Impact of the metabolic disease status in obesity and surgical weight loss on human adipose tissue bioenergetics

Obesity is associated with insulin resistance (IR) development, a risk factor for type 2 diabetes (T2D). How mitochondrial bioenergetics, in adipose tissue (AT), differs according to distinct metabolic profiles (i.e. insulin sensitive (IS), IR normoglycaemic (IR-NG), pre-diabetes (PD) and T2D) is still poorly understood. The purpose of this study was to evaluate and compare bioenergetics and energy substrate preference by omental AT (OAT) and subcutaneous AT (SAT) from subjects with obesity (OB, n = 40) at distinct metabolic stages. Furthermore, AT bioenergetics was also evaluated pre- and post-bariatric/metabolic surgery (BMS). High-resolution respirometry (HRR) was used to measure the real-time oxidative phosphorylation (OXPHOS) capacity and mitochondrial substrate preferences in both tissues. Substrate-uncoupler-inhibitor titration protocols were used: SUIT-P1 (complex I and II-linked mitochondrial respiration) and SUIT-P2 (fatty acid oxidation (FAO)-linked mitochondrial respiration). Flux control ratios (FCRs) were calculated. In SUIT-P1, lower OXPHOS capacity was observed in AT, particularly in SAT, during the establishment of IR (OB-IR-NG) and in the T2D group, due to alterations of mitochondrial coupling, evaluated by FCRs. In SUIT-P2, the OXPHOS coupling efficiency was highest in the OB-IR-NG group. AT from OB-IS, OB-IR-NG and OB-IR-PD preferred pyruvate, malate and glutamate oxidation and/or FAO during OXPHOS, whereas AT from T2D preferred succinate oxidation. BMS enhanced mitochondrial respiration in OAT, even under poor OXPHOS coupling efficiency. In conclusion, real-time OXPHOS analysis by HRR may be a sensitive biomarker of mitochondrial fitness, particularly in AT. Interventions based on modulating energetic substrate availability may become a good tool for obesity treatment stratification.