Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss

Abstract

Lifestyle interventions can reliably produce and sustain only modest (~5%-10%) weight loss (1), necessitating other types of antiobesity interventions, such as pharmacotherapy, to address obesity management. Antiobesity medication development initially relied on observations of weight loss in agents approved for other indications, which resulted in troubled first-generation medications being used for weight management. However, new pharmacological treatments have been emerging based on an understanding of the biology of appetite regulation (2-4). These agents have been developed by taking advantage of their known effects on reducing energy intake and they appear promising in delivering more desirable amounts of weight loss of up to 15% from baseline after 6 to 10 months of treatment (2-4). Apart from weight loss per se, a more specific goal of weight management should be health improvement through a reduction

Glucagon‐like peptide‐1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial

“…Despite the limited impact of SAR425899 on EE, the blunted metabolic adaptation observed in the SAR425899 group may be important for weight-loss maintenance [12]. Our findings are supported by our recent study in which we observed reduced metabolic adaptation to be a distinguishing phenotype in people who meet their predicted weight-loss targets versus those who do not [40].…”

“…We also found greater FatOx and ketogenesis that were not due to the greater changes in weight and body composition. These metabolic effects of SAR425899 are important concepts for the further development of weight‐loss therapies because both low EE and low FatOx are risk factors for weight gain that impair loss of FM [12, 37].…”

“…We also found greater FatOx and ketogenesis that were not due to the greater changes in weight and body composition. These metabolic effects of SAR425899 are important concepts for the further development of weight-loss therapies because both low EE and low FatOx are risk factors for weight gain that impair loss of FM [12,37]. Both preclinical and short clinical studies of the dual GLP-1R/ GCGR agonist oxyntomodulin have shown increases in total, resting, and/or activity related EE [10,38].…”

“…Importantly, this increased FatOx and ketogenic metabolic profile was independent of the greater changes in weight and body composition in the SAR425899 group. Therefore, our results suggest that, unlike caloric restriction [41], SAR425899 improves impairments in FatOx, and this might contribute to weight‐loss success under certain conditions [12].…”

“…Loss of body energy stores (BES) is primarily driven by the following: a reduction of EI [8, 9] and/or an increase in EE, and/or a reduction in EE that is smaller than expected based on changes in body composition (reduced metabolic adaptation) [8–11]. It is now recommended that next generation weight‐loss agents should target not only weight loss, but also a decrease in metabolic adaptation and an increase in fat oxidation (FatOx), thus preventing the loss of fat free mass (FFM) [12]. The contribution of these metabolic parameters to the weight loss induced by the dual activation of GLP‐1R and GCGR is unknown.…”