Driven by increased caloric intake relative to expenditure, obesity is a major health concern placing economic and operational strain on healthcare and social care worldwide. Pharmacologically, one of the most effective avenues for the management of excess adiposity is the suppression of appetite. However, owing to the body's natural physiological defense to weight loss and tolerability issues that typically accompany anorectic agents, leveraging this approach to induce sustained weight loss is often easier said than done. As such, to address these challenges, researchers have coupled a thorough understanding of the gut-brain axis with advancements in peptide engineering to design therapeutics mimicking the actions of endocrine hormones to promote a negative energy balance. Indeed, multireceptor agonists targeting the GLP-1, GIP, and glucagon receptors produce meaningful weight loss in people with obesity. Herein, we provide a rationale for how activation of the GIP receptor in the brain and the glucagon receptor in the liver and adipose tissue functions to synergize with GLP-1 receptor agonism to curb the drive to feed and ignite the combustion of excess calories for providing next-generation weight loss.