RESUMEN
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
Asunto(s)
Maleato de Dizocilpina , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Receptores de N-Metil-D-Aspartato , Animales , Humanos , Masculino , Ratones , Ratas , Tronco Encefálico/metabolismo , Tronco Encefálico/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/efectos adversos , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance.
