Semaglutide mitigates the loss of fat-free mass and decreased energy expenditure observed after diet restriction. Insights from an obese minipig model.

The objective of this is to compare the effects of diet restriction and semaglutide treatment on body composition (BC), energy expenditure (EE), and metabolic adaptation (MA) in Göttingen Minipigs as a model for human obesity. Diet-induced obese Göttingen Minipigs were divided into three groups ( = 8): a control group receiving vehicle and fed ad libitum, a group treated with the GLP-1 receptor agonist (GLP-1RA) semaglutide and fed ad libitum, and a diet-restricted group receiving vehicle and weight-matched the semaglutide group. BC, EE, and plasma parameters were measured at baseline and after 10 wk; tissue mitochondrial respiration and myosin conformation were measured after 10 wk. Diet-restricted minipigs gained 6.8% ( < 0.01) more body fat compared with semaglutide, mediated by a greater loss of fat-free mass (4.3 kg, < 0.05) and a tendency for a higher fat mass gain ( = ns). Diet restriction led to significantly decreased EE compared with the control group (-273 kcal/day, < 0.05), but no differences between groups were observed when adjusting EE for changes in BC. Energy balance modeling revealed significant MA in the diet-restricted animals ( < 0.01) compared with both control and semaglutide groups. Diet restriction was further associated with decreased proton leak and resting myosin ATP consumption in muscle. Semaglutide treatment improved BC and EE outcomes compared with diet restriction despite similar weight trajectories. Furthermore, semaglutide treatment prevented specific energy-conserving changes in tissues, thus highlighting novel mechanisms regulating energy balance during GLP-1RA treatment. Specific energy-conserving mechanisms and metabolic adaptation challenge weight loss efficiency and maintenance, and promote weight regain after diet restriction. Less is known about these mechanisms after pharmacologically induced weight loss. For the first time in a minipig model of obesity, the research demonstrated how GLP-1 receptor agonist (GLP-1RA) treatment, compared with a weight-matched diet-restricted group, positively influenced body composition, energy expenditure, mitochondrial thermogenesis, and myosin ATPase activity. These novel mechanisms of energy expenditure may have potential as future drug targets.