The review explains that gut hormones GLP‑1 and GIP can both help people lose weight, but the way they work is still being figured out. Surprisingly, drugs that either turn on (agonists) or block (antagonists) the GIP receptor can both cause weight loss, likely because engineered peptides trigger different cellular signals than the natural hormone. New compounds that mix GLP‑1 and GIP activity, like the experimental drug retatrutide, look promising for stronger weight‑loss effects, but more research is needed before they can be used safely outside clinical trials.

One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified. This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of 'biased agonism' wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction. Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.