A secondary β-hydroxybutyrate metabolic pathway linked to energy balance

Maria Dolores Moya-Garzon; Mengjie Wang; Veronica L Li; Xuchao Lyu; Wei Wei; Alan Sheng-Hwa Tung; Steffen H Raun; Meng Zhao; Laetitia Coassolo; Hashim Islam; Barbara Oliveira; Yuqin Dai; Jan Spaas; Antonio Delgado-Gonzalez; Kenyi Donoso; Aurora Alvarez-Buylla; Francisco Franco-Montalban; Anudari Letian; Catherine Ward; Lichao Liu; Katrin J Svensson; Emily L Goldberg; Christopher D Gardner; Jonathan P Little; Steven M Banik; Yong Xu; Jonathan Z Long

doi:10.1101/2024.09.09.612087

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance

bioRxiv [Preprint]. 2024 Sep 9:2024.09.09.612087. doi: 10.1101/2024.09.09.612087.

Authors

Maria Dolores Moya-Garzon^{1

2

3}, Mengjie Wang⁴, Veronica L Li^{1

5

2

3}, Xuchao Lyu^{1

2

3}, Wei Wei^{1

6

2}, Alan Sheng-Hwa Tung^{1

6

2}, Steffen H Raun⁷, Meng Zhao^{1

8

9}, Laetitia Coassolo^{1

8

9}, Hashim Islam¹⁰, Barbara Oliveira¹⁰, Yuqin Dai², Jan Spaas^{1

2}, Antonio Delgado-Gonzalez¹¹, Kenyi Donoso¹², Aurora Alvarez-Buylla⁶, Francisco Franco-Montalban¹³, Anudari Letian¹⁴, Catherine Ward¹⁵, Lichao Liu^{9

16}, Katrin J Svensson^{1

8

9}, Emily L Goldberg¹⁴, Christopher D Gardner¹⁵, Jonathan P Little¹⁰, Steven M Banik^{5

2}, Yong Xu⁴, Jonathan Z Long^{1

2

8

3

17}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
³ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁴ USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁶ Department of Biology, Stanford University, Stanford, CA, USA.
⁷ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ School of Health and Exercise Sciences, University of British Columbia, Kelowna, British Columbia, Canada.
¹¹ Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
¹² Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Campus de Cartuja sn, 18011, Granada, Spain.
¹⁴ Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
¹⁷ The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.

Abstract

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous 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. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

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Preprint

Abstract

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