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The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2,4\u2010dinitrophenol (<jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>), a proton ionophore previously used for weight loss. We found that <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content> treatment reduces mitochondrial membrane potential, increases intracellular Ca<jats:sup>2+<\/jats:sup> levels and reduces oxidative stress in cerebral cortical neurons. Gene expression profiling of the cerebral cortex of <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>\u2010treated mice revealed reprogramming of signaling cascades that included suppression of the mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) and insulin \u2013 <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K \u2013 <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> pathways, and up\u2010regulation of tuberous sclerosis complex 2, a negative regulator of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>. Genes encoding proteins involved in autophagy processes were up\u2010regulated in response to <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content>\u2010response element\u2010binding protein) signaling, Arc and brain\u2010derived neurotrophic factor, which play important roles in synaptic plasticity and adaptive cellular stress responses, were up\u2010regulated in response to <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>\u2010treated mice exhibited improved performance in a test of learning and memory. Immunoblot analysis verified that key <jats:styled-content style=\"fixed-case\">DNP<\/jats:styled-content>\u2010induced changes in gene expression resulted in corresponding changes at the protein level. Our findings suggest that mild mitochondrial uncoupling triggers an integrated signaling response in brain cells characterized by reprogramming of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> and insulin signaling, and up\u2010regulation of pathways involved in adaptive stress responses, molecular waste disposal, and synaptic plasticity.\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\/jnc13176-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Physiological bioenergetic challenges such as exercise and fasting can enhance neuroplasticity and protect neurons against injury and neurodegeneration. Here, we show that the mitochondrial uncoupling agent 2,4\u2010dinitrophenol (DNP) elicits adaptive signaling responses in the cerebral cortex involving activation of Ca<jats:sup>2+<\/jats:sup>\u2010CREB and autophagy pathways, and inhibition of mTOR and insulin signaling pathways. The molecular reprogramming induced by DNP, which is similar to that of exercise and fasting, is associated with improved learning and memory, suggesting potential therapeutic applications for DNP.<\/jats:p>","DOI":"10.1111\/jnc.13176","type":"journal-article","created":{"date-parts":[[2015,5,23]],"date-time":"2015-05-23T14:18:47Z","timestamp":1432390727000},"page":"677-692","source":"Crossref","is-referenced-by-count":65,"title":["The mitochondrial uncoupler <scp>DNP<\/scp> triggers brain cell <scp>mTOR<\/scp> signaling network reprogramming and\u00a0<scp>CREB<\/scp> pathway up\u2010regulation"],"prefix":"10.1111","volume":"134","author":[{"given":"Dong","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Gene Expression and Genomics Unit National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Gharavi","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Ra","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacy College of Pharmacy Molecular Inflammation Research Center for Aging Intervention Pusan National University Busan Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaewon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy College of Pharmacy Molecular Inflammation Research Center for Aging Intervention Pusan National University Busan Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sana","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Telljohann","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R.","family":"Nassar","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy G.","family":"Cutler","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin G.","family":"Becker","sequence":"additional","affiliation":[{"name":"Gene Expression and Genomics Unit National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark P.","family":"Mattson","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences National Institute on Aging Intramural Research Program Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,6,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3072"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1767"},{"key":"e_1_2_8_4_1","first-page":"5","article-title":"Neurotrophins in neuroendocrine control: brain derived\u2010neurotrophic factor (BDNF) and somatostatin involvement in the stress response and reproductive physiology","volume":"5","author":"Arancibia S.","year":"2003","journal-title":"Annu. 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