High-resolution respirometry reveals altered mammalian tissue ketone body oxidation in different cardiometabolic diseases

Abstract

Background and aimsReduced mitochondrial 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) {beta}-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear. MethodsTargeted 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 and mouse cohorts with T2D, obesity, and MASLD. ResultsIn 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 KB 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 KB 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 MASLD compared to humans without MASLD. ConclusionsMitochondrial 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.