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This cerebral substrate switch has been implicated in upregulating brain\u2010derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, learning and memory, and may underlie some of these neuroprotective effects. We examined the isolated and interactive effects of (1) 20\u2010h fasting, (2) 90\u2010min light exercise, and (3) high\u2010intensity exercise on peripheral venous BDNF in 12 human volunteers. A follow\u2010up study isolated the influence of cerebrovascular shear stress on circulating BDNF. Fasting for 20\u00a0h decreased glucose and increased ketones (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.0157) but had no effect on BDNF (<jats:italic>P<\/jats:italic>\u00a0\u2265\u00a00.4637). Light cycling at 25% of peak oxygen uptake () increased serum BDNF by 6 \u00b1 8% (independent of being fed or fasted) and was mediated by a 7 \u00b1 6% increase in platelets (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001). Plasma BDNF was increased from 336 pg l<jats:sup>\u22121<\/jats:sup> [46,626] to 390 pg l<jats:sup>\u22121<\/jats:sup> [127,653] by 90\u2010min of light cycling (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0128). Six 40\u2010s intervals at 100% of  increased plasma and serum BDNF, as well as the BDNF\u2010per\u2010platelet ratio 4\u2010 to 5\u2010fold more than light exercise did (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.0044). Plasma BDNF was correlated with circulating lactate during the high\u2010intensity intervals (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.47, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0057), but not during light exercise (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.7407). Changes in cerebral shear stress \u2013 whether occurring naturally during exercise or induced experimentally with inspired CO<jats:sub>2<\/jats:sub> \u2013 did not correspond with changes in BDNF (<jats:italic>P<\/jats:italic>\u00a0\u2265\u00a00.2730). BDNF responses to low\u2010intensity exercise are mediated by increased circulating platelets, and increasing either exercise duration or particularly intensity is required to liberate free BDNF.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15376-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Intermittent fasting and exercise both have potent neuroprotective effects and an acute upregulation of brain\u2010derived neurotrophic factor (BDNF) appears to be a common mechanistic link.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Switching the brain's fuel source from glucose to either ketone bodies or lactate, i.e. a cerebral substrate switch, has been shown to promote BDNF production in the rodent brain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Fasting for 20\u00a0h caused a 9\u2010fold increase in ketone body delivery to the brain but had no effect on any metric of BDNF in peripheral circulation at rest.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Prolonged (90\u00a0min) light cycling exercise increased plasma\u2010 and serum\u2010derived BDNF irrespective of being fed or fasted and seemed to be independent of changes in cerebral shear stress.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Six minutes of high\u2010intensity cycling intervals increased every metric of circulating BDNF by 4 to 5 times more than prolonged low\u2010intensity cycling; the increase in plasma\u2010derived BDNF was correlated with a 6\u2010fold increase in circulating lactate irrespective of feeding or fasting.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Compared to 1 day of fasting with or without prolonged light exercise, high\u2010intensity exercise is a much more efficient means to increase BDNF in circulation.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283582","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T01:00:33Z","timestamp":1673485233000},"page":"2121-2137","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Fasting for 20\u00a0h does not affect exercise\u2010induced increases in circulating BDNF in humans"],"prefix":"10.1113","volume":"601","author":[{"given":"Travis D.","family":"Gibbons","sequence":"first","affiliation":[{"name":"School of Physical Education Sport &amp; Exercise Sciences University of Otago  Dunedin New Zealand"},{"name":"Centre for Heart, Lung and Vascular Health University of British Columbia \u2010 Okanagan School of Health and Exercise Science  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Cotter","sequence":"additional","affiliation":[{"name":"School of Physical Education Sport &amp; Exercise Sciences University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Ainslie","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health University of British Columbia \u2010 Okanagan School of Health and Exercise Science  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wickliffe C.","family":"Abraham","sequence":"additional","affiliation":[{"name":"Department of Psychology Brain Health Research Centre University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce G.","family":"Mockett","sequence":"additional","affiliation":[{"name":"Department of Psychology Brain Health Research Centre University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly A.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma M. 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