Richard J. Johnson, Miguel A. Lanaspa, L. Gabriela Sanchez-Lozada, Dean Tolan, Takahiko Nakagawa, Takuji Ishimoto, Ana Andres-Hernando, Bernardo Rodriguez-Iturbe, Peter Stenvinkel

The fructose survival hypothesis for obesity

  • General Agricultural and Biological Sciences
  • General Biochemistry, Genetics and Molecular Biology

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 in advance 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)’.

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