3389/fendo.2019.00819.
Jeon, B. T. et al. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes 61, 1444–1454 (2012).
Google Scholar
So S. W., Fleming K. M., Nixon J. P. & Butterick T. A. Early life obesity increases neuroinflammation, amyloid beta deposition, and cognitive decline in a mouse model of Alzheimer’s disease. Nutrients. 2023;15. https://doi.org/10.3390/nu15112494.
Morris, J. K. et al. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin. Neurobiol. Aging 39, 19–24 (2016).
Google Scholar
Baker, L. D. et al. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68, 51–57 (2011).
Google Scholar
Mosconi, L., Pupi, A. & De Leon, M. J. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann. Ny. Acad. Sci. 1147, 180–195 (2008).
Google Scholar
Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018).
Google Scholar
Cunnane, S. et al. Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 27, 3–20 (2011).
Google Scholar
Mu Y. L., Gage F. H. Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol. Neurodegener. 2011;6. Artn 85. https://doi.org/10.1186/1750-1326-6-85.
Willette, A. A. et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 11, 504–510 e501 (2015).
Google Scholar
Kim, B., Elzinga, S. E., Henn, R. E., McGinley, L. M. & Feldman, E. L. The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer’s disease. Neurobiol. Dis. 132, 104541 (2019).
Google Scholar
Puig, K. L., Floden, A. M., Adhikari, R., Golovko, M. Y. & Combs, C. K. Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One 7, e30378 (2012).
Google Scholar
Vingtdeux, V. et al. Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. Neurobiol. Dis. 20, 625–637 (2005).
Google Scholar
Takashima, A. GSK-3 is essential in the pathogenesis of Alzheimer’s disease. J. Alzheimers Dis. 9, 309–317 (2006).
Google Scholar
Pettigrew, C. & Soldan, A. Defining cognitive reserve and implications for cognitive aging. Curr. Neurol. Neurosci. Rep. 19, 1 (2019).
Google Scholar
Stern, Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 11, 1006–1012 (2012).
Google Scholar
Whalley, L. J., Deary, I. J., Appleton, C. L. & Starr, J. M. Cognitive reserve and the neurobiology of cognitive aging. Ageing Res. Rev. 3, 369–382 (2004).
Google Scholar
Hammond, T. C. et al. beta-amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline. Commun. Biol. 3, 352 (2020).
Google Scholar
Niccoli, T. et al. Increased glucose transport into neurons rescues Aβ Toxicity in (vol 26, pg 2291, 2016). Curr. Biol. 26, 2550–2550 (2016).
Google Scholar
Andersen, J. V. et al. Alterations in cerebral cortical glucose and glutamine metabolism precedes amyloid plaques in the APPswe/PSEN1dE9 mouse model of Alzheimer’s disease. Neurochem Res 42, 1589–1598 (2017).
Google Scholar
Andersen, J. V. et al. Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease. Cell Death Dis. 12, 954 (2021).
Google Scholar
Westi, E. W., Andersen, J. V. & Aldana, B. I. Using stable isotope tracing to unravel the metabolic components of neurodegeneration: Focus on neuron-glia metabolic interactions. Neurobiol. Dis. 182, 106145 (2023).
Google Scholar
Williams H. C. et al. alters glucose flux through central carbon pathways in astrocytes. Neurobiol. Disease. 2020;136. ARTN 104742. https://doi.org/10.1016/j.nbd.2020.104742.
Huebbe, P. et al. APOE genotype regulates body weight and fatty acid utilization-Studies in gene-targeted replacement mice. Mol. Nutr. Food Res. 59, 334–343 (2015).
Conway, V. et al. Apolipoprotein E isoforms disrupt long-chain fatty acid distribution in the plasma, the liver and the adipose tissue of mice. Prostaglandins Leukot. Ess. Fat. Acids 91, 261–267 (2014).
Google Scholar
Arbones-Mainar, J. M. et al. Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4. Int J. Obes. (Lond.) 40, 1574–1581 (2016).
Google Scholar
Jones N. S., Watson K. Q. & Rebeck G. W. Metabolic disturbances of a high-fat diet are dependent on APOE genotype and sex. eNeuro. 2019;6. https://doi.org/10.1523/eneuro.0267-19.2019.
Burke, J. R. & Roses, A. D. Genetics of Alzheimer’s disease. Int J. Neurol. 25-26, 41–51 (1991).
Google Scholar
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).
Google Scholar
Roses, A. D. Apolipoprotein E is a relevant susceptibility gene that affects the rate of expression of Alzheimer’s disease. Neurobiol. Aging 15, S165–S167 (1994).
Google Scholar
Reger, M. A. et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J. Alzheimers Dis. 13, 323–331 (2008).
Google Scholar
Liguori, C. et al. Cerebrospinal fluid lactate levels and brain [18F]FDG PET hypometabolism within the default mode network in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging. 43, 2040–2049 (2016).
Google Scholar
Schurr, A., Payne, R. S., Miller, J. J. & Rigor, B. M. Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: An in vitro study. Brain Res. 744, 105–111 (1997).
Google Scholar
Schurr, A., West, C. A. & Rigor, B. M. Lactate-supported synaptic function in the rat Hippocampal slice preparation. Science 240, 1326–1328 (1988).
Google Scholar
Chamaa F., Magistretti P. J., Fiumelli H. Astrocyte-derived lactate in stress disorders. Neurobiol. Dis. 2024:106417. https://doi.org/10.1016/j.nbd.2024.106417.
Kálmán, J. et al. Lactate infusion fails to improve semantic categorization in Alzheimer’s disease. Brain Res. Bull. 65, 533–539 (2005).
Google Scholar
Ma Y. L. et al. Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: a real-world study. Front. Endocrinol. 2023;14. ARTN 1133991 https://doi.org/10.3389/fendo.2023.1133991.
Lovejoy, J., Newby, F. D., Gebhart, S. S. P. & Digirolamo, M. Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin. Metab.-Clin. Exp. 41, 22–27 (1992).
Google Scholar
Vettor, R. et al. Lactate infusion in anesthetized rats produces insulin resistance in heart and skeletal muscles. Metab.-Clin. Exp. 46, 684–690 (1997).
Google Scholar
Lin, Y. J. et al. Lactate is a key mediator that links obesity to insulin resistance via modulating cytokine production from adipose tissue. Diabetes 71, 637–652 (2022).
Google Scholar
Sauerbeck, A. D. et al. Spinal cord injury causes chronic liver pathology in rats. J. Neurotraum. 32, 159–169 (2015).
Google Scholar
Sun, X. F. et al. Liver-derived ketogenesis via overexpressing HMGCS2 promotes the recovery of spinal cord injury. Adv. Biol-Ger, (2023).
Eisenberg, D. et al. Interaction between increasing body mass index and spinal cord injury to the probability of developing a diagnosis of nonalcoholic fatty liver disease. Obes. Sci. Pract. 9, 253–260 (2023).
Google Scholar
ROSENBLOOM, J. The acetone bodies in diabetes mellitus: influence of low and high protein intake on the excretion of acetone, diacetic acid and beta-oxybutyric acid. J. Am. Med. Assoc. LXV, 1715–1717 (1915).
Google Scholar
Krikorian, R. et al. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol. Aging 33, 425.e419–425.e427 (2012).
Google Scholar
Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546.e535 (2017).
Google Scholar
Mujica-Parodi, L. R. et al. Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc. Natl Acad. Sci. USA 117, 6170–6177 (2020).
Google Scholar
Fortier, M. et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 15, 625–634 (2019).
Google Scholar
Likhodii, S. S. et al. Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet. Epilepsia 41, 1400–1410 (2000).
Google Scholar
Asrih M., Altirriba J., Rohner-Jeanrenaud F. & Jornayvaz F. R. Ketogenic diet impairs FGF21 signaling and promotes differential inflammatory responses in the liver and white adipose tissue. Plos One. 2015;10: ARTN e0126364 https://doi.org/10.1371/journal.pone.0126364.
Goldberg, E. L. et al. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue. Nat. Metab. 2, 50–61 (2020).
Google Scholar
Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557.e548 (2017).
Google Scholar
Yang H. J., Shan W., Zhu F., Wu J. P., Wang Q. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms. Front. Neurol. 2019;10. ARTN 585. https://doi.org/10.3389/fneur.2019.00585.
Koppel, S. J. & Swerdlow, R. H. Neuroketotherapeutics: A modern review of a century-old therapy. Neurochem. Int. 117, 114–125 (2018).
Google Scholar
Murugan, M. & Boison, D. Ketogenic diet, neuroprotection, and antiepileptogenesis. Epilepsy Res. 167, 106444 (2020).
Google Scholar
Browning, J. D. et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am. J. Clin. Nutr. 93, 1048–1052 (2011).
Google Scholar
Foster, G. D. et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Ann. Intern. Med. 153, 147–157 (2010).
Google Scholar
Laeger, T., Metges, C. C. & Kuhla, B. Role of β-hydroxybutyric acid in the central regulation of energy balance. Appetite 54, 450–455 (2010).
Google Scholar
Dashti, H. M. et al. Long-term effects of a ketogenic diet in obese patients. Exp. Clin. Cardiol. 9, 200–205 (2004).
Google Scholar
Kwiterovich, P. O. Jr., Vining, E. P., Pyzik, P., Skolasky R, Jr. & Freeman JM. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 290, 912–920 (2003).
Nelson, A. B., Queathem, E. D., Puchalska, P. & Crawford, P. A. Metabolic messengers: ketone bodies. Nat. Metab. 5, 2062–2074 (2023).
Google Scholar
Desrochers, S., David, F., Garneau, M., Jette, M. & Brunengraber, H. Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem. J. 285, 647–653 (1992).
Google Scholar
D’Agostino, D. P. et al. Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. Am. J. Physiol. – Regul. Integr. Comp. Physiol. 304, R829–R836 (2013).
Google Scholar
Webber, R. J. & Edmond, J. Utilization of L(+)-3-hydroxybutyrate, D(-)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J. Biol. Chem. 252, 5222–5226 (1977).
Google Scholar
Desrochers, S. et al. Metabolism of (R,S)-1,3-butanediol acetoacetate esters, potential parenteral and enteral nutrients in conscious pigs. Am. J. Physiol. 268, E660–E667 (1995).
Google Scholar
Clarke, K. et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul. Toxicol. Pharm. 63, 401–408 (2012).
Google Scholar
Shivva, V. et al. The population pharmacokinetics of D-β-hydroxybutyrate following administration of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. AAPS J. 18, 678–688 (2016).
Google Scholar
Monteyne A. J. et al. A ketone monoester drink reduces postprandial blood glucose concentrations in adults with type 2 diabetes: a randomised controlled trial. Diabetologia. 2024. https://doi.org/10.1007/s00125-024-06122-7.
Kashiwaya, Y. et al. A ketone ester diet increases brain malonyl-CoA and Uncoupling proteins 4 and 5 while decreasing food intake in the normal Wistar Rat. J. Biol. Chem. 285, 25950–25956 (2010).
Google Scholar
Veech R. L. Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. In: Ann.N. Y. Acad. Sci. 2013:42–48.
Deemer, S. E. et al. Exogenous dietary Ketone Ester decreases body weight and adiposity in mice housed at thermoneutrality. Obesity 28, 1447–1455 (2020).
Google Scholar
Dakhili, S. A. T. et al. Ketone ester administration improves glycemia in obese mice. Am. J. Physiol.-Cell Physiol. 325, C750–C757 (2023).
Google Scholar
Moore, M. P. et al. A dietary ketone ester mitigates histological outcomes of NAFLD and markers of fibrosis in high-fat diet fed mice. Am. J. Physiol. Gastrointest. Liver Physiol. 320, G564–G572 (2021).
Google Scholar
Quinones M. D. & Lemon P. W. R. Ketone Ester supplementation improves some aspects of cognitive function during a simulated soccer match after induced mental fatigue. Nutrients. 2022;14. https://doi.org/10.3390/nu14204376.
Margolis L. M., Pasiakos S. M. & Howard E. E. High-fat ketogenic diets and ketone monoester supplements differentially affect substrate metabolism during aerobic exercise. Am. J. Physiol. Cell Physiol. 2023. https://doi.org/10.1152/ajpcell.00359.2023.
Pawlosky, R. J. et al. Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer’s disease. J. Neurochem. 141, 195–207 (2017).
Google Scholar
Fulghum, K. & Hill, B. G. Metabolic mechanisms of exercise-induced cardiac remodeling. Front. Cardiovasc. Med. 5, 127 (2018).
Google Scholar
Rodahl, K., Miller, H. I. & Issekutz, B. Jr Plasma free fatty acids in exercise. J. Appl. Physiol. 19, 489–492 (1964).
Google Scholar
Kaijser, L. & Berglund, B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol. Scand. 144, 39–45 (1992).
Google Scholar
Johnson, R. H., Walton, J. L., Krebs, H. A. & Williamson, D. H. Metabolic fuels during and after severe exercise in athletes and non-athletes. Lancet 294, 452–455 (1969).
Google Scholar
Koeslag, J. H., Noakes, T. D. & Sloan, A. W. Post-exercise ketosis. J. Physiol. 301, 79–90 (1980).
Google Scholar
Fulghum K., Collins H. E., Jones S. P. & Hill B. G. Influence of biological sex and exercise on murine cardiac metabolism. J Sport Health Sci. 2022: https://doi.org/10.1016/j.jshs.2022.06.001.
Thyfault, J. P. & Bergouignan, A. Exercise and metabolic health: beyond skeletal muscle. Diabetologia 63, 1464–1474 (2020).
Google Scholar
Cao, X. & Thyfault, J. P. Exercise drives metabolic integration between muscle, adipose and liver metabolism and protects against aging-related diseases. Exp. Gerontol. 176, 112178 (2023).
Google Scholar
Morris J. K. et al. Aerobic exercise for Alzheimer’s disease: A randomized controlled pilot trial. Plos One. 2017;12. ARTN e0170547. https://doi.org/10.1371/journal.pone.0170547.
Baker, L. D. et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch. Neurol. 67, 71–79 (2010).
Google Scholar
Chow L. S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 2022. https://doi.org/10.1038/s41574-022-00641-2.
Takimoto, M. & Hamada, T. Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins. J. Appl Physiol. (1985) 116, 1238–1250 (2014).
Google Scholar
Fery, F. & Balasse, E. O. Ketone body turnover during and after exercise in overnight-fasted and starved humans. Am. J. Physiol. 245, E318–E325 (1983).
Google Scholar
Fery, F. & Balasse, E. O. Effect of exercise on the disposal of infused ketone bodies in humans. J. Clin. Endocrinol. Metab. 67, 245–250 (1988).
Google Scholar
Johnson, R. H. & Walton, J. L. The effect of exercise upon acetoacetate metabolism in athletes and non‐athletes. Q. J. Exp. Physiol. Cogn. Med. Sci. 57, 73–79 (1972).
Google Scholar
Cannataro, R. et al. Ketogenic diet acts on body remodeling and MicroRNAs expression profile. Microrna 8, 116–126 (2019).
Google Scholar
Ferrannini, E. et al. Shift to fatty substrate utilization in response to Sodium-Glucose Cotransporter 2 inhibition in subjects without diabetes and patients with Type 2 Diabetes. Diabetes 65, 1190–1195 (2016).
Google Scholar
Ferrannini, E. et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124, 499–508 (2014).
Google Scholar
Saucedo-Orozco, H., Voorrips, S. N., Yurista, S. R., de Boer, R. A. & Westenbrink, B. D. SGLT2 inhibitors and ketone metabolism in heart failure. J. Lipid Atheroscler. 11, 1–19 (2022).
Google Scholar
Capozzi, M. E. et al. The limited role of glucagon for ketogenesis during fasting or in response to SGLT2 inhibition. Diabetes 69, 882–892 (2020).
Google Scholar
Akuta N. et al. Favorable impact of long-term SGLT2 inhibitor for NAFLD complicated by diabetes mellitus: A 5-year follow-up study. Hepatol. Commun. (2022).
Cai, R.-P., Xu, Y.-L. & Su, Q. Dapagliflozin in patients with chronic heart failure: a systematic review and meta-analysis. Cardiol. Res Pr. 2021, 6657380–6657380 (2021).
Zelniker, T. A. et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393, 31–39 (2019).
Google Scholar
Ong Lopez, A. M. C. & Pajimna, J. A. T. Efficacy of sodium glucose cotransporter 2 inhibitors on hepatic fibrosis and steatosis in non-alcoholic fatty liver disease: an updated systematic review and meta-analysis. Sci. Rep. 14, 2122 (2024).
Google Scholar
Lupsa, B. C., Kibbey, R. G. & Inzucchi, S. E. Ketones: the double-edged sword of SGLT2 inhibitors. Diabetologia 66, 23–32 (2023).
Google Scholar
Fitchett, D. et al. investigators E-ROt. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur. Heart J. 37, 1526–1534 (2016).
Google Scholar
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