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Zweck, E.* ; Piel, S.* ; Schmidt, J.W.* ; Scheiber, D.* ; Schön, M.* ; Kahl, S.* ; Burkart, V.* ; Dewidar, B.* ; Remus, R.* ; Chadt, A.* ; Al-Hasani, H.* ; Mastrototaro, L.* ; Aubin, H.* ; Boeken, U.* ; Lichtenberg, A.* ; Distler, J.* ; Polzin, A.* ; Kelm, M.* ; Westenfeld, R.* ; Wagner, R.* ; Schrauwen, P.* ; Szendroedi, J. ; Roden, M.* ; Granata, C.*

Impaired mitochondrial ketone body oxidation in insulin resistant states.

EBioMedicine 122:106007 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Reduced mitochondrial respiratory function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) β-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear. METHODS: Targeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human or murine cohorts with T2D, obesity, and MASLD. FINDINGS: In humans with T2D, KB-driven mitochondrial OXPHOS capacity was ∼30% lower in the heart (p < 0.05) and skeletal muscle (p < 0.05) compared to non-diabetic controls. The relative contribution of KBs to maximal OXPHOS capacity in T2D was also lower in both the heart (∼25%, p < 0.05) and skeletal muscle (∼50%, p < 0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KBs to OXPHOS capacity was ∼15% lower (p < 0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p < 0.05) in obese humans with hepatic steatosis compared to humans without. INTERPRETATION: Mitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD. FUNDING: German Research Foundation, German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Center for Diabetes Research, German Heart Foundation, German Diabetes Society, Christiane-and-Claudia Hempel Foundation, European Community and Schmutzler Stiftung.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Diabetes Mellitus ; Ketone Bodies ; Masld ; Mitochondrial Respiration ; Obesity; Skeletal-muscle; Nonalcoholic Steatohepatitis; Metabolic Flexibility; Obesity; Bodies; Respiration; Kidney; Dysfunction; Humans; Roles
ISSN (print) / ISBN 2352-3964
e-ISSN 2352-3964
Zeitschrift EBioMedicine
Quellenangaben Band: 122, Heft: , Seiten: , Artikelnummer: 106007 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Förderungen Schmutzler-Stiftung
German Research Foundation (Deutsche Forschungsgemeinschaft)
DFG
German Diabetes Center - German Federal Ministry of Health (BMG)
Ministry of Culture and Science of the State of North Rhine-Westphalia - German Federal Ministry of Education and Research (BMBF)
MKW NRW
German Heart Foundation
German Diabetes Society (DDG)
Christiane-and-Claudia Hempel Foundation
European Community
Susanne-Bunnenberg-Stiftung at the Dsseldorf Heart Center