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Common insulin resistance relates to positive energy balance and is central to obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In early MASLD, the liver adapts to increased energy supply by upregulating its oxidative phosphorylation (OXPHOS) capacity (mitochondrial plasticity), which is lost during MASLD progression and in type 2 diabetes. This study examined whether improvements in insulin sensitivity after bariatric surgery restore hepatic mitochondrial plasticity and thereby ameliorate liver histology. Persons with insulin resistance and obesity (n=16, BMI 52±8 kg/m2; HbA1c 5.5±0.1%) underwent bariatric and follow-up surgeries, at which liver biopsies were taken. MASLD was assessed histologically. Hepatic maximal ADP-stimulated respiration, reflecting OXPHOS capacity, was measured by high-resolution respirometry, tissue-specific insulin sensitivity by hyperinsulinemic-euglycemic clamps with 2H2-glucose. Mean body weight loss (-48.5 kg over 0.5-5 years) increased whole-body (stimulated glucose disposal) as well as hepatic (suppressed endogenous glucose production) insulin sensitivity by 57 and 32% (both p0.05), respectively. Fasting adipose tissue insulin resistance (Adipo-IR) decreased by 61% (p=0.005). Steatosis grade decreased in all participants, whereas lobular inflammation and ballooning did not uniformly change after surgery. Hepatic mitochondrial DNA (mtDNA) content slightly rose (p=0.02), whereas OXPHOS capacity remained unchanged for TCA cycle- and β-oxidation-linked respiration upon normalization for both tissue wet weight and mtDNA. In conclusion, bariatric surgery led to robust improvements in whole-body, hepatic and adipose tissue insulin sensitivity as well as hepatic steatosis. However, the failure to restore hepatic mitochondrial plasticity and to reverse inflammation indicates the need for novel mitochondria-targeted concepts for MASLD treatment. Disclosure S. Kahl: None. J. Puetzer-Furmanczak: None. N. Trinks: None. B. Dewidar: None. K. Pafili: None. S. Trenkamp: None. I. Esposito: None. M. Schlensak: None. F.A. Granderath: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca. Funding German Federal Ministry of Health (BMG); Ministry of Culture and Science of the State North Rhine-Westphalia (MKW NRW) to DDZGerman Federal Ministry of Education and Research (BMBF) to German Center for Diabetes Research (DZD e. V.). HORIZON-HLTH-2022-STAYHLTH-02-01: Panel A to the INTERCEPT-T2D consortium EUREKA Eurostars-2 (E!-113230-DIA-PEP)German Science Foundation (DFG; SFB/CRC1116, RTG/GRK 2576) Schmutzler-Stiftung "Profilbildung 2020"
KAHL et al. (Fri,) studied this question.