ArticleCell2025
A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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43citing papers in PubMed, 1 pooled it
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Low-carbohydrate diets reduce cardiovascular risk factor levels in patients with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis of randomized controlled trials.Frontiers in nutrition · 2025Pooled it
- Medium-Chain Triglyceride Dietary Supplements Reduce Glucose Metabolism of Gait-Related Skeletal Muscle in Older Adults: A LongitudinalNutrients · 2025Trial
- Exercise intensity determines circulating levels of Lac-Phe and other exerkines: a randomized crossover trial.Metabolomics : Official journal of the Metabolomic Society · 2025Trial
- Exercise intensity as a modulator of gut microbiota and host metabolic health in obesity.Gut microbes · 2026Review
- Exercise-induced protein lactylation: From molecular mechanisms to precision health applications.iScience · 2026Review
- RagC senses β-hydroxybutyrate abundancy to suppress mTORC1.Protein & cell · 2026Article
- Ketosis elevates plasma concentrations of D-β-hydroxybutyryl-phenylalanine (BHB-Phe) in humans.Nutrition & metabolism · 2026Article
- Tissue-dependent enzymatic control of N-acetyl-β-alanine by PTER.The Journal of biological chemistry · 2026Article
- A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19.bioRxiv : the preprint server for biology · 2026Article
- Ketogenic Diet in Obesity and Diabetes: A Narrative Review.Nutrients · 2026Review
- The significance of the ketolytic gene OXCT1 in metabolism, intracellular signaling and disease development.Cellular and molecular life sciences : CMLS · 2026Review
- Synergistic Intervention for Obesity: Integrating Central Appetite Regulation and Peripheral Energy Expenditure.Current obesity reports · 2026Review
- Decoding stereospecific metabolic regulation of protein modifications.Nature chemistry · 2026Article
- Metabotherapy for intestinal disease: using metabolites to prevent and treat disorders of the gut.Nature reviews. Gastroenterology & hepatology · 2026Review
- Lactate as a Chemical Modification on Proteins and Metabolites.Annual review of biochemistry · 2026Review
- Muscle movement and metabolism: exercise and skeletal muscle as mediators of health-a report from the 26th Annual Harvard Nutrition Obesity Symposium, 2025.The American journal of clinical nutrition · 2026Article
- Ketogenic Diet Promotes Reward Learning by Upregulating Hippocampal CAMK2A Expression and Activating Dopamine Synaptic Signaling.International journal of molecular sciences · 2026Article
- Review
- β-Hydroxybutyrate Attenuates Diabetic Kidney Disease Partially Via β-hydroxybutyrylation of Nrf2.Inflammation · 2026Article
- β-Hydroxybutyrate upregulates hepatic histone β-hydroxybutyrylation modification, promotes the expression of PPARα, and alleviates the hepatic steatosis in MASLD.Clinical epigenetics · 2026Article
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Authors and funding
27 authors.
Maria Dolores Moya-GarzonDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
Mengjie WangUSDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Veronica L LiDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
Xuchao LyuDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
Wei WeiDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Alan Sheng-Hwa TungDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Steffen H RaunDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Meng ZhaoDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Laetitia CoassoloDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Hashim IslamSchool of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
Barbara OliveiraSchool of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
Yuqin DaiSarafan ChEM-H, Stanford University, Stanford, CA, USA.
Jan SpaasDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Antonio Delgado-GonzalezDepartment of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
Kenyi DonosoDepartment of Urology, Stanford University School of Medicine, Stanford, CA, USA.
Aurora Alvarez-BuyllaDepartment of Biology, Stanford University, Stanford, CA, USA.
Francisco Franco-MontalbanDepartamento de Química Farmacéutica y Orgánica, Universidad de Granada, Campus de Cartuja sn, 18071 Granada, Spain.
Anudari LetianDepartment of Physiology, University of California, San Francisco, San Francisco, CA, USA.
Catherine P WardStanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Lichao LiuStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Katrin J SvenssonDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Emily L GoldbergDepartment of Physiology, University of California, San Francisco, San Francisco, CA, USA.
Christopher D GardnerStanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Jonathan P LittleSchool of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
Steven M BanikDepartment of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Yong XuUSDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: yongx@bcm.edu.
Jonathan Z LongDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. Electronic address: jzlong@stanford.edu.
Funding
Stanford Islet Research CoreP30DK116074 · NIDDK · STANFORD UNIVERSITY · PI Seung K Kim · 2017 to 2026
$19.5MMechanisms controlling fructose uptake and utilizationR01DK125260 · NIDDK · STANFORD UNIVERSITY · PI Katrin Jennifer Svensson · 2020 to 2026
$3.5MCardiovascular and Chronic Disease Prevention Training ProgramT32HL161270 · NHLBI · STANFORD UNIVERSITY · PI CHRISTOPHER D GARDNER · 2022 to 2026
$2.6MNeurobiology for Lac-Phe HypophagiaR01DK136479 · NIDDK · UNIVERSITY OF SOUTH FLORIDA · PI YONG XU · 2023 to 2026
$2.5MMolecular Pharmacology Training ProgramT32GM136631 · NIGMS · STANFORD UNIVERSITY · PI BOGYO, MATTHEW, CHEN, JAMES K · 2021 to 2025
$2.0MChemical control of energy metabolism by N-acyl amino acidsR01DK124265 · NIDDK · STANFORD UNIVERSITY · PI LONG, JONATHAN Z · 2020 to 2024
$2.0MMolecular Pharmacology Training GrantT32GM113854 · NIGMS · STANFORD UNIVERSITY · PI MOCHLY-ROSEN, DARIA · 2015 to 2019
$1.1MImpact of ketone bodies on age-related inflammation and healthspan extensionR00AG058801 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GOLDBERG, EMILY LAUREN · 2020 to 2022
$743kThe role of circulating Slit2 in adipose thermogenesis and diabetesR00DK111916 · NIDDK · STANFORD UNIVERSITY · PI SVENSSON, KATRIN JENNIFER · 2018 to 2020
$731kInvestigating Isthmin as an adipose-to-muscle messenger that promotes muscle protein synthesisK99AR081618 · NIAMS · STANFORD UNIVERSITY · PI ZHAO, MENG · 2023 to 2024
$182kThe role of circulating Slit2 in adipose thermogenesis and diabetesK99DK111916 · NIDDK · DANA-FARBER CANCER INST · PI SVENSSON, KATRIN JENNIFER · 2016 to 2017
$180kNutrition Regulates Sexual FunctionF32HD112123 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI WANG, MENGJIE · 2024 to 2025
$131kAmerican Heart Association-American Stroke Association 24POST1196199NHLBI NIH HHS T32 HL161270NIAMS NIH HHS K99 AR081618NIA NIH HHS R00 AG058801NICHD NIH HHS F32 HD112123NIDDK NIH HHS K99 DK111916NIDDK NIH HHS P30 DK116074NIDDK NIH HHS R00 DK111916NIDDK NIH HHS R01 DK124265NIDDK NIH HHS R01 DK125260NIDDK NIH HHS R01 DK136479NIGMS NIH HHS T32 GM113854NIGMS NIH HHS T32 GM136631
Abstract
β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.
Indexed as
3-Hydroxybutyric AcidKetonesObesityAmino AcidsAnimalsDiet, KetogenicHumansKetone BodiesMaleMiceMice, Inbred C57BLMice, Knockout3-Hydroxybutyric AcidAmino AcidsKetone BodiesKetonesBHBenzymeketonemetabolitemetabolomicsobesity
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