The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity
Authors: Lorenzo Petra I. , Fuente-Martín Esther , Mellado-Gil José M. , Martínez José A. Guerrero , Cobo-Vuilleumier Nadia , Comaills Valentine , Vazquez Eugenia Martin , Romero-Zerbo Silvana Y. , Franco Jaime Muñoz , Perez-Cabello Jesús A. , Canalejo Sabrina Rivero , Campos-Caro Antonio , Lachaud Christian Claude , Aguilar-Diosdado Manuel , Fuentes Eduardo García , Martin-Montalvo Alejandro , Dolado Manuel Álvarez , Martin Franz , Rojo-Martinez Gemma , Pozo David , Bérmudez-Silva Francisco J. , Reyes José C. , Gauthier Benoit R. 
Published: February 2021

ABSTRACTRationaleWe recently demonstrated that the ‘Metabesity’ factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1/CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues.MethodsHMG20A expression profile was assessed by quantitative PCR (RT-PCR) and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to a high-fat diet, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. To investigate the function and regulatory mechanism of HMG20A, RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. The regulatory function of HMG20A on astrogliosis was also assessed pharmacologically using ORY1001. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes.ResultsWe show thatHmg20ais predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain.Hmg20Aexpression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels ofGfapandIl1bindicative of inflammation and astrogliosis. Expression levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways with a concomitant increase in apoptosis and reduced mitochondrial bioenergetics. Motoneuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. Astrogliosis was induced using ORY1001, a pharmacological inhibitor of the LSD1/CoREST complex, mimicking the effect of HMG20A.ConclusionHMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce astrogliosis in an attempt to preserve the neuronal network and glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote astrogliosis and increase susceptibility of neurons to stress-mediated apoptosis. Such effects could be therapeutically reversed by ORY1001-induced astrogliosis.