Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Douris, Nicholas¹  Melman, Tamar²  Pecherer, Jordan M.¹  Pissios, Pavlos¹  Flier, Jeffrey S.¹  Cantley, Lewis C.^2,3  Locasale, Jason W.^2,4  Maratos-Flier, Eleftheria¹ 

[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[3] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[4] Cornell Univ, Div Nutr Sci, Ithaca, NY 14850 USA

关键词: Ketogenic diet;    Liver;    Ketogenesis;    Hepatic steatosis;    Free fatty acid metabolism;    Metabolomics;    Mass spectrometry;   

DOI  :  10.1016/j.bbadis.2015.07.009

来源: Elsevier

【 摘 要 】

Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80 weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630 days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of beta-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice. (C) 2015 Published by Elsevier B.V.

【 授权许可】

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