A new study discovers how the GIPR signaling in brain cells helps weight loss drugs GLP-1 to bypass the blood-brain barrier and to amplify their insurance-power insurance effects, offering a mechanistic explanation for the clinical power of co-agonists.
Study: The signaling of insulinotropic polypeptide receptors dependent on glucose in oligodendrocytes increases the weight loss action of GLP-1R agonism. Image credit: Juan Gaertner / Shutterstock
In a recent study published in the journal Cellular metabolismA group of researchers has tested whether the signaling of the insulinotropic polypeptide receptor dependent on glucose (GIPR) in oligodendrocytes (OLS) increases access to the brain and weight loss efficiency of agonists of the Peptide-1 receptor of Glucagon type (GLP-1R).
Background
One in eight adults lives with obesity, and many now use incretinous medicines that can reduce weight by more than 20%. Incretins act via GIPR and GLP-1R, but the reason why the combinations helps not to be clear. The median eminence (ME), an interface where blood signals meet neurons, can be a door.
OLS, known for a long time to make myelin, also reshapes this door in response to the diet. The precision of the signaling of the insulinotropic polypeptide (GIP) insulinotropic dependent on glucose (GIP) in OLS increases the entrance to the brain and the effects of peptide-1-type glucagon (GLP-1) could guide stronger treatments; Additional research is necessary.
About the study
The researchers used adult mice to test whether the GIPR signaling in OLS shapes access to the brain and the effectiveness of GLP-1R agonists. They generated inductible OL Knockuts crossing the recombinase-ESTRogenic receptor of the protein protein 1-Cre (PLP1-Creert2) with GIPR floated mice, triggered a recombination with tamoxifen in the postnatal day 60 and an obesity induced with a regime rich in 60%. A GIPR agonist with prolonged action (LAGIPRA) and a GLP-1R agonist with prolonged action (LAGLP-1RA; LIRAGLUTIDE) were administered alone or together.
To map the entrance to the drug, a GLP-1R agonist with short-term action labeled with IR800 (IR800-EXENDIN-4) was injected; The brains have been eliminated and imagined by microscopy with light leaves. Oligodendrogenesis and myelinization have been quantified by in situ fluorescent hybridization and immunocoloration for the basic protein of myelin, the amplified sequence of breast carcinoma 1 and the morphogenetic bone 4 protein, with an action of 5-ethynyl-2′-desoxyuridine pulse action.
Vascular permeability has been evaluated by the expression of the vascular endothelial growth factor (VEGF-A), the immunoreactivity of the vascular endothelial growth factor (VEGF) and the antigen of endothelial cells of mouse 32 (MECA32) positive Fenestrated capillary. Metabolic readings included energy expenditure, food intake and glucose and insulin tolerance.
Finally, an adeno-associated virus coding for the M4 Human Muscarin M4 inhibitory receiver designed for activation by designer drugs (HM4DI) targeted from paraventricular hypothalamus (PVH) of vasopressin (AVP) in the mice of vasopressine of vasopressine (AVP-CRE) Vasopressin (AVP-CRE); The Deschloroclozapine was administered to activate HM4DI and remove these neurons during Liraglutide tests.
Study results
In the Me, GIPR was enriched in mature OLS, with a rare expression in the progenitor cells of OL; A fat diet has increased the OL density and the number of OL GIPR positive specifically in this region. This effect was not observed in the leaflets of the white substance such as the Callosum corpus, indicating a localized role.
The abolition of GIPR specific to OL has reduced adult oligodendrogenesis and OL survival in the ME and lowered the basic protein of myelin, while the main white matter lanes have shown little change, indicating a localized role in the metabolic gateway of the brain. The mice devoid of OL GIPR showed an energy expenditure and reduced intake, preserved tolerance with oral glucose, altered insulin tolerance and changes in metabolites linked to the branched chain, in accordance with the altered manipulation of the substrate during obesity.
Pharmacological activation has produced additional effects. In lean mice, a GIPR agonist with prolonged action increased cells in the OL line and myelin in the Me. In the obesity induced by food (DIO), the same agonist increased the new production of OL and the turnover restored, while increasing the vascular access signals: VEGF-A transcriptions and the immunoreactivity of the VEGF increased, and the Fenestré capillaries marked by MECA32 have become dense, indicating an increased vascular permeability.
The precrepated obese mouses with the agonist GIPR increased the absorption of the brain of a GLP-1R agonist with short action marked by 800 in the adjacent arched nucleus of the hypothalamus (ARH), indicating improved access through the Me-Arh border. Above all, this increase in absorption required OL GIPR; He was absent after the abolition of OL GIPR.
The efficiency reflected entry, as in wild-type mice, GLP-1R agonism with long working hours lowered food and body weight, and co-administration with the agonist GIPR amplified the two results; In the OL GIPR Knockouts, the GIPR agonist can no longer potentiate weight loss or anorexia driven by GLP-1R, indicating that OL GIPR signaling is required for complete synergy.
Imaging has shown that GLP-1R agonists with short action for short peripheral action accumulated along the myelinized axonal beams in the Me, roommating with a basic protein of myelin; Revealing a new mechanism: GLP-1R agonists administered peripherals access the brain via myelinized axons in the ME, bypassing the blood-brain barrier (BBB).
Super-resolution microscopy located GLP-1R on AVP axons and nodes marked by the protein associated with Contactin (CASPR). Finally, the chemoogenetic silence of AVP PVH neurons with the Deschloroclozapine prevented hypophagy and weight loss induced by Liraglutide, demonstrating that these neurons are necessary for the weight loss action of the systemic drug.
Conclusions
To summarize, this study connects incretinous pharmacology to a concrete brain entry mechanism: signaling via GIPR in OLS increases vascular permeability via the induction of the VEGF-A and the increase in capillary fenestration and allows agonists of GLP-1R to reach AVP axons regulating appetite.
The requirement of this path can help explain why GIPR / GLP-1R co-agonists have greater efficiency than unique agents and offer a mechanistic base for their improved clinical performance. Clinically, the mechanism helps to interpret the power of the co-agonists used for obesity and diabetes type 2 and points to biomarkers, such as induction or imagery of the VEGF-A of access to Me, to guide the dosage or combinations while limiting side effects.
However, the authors note several limitations: the model of Knockout OL GIPR only obtained a partial suppression; Experiments have mainly evaluated Liraglutide rather than other GLP-1R agonists; And the behavioral results, although informative, were not exhaustive. These warnings temper the conclusions and highlight the need for additional research to confirm generalization and clinical relevance.
Why does Zepbound (shooting) lead to more weight loss than ozempic (semaglutide)?
The double receiver (GLP-1 + GIP) has more pronounced effects in the Cervehttps: //t.co/1aldifds2o pic.twitter.com/ws81pf5cxf– Eric Topol (@erictopol) August 13, 2025