Mouse study links brain GIP receptors to dual GLP-1/GIP agonist advantage

A study published April 6, 2021, in the journal Cell Metabolism reports that GIP receptors in the central nervous system are required for the extra weight-loss effect that dual GLP-1/GIP agonists have over GLP-1-only drugs — at least in mice ^[1].

The paper, titled "The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling," reports two main findings ^[1]. Mice that lacked GIP receptors in the central nervous system were protected from diet-induced obesity ^[1]. And when a drug that activates both the GLP-1 and GIP receptors was given to those animals, it lost its superiority over a drug that activates only the GLP-1 receptor ^[1]. In other words, the added benefit of hitting GIP disappeared once the brain could no longer respond to GIP.

The result points to the brain — rather than the gut or the pancreas alone — as the place where GIP acts on body weight and food intake ^[1]. GIP stands for glucose-dependent insulinotropic polypeptide ^[1].

Dual GLP-1/GIP agonists are a drug category that activates two hormone receptors with one molecule. Tirzepatide, sold in the US as Mounjaro and Zepbound, is the dual GLP-1/GIP agonist on the market. Semaglutide, sold as Ozempic, Wegovy and Rybelsus, activates the GLP-1 receptor alone.

The findings come from mice. Whether the same biology holds in people has not been reported, and no human results appear in the study ^[1]. Which specific compounds were tested, at what doses, and how large the weight differences between the animal groups were, have not been reported in detail here ^[1].

Why it matters for patients

The practical picture for people taking or considering these medications has not changed because of this paper. The drugs currently sold were evaluated in human trials, and a mouse experiment does not add to or subtract from those results.

What the study does is sharpen a question researchers are working on. If GIP's contribution to weight loss depends on the brain, then part of the difference between a dual agonist and a GLP-1-only drug may come down to how well a drug reaches and acts on GIP receptors in the central nervous system ^[1]. The work also raises a possibility that has not been tested in people: that reducing GIP signaling in the brain, rather than increasing it, could affect weight, since mice without central GIP receptors were protected from diet-induced obesity ^[1].

Nothing in this study addresses dosing, side effects, or which medication is better for any individual. Questions about treatment belong with a clinician.

What happens next

The paper does not list dated next steps. Confirming the mechanism would require work in additional animal models and, eventually, studies in people; human results have not been reported ^[1]. Whether drugmakers are pursuing treatments designed around GIP receptors in the brain has not been disclosed.