Obesity prevalence is the primary cause of metabolic issues that lead to preventable and premature death. The rate of obesity has increased since 2017 from 30.5% to 41.9%. Additionally, the rates of severe obesity have almost doubled from 4.7% to 9.2%, with an annual medical cost of approximately 173 billion US dollars. While caloric restriction and increased caloric output are highly effective in reducing weight, research into the pharmaceutical management of overweight individuals is gaining significant traction.
Currently, there are 6 therapeutics with an FDA indication for weight loss and management. Their mechanisms of action range from working as a stimulant to being a glucagon-like peptide-1 (GLP-1) receptor agonist in order to suppress appetite and reduce caloric intake. However, new mechanisms are needed to manage weight and are under investigation. Researchers from McMaster University in Canada have uncovered a novel mechanism by increasing energy expenditure in skeletal muscle during caloric restriction, eliciting more significant weight loss than caloric restriction alone.
Caloric restriction has been shown to successfully treat non-alcoholic fatty liver disease as well as boost insulin sensitivity in type 2 diabetes; however, maintaining weight loss is often challenging due to adaptive thermogenesis. Researchers have revealed that treatment with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glucose control by suppressing food intake via glial-cell-derived neurotrophic factor family receptor α-like (GFRAL). Additionally, GDF15 helps counter reductions in energy expenditure, leading to greater weight loss. This process involves GFRAL–β-adrenergic signaling that enhances muscle fatty acid breakdown. Targeting this pathway could maintain energy expenditure during caloric restriction and help revolutionize pharmaceutical weight management.
