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Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.

ABSTRACT: Citrate is an essential substrate for energy metabolism that plays critical roles in regulating cell growth and survival. However, the action of citrate in regulating metabolism, cognition, and aging at the organismal level remains poorly understood. Here, we report that dietary supplementation with citrate significantly reduces energy status and extends lifespan in Drosophila melanogaster. Our genetic studies in fruit flies implicate a molecular mechanism associated with AMP-activated protein kinase (AMPK), target of rapamycin (TOR), and ketogenesis. Mice fed a high-fat diet that supplemented with citrate or the ketone body β-hydroxybutyrate (βOHB) also display improved metabolic health and memory. These results suggest that dietary citrate supplementation may prove to be a useful intervention in the future treatment of age-related dysfunction.

SUBMITTER: Fan SZ

PROVIDER: S-EPMC8672782 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.

Fan Shou-Zen SZ Lin Cheng-Sheng CS Wei Yu-Wen YW Yeh Sheng-Rong SR Tsai Yi-Hsuan YH Lee Andrew Chengyu AC Lin Wei-Sheng WS Wang Pei-Yu PY

Aging cell 20211031 12

Citrate is an essential substrate for energy metabolism that plays critical roles in regulating cell growth and survival. However, the action of citrate in regulating metabolism, cognition, and aging at the organismal level remains poorly understood. Here, we report that dietary supplementation with citrate significantly reduces energy status and extends lifespan in Drosophila melanogaster. Our genetic studies in fruit flies implicate a molecular mechanism associated with AMP-activated protein k ...[more]

PMID: 34719871

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Project description:This experiment was to evaluate the influence of sodium butyrate (SB) addition on milk production, ruminal fermentation, nutrient digestion, and the development and metabolism regulation of the mammary gland in dairy cows. Forty Holstein dairy cows averaging 710 ± 18.5 kg body weight, 72.8 ± 3.66 d in milk (DIM), and 41.4 ± 1.42 kg/d milk production were divided into four treatments blocked by DIM and milk production. Treatments were control group, low SB, medium SB, and high SB with 0, 100, 200 and 300 g/d of SB addition per cow, respectively. The study lasted for 105 d. Production of milk, milk protein and lactose quadratically increased (P < 0.05), while fat-corrected milk, energy-corrected milk and milk fat yields linearly increased (P < 0.05) with increasing SB addition. The digestibility of dietary dry matter, organic matter, and crude protein linearly increased (P < 0.05), whereas the digestibility of ether extract, neutral detergent fibre, and acid detergent fibre quadratically increased (P < 0.05). Ruminal pH quadratically decreased (P = 0.04), while total volatile fatty acids (VFA) quadratically increased (P = 0.03) with increasing SB addition. The acetic acid to propionic acid ratio increased (P = 0.03) linearly due to the unaltered acetic acid molar percentage and a linear decrease in propionic acid molar percentage. Ruminal enzymatic activity of carboxymethyl-cellulase and α-amylase, populations of total bacteria, total anaerobic fungi, total protozoa, Ruminococcus albus, R. flavefaciens, Butyrivibrio fibrisolvens, Fibrobacter succinogenes, and Ruminobacter amylophilus linearly increased (P < 0.05). Blood glucose, urea nitrogen, and non-esterified fatty acids linearly decreased (P < 0.05), while total protein concentration linearly increased (P = 0.04). Moreover, the addition of SB at 200 g/d promoted (P < 0.05) mRNA and protein expression of PPARγ, SREBF1, ACACA, FASN, SCD, CCNA2, CCND1, PCNA, Bcl-2, GPR41, and the ratios of p-Akt/Akt and p-mTOR/mTOR, but decreased (P < 0.05) mRNA and protein expressions of Bax, caspase-3, and caspase-9. The results suggest that milk production and milk fat synthesis increased with SB addition by stimulating rumen fermentation, nutrient digestion, gene and protein expressions concerned with milk fat synthesis and mammary gland development.

Project description:Theabrownin, an activated and ample pigment in Pu-erh tea, is known to exert antiobesity and antihyperlipidemic effects in humans, mice, and rats. In this study, we aimed to explore the effects of theabrownin (TB) dietary supplementation on production performance, egg quality, intestinal health, and antioxidant capacities in laying hens. In total, 160 Lohmann laying hens (25 weeks old) were randomly split into four groups (each group 40 hens), namely the CONT (control, basal diet + 0 mg/kg TB), TB1 (basal diet + 100 mg/kg TB), TB2 (basal diet + 200 mg/kg TB), and TB4 (basal diet + 400 mg/kg TB) groups, respectively. These were supplemented with TB for 12 weeks. The results showed that the TB1 group exhibited a significantly higher laying rate during 9 to 12 weeks and higher egg weight and feed conversion efficiency (lower FCR) during 5 to 8 weeks and in the overall period (1 to 12 weeks) than the CONT group (p < 0.05). Compared with the CONT group, the eggs from the TB4 group had higher albumen height and Haugh unit than those from the other treatment groups after the 8th and 12th week; notably, the same was also observed in the TB1 and TB2 groups but only after the 12th week (p < 0.05). The albumen quality (albumen height and Haugh unit) after 3 weeks of storage was significantly higher in the TB1, TB2 and TB4 groups than in the CONT group (p < 0.05). Furthermore, TB supplementation lowered the serum levels of total cholesterol and total triglyceride (p < 0.05). Expression analysis revealed that TB2 and TB4 groups had reduced expression of tumor necrosis factor-α (p < 0.05), while TB1, TB2, and TB4 had significantly decreased expression of interleukin-1β and IL-6 (p < 0.05). Conversely, zonula occludens-1, claudin-1, and mucin-2 were upregulated in the TB2 and TB4 groups (p < 0.05). Meanwhile, dietary TB supplementation ameliorated the antioxidant status of the ovary and the magnum, showing a significant reduction in malondialdehyde and 8-hydroxydeoxyguanosine levels in the magnum, the upregulation of glutathione in the ovary, and superoxide dismutase and catalase in the magnum (p < 0.05). Overall, dietary supplementation with TB (>100 mg/kg) improved production performance and egg storage quality by improving the intestinal health and antioxidant capacities of the reproductive system in laying hens.

Project description:BACKGROUNDHepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of nonalcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.METHODSForty consecutive nondiabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24 hours, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry.RESULTSWithin a subset of subjects, DNL was detectable after a 24-hour fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, non-esterified fatty acid, and ketones. Additionally, they sustained glycogenolysis and were spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis.CONCLUSIONMetabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL.TRIAL REGISTRATIONData were obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease, ClinicalTrials.gov NCT02690792.FUNDINGThis work was supported by the University of Texas Southwestern NORC Quantitative Metabolism Core (NIH P30DK127984), the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078184, R01DK128168, R01DK087977, R01DK132254, and K01DK133630), the NIH/National Institute on Alcohol Abuse and Alcoholism (K01AA030327), and the Robert A. Welch Foundation (I-1804).

Dataset Information

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.

Publications

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.

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