Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE−/− Mice
Open accessAbstract
Aim: Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given ad libitum in old ApoE-/- mice. Methods: 45-weeks old obese ApoE-/-mice fed with a high cholesterol diet ad libitum were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress and inflammation markers in plasma, aorta and brain were then assessed. Results: In EX ApoE-/- mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE-/- EX mice (mean of 12.5 km/week during twelve weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up (r²=0.87; p=0.049) with a faster evolution compared to SED ApoE-/-mice. Conclusion: We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE-/- animals under high cholesterol diet given ad libitum. Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE-/- mice.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Transgenic mice lacking Apoe develop an early BBB breakdown.
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [147]
The Results (Brain imaging and immunochemistry; page unavailable) report focal BBB leakage in ApoE−/− mice at the start of the study, unlike age-matched wild-type mice. But the study used 45-week-old mice; finding leakage early in its follow-up does not establish that BBB breakdown develops early in life. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
ElAli, A., Doeppner, T. R., Zechariah, A., & Hermann, D. M. (2011) · Stroke · doi:10.1161/strokeaha.111.615559 · Cited by 150 · see citing works
ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage
Hafezi-Moghadam, A., Thomas, K. L., & Wagner, D. D. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00563.2005 · Cited by 149 · see citing works
APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction
Soto, I., Graham, L. C., Richter, H. J., Simeone, S. N., Radell, J. E., Grabowska, W., Funkhouser, W. K., Howell, M. C., & Howell, G. R. (2015) · PLOS Biology · doi:10.1371/journal.pbio.1002279 · Cited by 140 · see citing works
Flagged first, then by citations
Research works printed but not linked: 44
- Akoudad S. Ikram M. A. Koudstaal P. J. Hofman A. Niessen W. J. Greenberg S. M.. (2014). Cerebral microbleeds are associated with the progression of ischemic vascular lesions. Cerebrovasc. Dis. 37, 382– 388. 10.1159/000362590 24970709 PMC5291936 · DOI
- Auer M. K. Sack M. Lenz J. N. Jakovcevski M. Biedermann S. V. Falfán-Melgoza C.. (2015). Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study. J. Cereb. Blood Flow Metab. 35, 554– 564. 10.1038/jcbfm.2014.231 25564238 PMC4420876 · DOI
- Badaut J. Copin J.-C. Fukuda A. M. Gasche Y. Schaller K. Da Silva R. F.. (2012). Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit. J. Neuroinflammation 9, 132. 10.1186/1742-2094-9-132 22709928 PMC3419627 · DOI
- Bergouignan A. Antoun E. Momken I. Schoeller D. A. Gauquelin-Koch G. Simon C.. (1985). Effect of contrasted levels of habitual physical activity on metabolic flexibility. J. Appl. Physiol. 114, 371– 379. 10.1152/japplphysiol.00458.2012 23239872 · DOI · Paper page
- Berkseth K. E. Guyenet S. J. Melhorn S. J. Lee D. Thaler J. P. Schur E. A.. (2014). Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155, 2858– 2867. 10.1210/en.2014-1121 24914942 PMC4098007 · DOI
- Böhm A. Weigert C. Staiger H. Häring H.-U. (2016). Exercise and diabetes: relevance and causes for response variability. Endocrine 51, 390– 401. 10.1007/s12020-015-0792-6 26643313 PMC4762932 · DOI
- Chirico E. N. Martin C. Faës C. Féasson L. Oyono-Enguéllé S. Aufradet E.. (2012). Exercise training blunts oxidative stress in sickle cell trait carriers. J. Appl. Physiol. 112, 1445– 1453. 10.1152/japplphysiol.01452.2011 22323645 · DOI
- Chirico E. N. Di Cataldo V. Chauveau F. Geloën A. Patsouris D. Thézé B.. (2016). MRI biomarkers of exercise-induced improvement of oxidative stress and inflammation in the brain of old high fat fed ApoE−/− mice. J. Physiol. [Epub ahead of print]. 10.1113/JP271903 27641234 PMC5134731 · DOI
- Copes L. E. Schutz H. Dlugosz E. M. Acosta W. Chappell M. A. Garland T. (2015). Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: results from an artificial selection experiment. Physiol. Behav. 149, 86– 94. 10.1016/j.physbeh.2015.05.025 26025787 · DOI
- Erion J. R. Wosiski-Kuhn M. Dey A. Hao S. Davis C. L. Pollock N. K.. (2014). Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J. Neurosci. 34, 2618– 2631. 10.1523/JNEUROSCI.4200-13.2014 24523551 PMC3921429 · DOI
- Gleeson M. Bishop N. C. Stensel D. J. Lindley M. R. Mastana S. S. Nimmo M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607– 615. 10.1038/nri3041 21818123 · DOI · Paper page
- Goh J. Ladiges W. (2015). Voluntary wheel running in mice. Curr. Protoc. Mouse Biol. 5, 283– 290. 10.1002/9780470942390.mo140295 26629772 PMC4686373 · DOI
- Gotthardt J. D. Verpeut J. L. Yeomans B. L. Yang J. A. Yasrebi A. Roepke T. A.. (2016). Intermittent fasting promotes fat loss with lean mass retention, increased hypothalamic norepinephrine content, and increased neuropeptide y gene expression in diet-induced obese male mice. Endocrinology 157, 679– 691. 10.1210/en.2015-1622 26653760 PMC4733124 · DOI
- Hicks J. A. Hatzidis A. Arruda N. L. Gelineau R. R. De Pina I. M. Adams K. W.. (2016). Voluntary wheel-running attenuates insulin and weight gain and affects anxiety-like behaviors in C57BL6/J mice exposed to a high-fat diet. Behav. Brain Res. 310, 1– 10. 10.1016/j.bbr.2016.04.051 27154535 · DOI
- Johnson J. L. Jackson C. L. (2001). Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis 154, 399– 406. 10.1016/S0021-9150(00)00515-3 11166772 · DOI
- Kanoski S. E. Davidson T. L. (2011). Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol. Behav. 103, 59– 68. 10.1016/j.physbeh.2010.12.003 21167850 PMC3056912 · DOI
- Koga S. Kojima A. Ishikawa C. Kuwabara S. Arai K. Yoshiyama Y. (2014). Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression. Neurobiol. Dis. 71, 180– 192. 10.1016/j.nbd.2014.08.015 25132556 · DOI
- Laufs U. Wassmann S. Czech T. Münzel T. Eisenhauer M. Böhm M.. (2005). Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 809– 814. 10.1161/01.ATV.0000158311.24443.af 15692095 · DOI · Paper page
- Leasure J. L. Jones M. (2008). Forced and voluntary exercise differentially affect brain and behavior. Neuroscience 156, 456– 465. 10.1016/j.neuroscience.2008.07.041 18721864 · DOI
- Lee D. Thaler J. P. Berkseth K. E. Melhorn S. J. Schwartz M. W. Schur E. A. (2013). Longer T(2) relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 304, E1245– E1250. 10.1152/ajpendo.00020.2013 23548614 PMC3680680 · DOI
- Mori Y. Chen T. Fujisawa T. Kobashi S. Ohno K. Yoshida S.. (2014). From cartoon to real time MRI: in vivo monitoring of phagocyte migration in mouse brain. Sci. Rep. 4: 6997. 10.1038/srep06997 25385430 PMC4227027 · DOI
- Naville D. Labaronne E. Vega N. Pinteur C. Canet-Soulas E. Vidal H.. (2015). Metabolic outcome of female mice exposed to a mixture of low-dose pollutants in a diet-induced obesity model. PLoS ONE 10: e0124015. 10.1371/journal.pone.0124015 25909471 PMC4409066 · DOI
- Nighoghossian N. Wiart M. Cakmak S. Berthezène Y. Derex L. Cho T.-H.. (2007). Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke 38, 303– 307. 10.1161/01.STR.0000254548.30258.f2 17170357 · DOI
- Oberley L. W. Spitz D. R. (1984). Assay of superoxide dismutase activity in tumor tissue. Methods Enzymol. 105, 457– 464. 6547201
- Ohkawa H. Ohishi N. Yagi K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95, 351– 358. 36810
- Paglia D. E. Valentine W. N. (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 70, 158– 169. 6066618
- Patel P. Abate N. (2013). Body fat distribution and insulin resistance. Nutrients 5, 2019– 2027. 10.3390/nu5062019 23739143 PMC3725490 · DOI
- Pialoux V. Brown A. D. Leigh R. Friedenreich C. M. Poulin M. J. (2009). Effect of cardiorespiratory fitness on vascular regulation and oxidative stress in postmenopausal women. Hypertension 54, 1014– 1020. 10.1161/HYPERTENSIONAHA.109.138917 19786647 · DOI
- Rao X. Zhong J. Xu X. Jordan B. Maurya S. Braunstein Z.. (2013). Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cβ in mice. PLoS ONE 8: e81364. 10.1371/journal.pone.0081364 24349059 PMC3857188 · DOI
- Rieusset J. Chauvin M.-A. Durand A. Bravard A. Laugerette F. Michalski M.-C.. (2012). Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance. Biochem. Biophys. Res. Commun. 417, 439– 445. 10.15171/bi.2016.16 22177958 · DOI
- Ringseis R. Eder K. Mooren F. C. Krüger K. (2015). Metabolic signals and innate immune activation in obesity and exercise. Exerc. Immunol. Rev. 21, 58– 68. 25825956
- Roberts C. K. Hevener A. L. Barnard R. J. (2013). Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr. Physiol. 3, 1– 58. 10.1002/cphy.c110062 23720280 PMC4129661 · DOI
- Schreiber S. Bueche C. Z. Garz C. Kropf S. Angenstein F. Goldschmidt J.. (2012). The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase? J. Cereb. Blood Flow Metab. 32, 278– 290. 10.1038/jcbfm.2011.122 21878945 PMC3272595 · DOI
- Shepherd D. Garland P. B. (1969). The kinetic properties of citrate synthase from rat liver mitochondria. Biochem. J. 114, 597– 610. 5820645 PMC1184933
- Sigovan M. Kaye E. Lancelot E. Corot C. Provost N. Majd Z.. (2012). Anti-inflammatory drug evaluation in ApoE−/− mice by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. Invest. Radiol. 47, 546– 552. 10.1097/RLI.0b013e3182631e68 22864378 · DOI
- Spielman L. J. Little J. P. Klegeris A. (2014). Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J. Neuroimmunol. 273, 8– 21. 10.1016/j.jneuroim.2014.06.004 24969117 · DOI · Paper page
- Szostak J. Laurant P. (1979). The forgotten face of regular physical exercise: a “natural” anti-atherogenic activity. Clin. Sci. (Lond.) 121, 91– 106. 10.1042/CS20100520 21729002 · DOI
- Thaler J. P. Yi C.-X. Schur E. A. Guyenet S. J. Hwang B. H. Dietrich M. O.. (2012). Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153– 162. 10.1172/JCI59660 22201683 PMC3248304 · DOI · Paper page
- Van der Donckt C. Roth L. Vanhoutte G. Blockx I. Bink D. I. Ritz K.. (2015). Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice. Neuroscience 295, 11– 22. 10.1016/j.neuroscience.2015.03.023 25797463 · DOI
- Walker L. C. Parker C. A. Lipinski W. J. Callahan M. J. Carroll R. T. Gandy S. E.. (1997). Cerebral lipid deposition in aged apolipoprotein-E-deficient mice. Am. J. Pathol. 151, 1371– 1377. 9358763 PMC1858096
- Wardlaw J. M. Smith E. E. Biessels G. J. Cordonnier C. Fazekas F. Frayne R.. (2013). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822– 838. 10.1016/S1474-4422(13)70124-8 23867200 PMC3714437 · DOI · Paper page
- Witko-Sarsat V. Friedlander M. Capeillère-Blandin C. Nguyen-Khoa T. Nguyen A. T. Zingraff J.. (1996). Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int. 49, 1304– 1313. 8731095
- Xu X. Ying Z. Cai M. Xu Z. Li Y. Jiang S. Y.. (2011). Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1115– R1125. 10.1152/ajpregu.00806.2010 21368268 PMC3094041 · DOI
- Yi C.-X. Al-Massadi O. Donelan E. Lehti M. Weber J. Ress C.. (2012). Exercise protects against high-fat diet-induced hypothalamic inflammation. Physiol Behav. 106, 485– 490. 10.1016/j.physbeh.2012.03.021 22483785 · DOI
Cited by
Sorted by citations
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Alzheimer’s disease: A matter of blood–brain barrier dysfunction?
Montagne, A., Zhao, Z., & Zlokovic, B. V. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171406 · Cited by 672 · see citing works
- Authors
- Di Cataldo, V., Géloën, A., Langlois, J.-B., Chauveau, F., Thézé, B., Hubert, V., Wiart, M., Chirico, E. N., Rieusset, J., Vidal, H., Pialoux, V., & Canet-Soulas, E.
- Affiliations
- Lyon 1 Université (FR)
- Centre d'Exploration et de Recherche Médicale par Emission de Positons (FR)
- ORCID
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2016-10-06
- Volume
- 7
- Pages
- 453-453
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC5052582
- OpenAlex
- W2528228860
- Cited by
- 15
- References
- 3
- Citations by year
- 2023: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 2
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Institut Universitaire de France
- Université Claude Bernard Lyon 1
- Topics
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- exercise training, high-cholesterol diet, ApoE-deficient mice, aging, neuroinflammation, blood-brain barrier disruption, insulin resistance, oxidative stress, atherosclerosis, cerebral vasculature, caloric restriction, sedentary behavior
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review