The long-term treatment of obesity remains challenged by powerful biological responses that resist weight loss and promote weight regain. Among these, metabolic adaptation, a reduction in energy expenditure beyond that predicted by changes in body composition, has been proposed as a key mechanism defending body weight following weight loss. Although this response likely evolved to protect against starvation, it may contribute to the difficulty many individuals experience in maintaining weight loss in modern environments. Evidence from human indirect calorimetry studies also suggests marked inter-individual variability in metabolic adaptation, raising important questions regarding its biological determinants and clinical significance. The emergence of highly effective incretin-based therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and newer multi-agonist approaches, has transformed expectations for obesity treatment by achieving levels of weight loss previously attainable only with bariatric surgery. However, their effects on the physiological systems that defend body weight remain incompletely understood. While these therapies primarily reduce energy intake through effects on appetite, satiation, and food reward pathways, increasing attention has focused on their potential influence on energy expenditure, substrate utilization, and other mechanisms relevant to long-term weight regulation. Emerging evidence suggests that changes in fuel selection, including increased fat oxidation, may contribute to their metabolic effects, although the extent to which these therapies modify metabolic adaptation remains uncertain. This presentation will examine the physiological basis of metabolic adaptation and critically evaluate current evidence regarding the effects of GLP-1 receptor agonists and emerging multi-agonist therapies on energy expenditure, substrate metabolism, and body composition.