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Abstract

Obesity is a major risk factor for type 2 diabetes (T2D), in part due to its association with chronic low-grade inflammation and insulin resistance. Monocytes represent an important immune cell subset implicated in obesity-related inflammation. Evidence suggests that monocyte phenotype is related to their metabolic profile, however monocyte metabolism in obesity remains poorly characterized. Second, mitochondrial dysfunction is commonly exhibited during obesity and type 2 diabetes, however, these studies often do not account for activity levels, which have been shown to greatly impact mitochondrial function. Therefore, this study aimed to compare mitochondrial respiration in circulating monocytes and vastus lateralis skeletal muscle between lean individuals and those living with obesity, while matching participants for habitual activity levels. In a cross-sectional study design, 37 healthy adults (lean: n=20; obesity: n=17) - matched for physical activity, age, and sex distribution - completed two experimental visits involving a skeletal muscle biopsy, serial blood sampling throughout a mixed meal tolerance test (MMTT), and accelerometer-based physical activity tracking. Mitochondrial respiration was assessed using high-resolution respirometry in monocytes isolated from fasted blood samples and in permeabilized skeletal muscle fibers from the vastus lateralis biopsy. We found that monocyte respiration was significantly higher in lean individuals for CI+II oxidative phosphorylation (OXPHOS) and maximal uncoupled respiration (p < 0.05), suggesting diminished respiratory capacity in monocytes from individuals with obesity. Opposingly we found that skeletal muscle respiration was significantly higher in the group living with obesity across all respiratory states (p < 0.05). Activity levels were similar between groups, suggesting results were not confounded by habitual physical activity. These findings highlight distinct, tissue-specific alterations in mitochondrial metabolism in young individuals with obesity compared to lean counterparts. We hypothesize that the reduction in monocyte respiration may reflect systemic impairments in mitochondrial function, while increased skeletal muscle respiration may represent an early compensatory mechanism to energy surplus and lipid oversupply.