Matheus Melo Fabiano; Marcia Barbosa Aguila & Carlos A. Mandarim-de-Lacerda

GLP-1 is an incretin secreted by intestinal cells and neurons in the brainstem, controlling glucose levels and food intake (appetite and satiety). Glucagon-like peptide type 1 receptor agonists (GLP-1RAs), as monotherapy or combined with other molecules, are indicated to treat type 2 diabetes mellitus (T2DM) and obesity because they act on the pancreatic beta-cell and insulin production and cause weight loss. However, the central action and neural pathways through which GLP-1Ras act must be better understood. Proopiomelanocortin (POMC) and neuropeptide Y (NPY) are critical neuropeptides intrinsically involved in the signaling pathway regulating appetite and satiety through GLP-1 and its agonists. Notably, the focus on combating obesity could be blocking the stimulation of orexigenic pathways and inhibiting anorexigenic pathways. Therefore, due to the high complexity of the neural circuits involved in appetite and satiety signaling and the multiple GLP-1RAs actions, more research still needs to be performed to elucidate these mechanisms. In addition, T2DM and obesity are associated with neuroinflammation and microglial activation, leading to a favorable environment for the development of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. In this case, the Hippocampus is the privileged target. In this text, we will review the main points related to the hypothalamic and hippocampal location and the activation pathways of POMC and NPY neurons that are targets of GLP-1RAs and have demonstrated an effective pharmacological treatment that has changed the perspective of the evolution of T2DM and obesity.

KEYWORDS: Hypothalamus; Hippocampus; POMC neurons; NPY neurons; GLP-1.

FABIANO, M. M.; AGUILA, B. M. & MANDARIM-DE-LACERDA, C. A. The hypothalamus and hippocampus are targets for new drugs controlling the energy balance and treating type 2 diabetes mellitus, obesity, and neurodegenerative diseases. Int. J. Morphol., 43(1):182-193, 2025.