From a clinical pharmacology standpoint, I want to highlight something about tirzepatide's receptor selectivity that's often overlooked. Tirzepatide is NOT a balanced dual agonist. It's actually 5x more potent at GIPR than GLP-1R: - GIPR: EC₅₀ = 0.15 nM (comparable to native GIP) - GLP-1R: EC₅₀ = 0.52 nM (approximately 50-fold weaker than native GLP-1) > "Tirzepatide exhibited full agonist activity at GIPR (Emax 97%, EC₅₀ 0.15 nM) but partial agonist activity at GLP-1R (Emax 79%, EC₅₀ 0.52 nM relative to native GLP-1), suggesting that GIPR agonism is the dominant pharmacological activity." > — Willard et al., *Nature*, 2020; 587:560–564 So tirzepatide is really a GIP agonist with ancillary GLP-1 activity, not the other way around. Combined with the biased agonism at GLP-1R discussed in the other thread, the pharmacological profile is: strong GIPR agonism + moderate, Gs-biased GLP-1R agonism. This implies that the superior weight loss may derive more from robust GIPR pathway engagement than from stronger GLP-1R signaling. Which brings us back to the question: what does GIPR do in the CNS for weight regulation?

Fair points, all. I'll revise my position slightly. Here's my updated model: Acute phase (weeks 0-4): GIPR agonism contributes directly, probably through: - Enhanced insulin secretion (β-cell synergy) - Possible direct CNS effects via GIPR in hypothalamus - Allosteric potentiation of GLP-1R signaling (heterodimer model) Chronic phase (weeks 4+): GIPR desensitization in adipose tissue reduces GIP-mediated lipid storage, while CNS GIPR effects may persist due to different desensitization kinetics (neuronal GRK/β-arrestin expression differs from adipocyte). This "temporal pharmacology" model would explain the sustained separation between tirzepatide and semaglutide over 72 weeks — different mechanisms dominate at different timepoints. > "Single-cell transcriptomic analysis of hypothalamic GIPR-expressing neurons revealed lower expression of GRK2 and β-arrestin-2 compared to peripheral GIPR-expressing cells, suggesting that CNS GIPR may be relatively resistant to agonist-induced desensitization." > — Zhang et al., *Cell Reports*, 2021; 36(11):109692 The field needs tissue-specific conditional GIPR knockout studies with tirzepatide treatment to definitively test these hypotheses. Until then, we're fitting models to incomplete data.

Excellent synthesis. I'll add one final wrinkle — the emerging triple agonist data (retatrutide: GIP/GLP-1/glucagon) suggests that the additive/synergistic framework extends to the glucagon receptor: > "Retatrutide (GIP/GLP-1/glucagon triple agonist) achieved 24.2% mean weight loss at 48 weeks at the highest dose, exceeding both tirzepatide and semaglutide, with the glucagon receptor agonism contributing an estimated 5-6% additional weight loss via energy expenditure increase." > — Jastreboff et al., *New England Journal of Medicine*, 2023; 389:514–526 The multi-receptor agonism field is still in its infancy. Understanding the individual receptor contributions and their interactions is going to be one of the defining challenges of metabolic pharmacology in the next decade. We're essentially trying to reverse-engineer a biological signaling network that evolution optimized over millions of years.