Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO 80016, USA.
Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología 'Ignacio Chavez', Mexico City 14080, Mexico.
Philos Trans R Soc Lond B Biol Sci. 2023 Sep 11;378(1885):20220230. doi: 10.1098/rstb.2022.0230. Epub 2023 Jul 24.
The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) that aims to protect animals of crisis. 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 'thrifty genes' 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. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.
果糖生存假说提出，肥胖和代谢紊乱可能是由于过度刺激一种基于进化的生物反应（生存开关）而发展起来的，这种反应旨在保护动物免受危机。该反应的特征是饥饿、口渴、觅食、体重增加、脂肪堆积、胰岛素抵抗、全身炎症和血压升高。该过程是通过摄入果糖或通过多元醇途径刺激内源性果糖产生而引发的。与其他营养素不同，果糖会降低细胞中的有效能量（三磷酸腺苷），同时阻止其从脂肪储存中再生。这是通过细胞内尿酸、线粒体氧化应激、AMP 激酶抑制和加压素刺激来介导的。线粒体氧化磷酸化受到抑制，糖酵解受到刺激。虽然这种反应的目的是适度和短暂的，但由于人类获得了“节俭基因”，再加上富含果糖或产生果糖的西方饮食，这种反应被夸大了。我们提出，过量的果糖代谢不仅可以解释肥胖，还可以解释糖尿病、高血压、非酒精性脂肪肝疾病、肥胖相关癌症、血管和阿尔茨海默病痴呆症，甚至衰老的流行。此外，该假说将目前关于肥胖的假说统一起来。减少该通路的激活和/或阻断以及刺激线粒体再生可能有益于健康寿命。本文是讨论会议议题“肥胖的原因：理论、推测和证据（第一部分）”的一部分。
