GIPR's Dual Action for Weight Loss Unveiled
- 15 ago
- 2 Min. de lectura
The global public health crisis of obesity is witnessing significant advancements with new therapies that unravel the body's complex hormonal mechanisms. Recent studies shed light on how the surprising GIPR's dual action for weight loss, through both activation and blockade of the glucose-dependent insulinotropic polypeptide receptor (GIPR), promises more effective treatments with less frequent dosing.
One of the most notable developments is AMG 133 (maridebart cafraglutide), an innovative bispecific molecule. This compound was engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two glucagon-like peptide-1 (GLP-1) analogue agonist peptides. Preclinical trials in obese mice and monkeys demonstrated its ability to reduce body weight and improve metabolic markers, including decreased food intake, blood glucose, insulin, and lipids.
A phase 1 clinical study in humans with obesity confirmed these promising findings. AMG 133 showed an acceptable safety and tolerability profile, along with pronounced, dose-dependent weight loss that was maintained for up to 150 days after the last dose in multiple ascending dose cohorts. The most common side effects were mild gastrointestinal symptoms, such as nausea and vomiting, which generally resolved within 48 hours after initial administration. Its prolonged half-life, approximately 14 to 24 days, allows for less frequent dosing—every 4 weeks—representing a significant improvement compared to other treatments that require daily or weekly injections.
What has puzzled scientists is how both activation (agonism) and blockade (antagonism) of GIPR can promote weight loss when combined with GLP-1 activation. New research has solved this mystery: GIPR agonists and antagonists achieve weight loss through completely different and independent brain mechanisms.
GIPR agonists require intact GIPR signaling in gamma aminobutyric acid (GABA)-releasing neurons (GABAergic neurons) in the brain for their effects.
On the other hand, GIPR antagonists do not depend on this neuronal pathway. Instead, their effect is intrinsically linked to functional GLP-1R signaling, activating similar pathways in the hindbrain, a key region for appetite control and energy balance.
Furthermore, a recent study has revealed a fundamental explanation for the greater efficacy of GIPR/GLP-1R co-agonists (such as tirzepatide). GIPR signaling in oligodendrocytes (OLs) in the brain's median eminence (ME) increases vascular permeability at this critical blood-to-neuron interface. This, in turn, facilitates the access of GLP-1R agonists to the brain, allowing them to reach appetite-regulating neurons and thus amplifying their appetite-suppressing and weight-loss effects.
These discoveries not only validate the combined approach of GIPR antagonism and GLP-1R agonism for treating obesity but also pave the way for the development of more specific and potent drugs. The future of obesity medicine looks promising, with therapies that act more intelligently and durably on the body and brain.
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