Autophagy-mediated NCOR1 degradation is required for brown fat maturation and thermogenesis

Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a macroautophagic/autophagic-dependent mechanism of peroxisome proliferator-activated receptor gamma (PPARG) activity regulation that indu...

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Bibliographic Details
Authors: Sabaté Pérez, Alba, Romero, Montserrat, Sànchez Fernàndez de Landa, Paula, Carobbio, Stefania, Mouratidis, Michail, Sala Cano, David, Engel Rocamora, Pablo, Villena, Josep A., Virtue, Sam, Vidal Puig, Antonio, Palacín Prieto, Manuel, Testar, Xavier, Zorzano Olarte, Antonio
Format: article
Status:Versión aceptada para publicación
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/201831
Online Access:https://hdl.handle.net/2445/201831
Access Level:Open access
Keyword:Metabolisme
Obesitat
Autofàgia
Teixit adipós
Metabolism
Obesity
Autophagy
Adipose tissues
Description
Summary:Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a macroautophagic/autophagic-dependent mechanism of peroxisome proliferator-activated receptor gamma (PPARG) activity regulation that induces brown adipose differentiation and thermogenesis and that is mediated by TP53INP2. Disruption of TP53INP2-dependent autophagy reduced brown adipogenesis in cultured cells. In vivo specific-tp53inp2 ablation in brown precursor cells or in adult mice decreased the expression of thermogenic and mature adipocyte genes in BAT. As a result, TP53INP2-deficient mice had reduced UCP1 content in BAT and impaired maximal thermogenic capacity, leading to lipid accumulation and to positive energy balance. Mechanistically, TP53INP2 stimulates PPARG activity and adipogenesis in brown adipose cells by promoting the autophagic degradation of NCOR1, a PPARG co-repressor. Moreover, the modulation of TP53INP2 expression in BAT and in human brown adipocytes suggests that this protein increases PPARG activity during metabolic activation of brown fat. In all, we have identified a novel molecular explanation for the contribution of autophagy to BAT energy metabolism that could facilitate the design of therapeutic strategies against obesity and its metabolic complications.

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