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The response is characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation and increased blood pressure. The process is initiated by the ingestion of fructose or by stimulating endogenous fructose production via the polyol pathway. Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, the inhibition of AMP kinase and stimulation of vasopressin. Mitochondrial oxidative phosphorylation is suppressed, and glycolysis stimulated. While this response is aimed to be modest and short-lived, the response in humans is exaggerated due to gain of \u2018thrifty genes\u2019 coupled with a western diet rich in foods that contain or generate fructose. We propose excessive fructose metabolism not only explains obesity but the epidemics of diabetes, hypertension, non-alcoholic fatty liver disease, obesity-associated cancers, vascular and Alzheimer's dementia, and even ageing. Moreover, the hypothesis unites current hypotheses on obesity. Reducing activation and\/or blocking this pathway and stimulating mitochondrial regeneration may benefit health-span.<\/jats:p>\n                  <jats:p>This article is part of a discussion meeting issue \u2018Causes of obesity: theories, conjectures and evidence (Part I)\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2022.0230","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T02:53:40Z","timestamp":1690167220000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":59,"title":["The fructose survival hypothesis for obesity"],"prefix":"10.1098","volume":"378","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3312-8193","authenticated-orcid":true,"given":"Richard J.","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Medicine 1 , ,"},{"name":"University of Colorado Anschutz Medical Center 1 , ,"},{"name":"Aurora, CO 80016, USA 1 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Lanaspa","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 , ,"},{"name":"University of Colorado Anschutz Medical Center 1 , ,"},{"name":"Aurora, CO 80016, USA 1 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Gabriela","family":"Sanchez-Lozada","sequence":"additional","affiliation":[{"name":"Department of Cardio-Renal Physiopathology 2 , ,"},{"name":"Instituto Nacional de Cardiolog\u00eda \u2018Ignacio Chavez\u2019 2 , ,"},{"name":"Mexico City 14080, Mexico 2 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Tolan","sequence":"additional","affiliation":[{"name":"Biology Department 3 , ,"},{"name":"Boston University 3 , ,"},{"name":"Boston, MA 02215, USA 3 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiko","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Nephrology 4 , ,"},{"name":"Rakuwakai-Otowa Hospital 4 , ,"},{"name":"Kyoto 607-8062, Japan 4 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Ishimoto","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Rheumatology 5 , ,"},{"name":"Aichi Medical University 5 , ,"},{"name":"Aichi 480-1103, Japan 5 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Andres-Hernando","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 , ,"},{"name":"University of Colorado Anschutz Medical Center 1 , ,"},{"name":"Aurora, CO 80016, USA 1 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Rodriguez-Iturbe","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Mineral Metabolism 6 , ,"},{"name":"Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n \u2018Salvador Zubir\u00e1n\u2019 6 , ,"},{"name":"Mexico City 14080, Mexico 6 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Stenvinkel","sequence":"additional","affiliation":[{"name":"Department of Renal Medicine 7 , ,"},{"name":"Karolinska Institutet 7 , ,"},{"name":"Stockholm 171 77, Sweden 7 , ,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"2026010106394473700_RSTB20220230C1","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1021\/acs.accounts.6b00496","article-title":"Uniting natural history with the molecular sciences. 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