title: Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to pituitary dysfunction, neurodegeneration and development of obesity.
abstract: MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. However, their potential role in the central regulation of whole-body energy homeostasis is still unknown. In this study we show that the expression of Dicer, an essential endoribonuclease for miRNA maturation, is modulated by nutrient availability and excess in the hypothalamus. Conditional deletion of Dicer in POMC-expressing cells resulted in obesity, characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary-adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that started around 3 weeks of age. Hypothalamic transcriptomic analysis in presymptomatic POMCDicerKO mice revealed the downregulation of genes implicated in biological pathways associated with classical neurodegenerative disorders, such as MAPK signaling, ubiquitin-proteosome system, autophagy and ribosome biosynthesis. Collectively, our results highlight a key role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity.
authors.affiliation: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain ; Department of Endocrinology and Nutrition, Hospital Clínic, School of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Schneeberger
authors.forename: Jordi
authors.initials: J
authors.lastname: Altirriba
authors.forename: Ainhoa
authors.initials: A
authors.lastname: García
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Esteban
authors.forename: Carlos
authors.initials: C
authors.lastname: Castaño
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Lavandeira
authors.forename: Clara V
authors.initials: CV
authors.lastname: Alvarez
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
keywords: 3V, third ventricle; ACTH, adrenocorticotropic hormone; AP, adenopituitary; ARC, arcuate nucleus of the hypothalamus; AUC, area under the curve; Acp2, acid phosphatase 2, lysosomal; AgRP, agouti-related protein; Ago2, Argonaute 2; CART, cocaine and amphetamine-related transcript; CNS, central nervous system; CRH, corticotropin releasing hormone; Crhr1, corticotrophin releasing hormone receptor 1; Cx, Cortex; DIO, diet-induced obesity; Dicer; Fa, Fascicular zone; GFP, green fluorescent protein; Gapdh, Glyceraldehyde 3-phosphate dehydrogenase; Gh, growth hormone; Gl, Glomerular zone; Hprt, Hypoxanthine guanine phosphoribosyl transferase; Hypothalamus; IL, intermediate lobe; IP, intraperitoneal; LH, lateral hypothalamus; MC3R, melanocortin receptor 3; MC4R, melanocortin receptor 4; MZ, Marginal Zone; Me, Medula; Myc, myelocytomatosis oncogene; NP, neurohypophysis; NPY, neuropeptide Y; NS, not significant; Naglu, alpha-N-acetylglucosaminidase; Neurodegeneration; Nhlrc1, NHL repeat containing 1; Ntrk2, Neurotrophic tyrosine kinase, receptor, type 2; Obesity; POMC; POMC, pro-opiomelanocortin; POMCDicerKO, mice lacking Dicer in POMC-expressing cells; PVN, paraventricular nucleus; Park2, Parkin; Pit1, pituitary-specific transcription factor 1; Re, Reticular zone; Rps24, ribosomal protein S24; Rps9, ribosomal protein S9; Tpit, T box transcription factor; Tshβ, thyroid-stimulating hormone β chain; UD, undetectable; UPS, ubiquitin proteosome system; UTR, untranslated region; VMH, ventromedial hypothalamus; YFP, yellow fluorescent protein.; miRISC, miRNA-induced silencing complexes; miRNA, microRNA; microRNA; qPCR, quantitative real-time PCR