Activation, inhibition, same effect: the infinite complexity of human biology
If you are like me and have been following the rise and rise and rise of GLP-1 analogues and other incretin drugs against obesity, diabetes, cardiovascular disease, w̶o̶r̶l̶d̶ ̶c̶o̶n̶f̶l̶i̶c̶t̶ and more, you may have been puzzled by the different approaches drugmakers are taking when it comes to one of the incretin hormones, the glucose-dependent insulinotropic polypeptide (GIP). For example, @eli lilly's mega-blockbuster tirzepatide combines GLP-1 receptor agonism with GIP receptor (GIPR) agonism, meaning that it "activates" both receptors: it's a double agonist. By contrast, Amgen, for example, has seen positive Phase 2 results with MariTide, which combines a GIPR antagonist with two GLP-1 analogues (GLP-1R agonists), with somewhat different metabolic parameters.
How is it possible that both agonism and antagonism of the same receptor can have the same effect? Usually, when you do something, the results are different from doing the opposite.
A fantastic paper illuminates the different pathways that lead to enhanced body weight loss when combined with GLP-1R agonism. The study (GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice, Nature Metabolism) led by @timo müller and @matthias Tschöp of @Helmhotz Berlin with colleagues from Germany, Poland and... Indianapolis of course (hi @pat knerr!, @jonathan douros, @brian finan, @richard dimarchi, @kyle sloop, @ricardo samms), shows "that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling."
Another timely article in the same issue by an @Amgen team led by @murielle véniant (GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice, Nature Metabolism) observes a synergistic weight loss effect with the GLP-1R agonism combined with GIPR antagonism that requires both signaling pathways. To quote from a companion commentary (paywalled), "A convergence of CNS signaling mechanisms used by GLP-1R agonists and GIPR antagonists is supported by in vivo data from both" studies. By contrast, GIPR agonism seems to be recruiting different neural pathways that remain to be discovered. Lastly, the Amgen study identified the transcriptomic signatures of "tissue remodelling, improved lipid metabolism, and decreased inflammation in both adipose tissue and liver."
In other words, there is nothing simple about incretins and their receptors.