title: The pathophysiology of defective proteostasis in the hypothalamus - from obesity to ageing.
abstract: Hypothalamic dysfunction has emerged as an important mechanism involved in the development of obesity and its comorbidities, as well as in the process of ageing and age-related diseases, such as type 2 diabetes mellitus, hypertension and Alzheimer disease. In both obesity and ageing, inflammatory signalling is thought to coordinate many of the cellular events that lead to hypothalamic neuronal dysfunction. This process is triggered by the activation of signalling via the toll-like receptor 4 pathway and endoplasmic reticulum stress, which in turn results in intracellular inflammatory signalling. However, the process that connects inflammation with neuronal dysfunction is complex and includes several regulatory mechanisms that ultimately control the homeostasis of intracellular proteins and organelles (also known as 'proteostasis'). This Review discusses the evidence for the key role of proteostasis in the control of hypothalamic neurons and the involvement of this process in regulating whole-body energy homeostasis and lifespan.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra, 3004-504, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Cavadas
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal.
authors.forename: Célia A
authors.initials: CA
authors.lastname: Aveleira
authors.affiliation: Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 1308-970, Brazil.
authors.forename: Gabriela F P
authors.initials: GF
authors.lastname: Souza
authors.affiliation: Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 1308-970, Brazil.
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease; D003924:Diabetes Mellitus, Type 2; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D006801:Humans; D006973:Hypertension; D007031:Hypothalamus / Q000378:metabolism*; D007249:Inflammation; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D011506:Proteins; D051197:Toll-Like Receptor 4