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

ABSTRACT: 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 80weeks 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. 630days) 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 ?-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.

SUBMITTER: Douris N

PROVIDER: S-EPMC4862866 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Douris Nicholas N Melman Tamar T Pecherer Jordan M JM Pissios Pavlos P Flier Jeffrey S JS Cantley Lewis C LC Locasale Jason W JW Maratos-Flier Eleftheria E

Biochimica et biophysica acta 20150711 10 Pt A

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 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expressio ...[more]

PMID: 26170063

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Project description:The ketogenic diet (KD) is a nonpharmacologic treatment to reduce seizures with moderate to high success in pediatric patients with intractable epilepsy. Initiated in hospital, parents continue the treatment at home ensuring the ratio of high fat to low carbohydrate/protein is maintained to achieve metabolic ketosis. We conducted a systematic review to examine the quality of life (QoL) for families with a child using the KD for the reduction in epileptic seizures. A systematic review of the literature was conducted from 2007-2014 using key terms and combinations of: "epilepsy," "ketogenic diet," "children," "family," and "quality of life." We accessed CINAHL, Medline, PubMed, and PsycINFO. After removing duplicates, we screened 598 papers by title and abstract. Articles comparing alternate diets such as the Atkins diet to the KD, or those focusing on the KD and societal costs, were excluded. Eighteen articles remained, including 7 intervention studies (randomized controlled trial and quasiexperimental), 7 descriptive studies (retrospective), 2 observational studies, and 2 case studies. Most participants were diagnosed with epilepsy at the age of 5 y, and had a trial of antiepileptic drugs (AEDs) and had been using the KD after discharge from the hospital. QoL was infrequently reported as a primary variable and was defined in a variety of ways. We found recurring themes that could affect QoL: efficacy of seizure reduction, nutritional status, child growth and development, and child and family psychosocial impact. The dominant psychological factor was the need for counseling for parents and clear expectations on expected outcomes. Nonadherence and dropout rates were frequent, but unfortunately the reasons and timing were not well documented, and some of these could be associated with QoL. The success of the KD in seizure reduction addressed a primary parental concern. Further research should address KD adherence and dropout rates, and investigate factors of quality of life.

Project description:Biotin functions as a cofactor for several carboxylase enzymes with key roles in metabolism. At present, the dietary requirement for biotin is unknown and intake recommendations are provided as Adequate Intakes (AIs). The biotin AI for adults and pregnant women is 30 ?g/d, whereas 35 ?g/d is recommended for lactating women. However, pregnant and lactating women may require more biotin to meet the demands of these reproductive states.The current study sought to quantify the impact of reproductive state on biotin status response to a known dietary intake of biotin.To achieve this aim, we measured a panel of biotin biomarkers among pregnant (gestational week 27 at study entry; n = 26), lactating (postnatal week 5 at study entry; n = 28), and control (n = 21) women who participated in a 10- to 12-wk feeding study providing 57 ?g of dietary biotin/d as part of a mixed diet.Over the course of the study, pregnant women excreted 69% more (vs. control; P < 0.001) 3-hydroxyisovaleric acid (3-HIA), a metabolite that accumulates during the catabolism of leucine when the activity of biotin-dependent methylcrotonyl-coenzyme A carboxylase is impaired. Interestingly, urinary excretion of 3-hydroxyisovaleryl-carnitine (3-HIA-carnitine), a downstream metabolite of 3-HIA, was 27% lower (P = 0.05) among pregnant (vs. control) women, a finding that may arise from carnitine inadequacy during gestation. No differences (P > 0.05) were detected in plasma biotin, urinary biotin, or urinary bisnorbiotin between pregnant and control women. Lactating women excreted 76% more (vs. control; P = 0.001) of the biotin catabolite bisnorbiotin, indicating that lactation accelerates biotin turnover and loss. Notably, with respect to control women, lactating women excreted 23% less (P = 0.04) urinary 3-HIA and 26% less (P = 0.05) urinary 3-HIA-carnitine, suggesting that lactation reduces leucine catabolism and that these metabolites may not be useful indicators of biotin status during lactation.Overall, these data demonstrate significant alterations in markers of biotin metabolism during pregnancy and lactation and suggest that biotin intakes exceeding current recommendations are needed to meet the demands of these reproductive states. This trial was registered at clinicaltrials.gov as NCT01127022.

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

Publications

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

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