Role of histone deacetylase 3 (HDAC3) in adipose tissue metabolism and immunophenotype: Selected Abstract - SITeCS Congress 2022

Selected Abstract - SITeCS Congress 2022

Lara Coppi
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Carolina Peri
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Fabrizia Bonacina
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Raffaella Longo
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Dalma Cricrí
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Silvia Pedretti
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Rui Silva
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Ilenia Severi
Department of Experimental and Clinical Medicine, Marche Polytechnic University
Antonio Giordano
Department of Experimental and Clinical Medicine, Marche Polytechnic University
G. Danilo Norata
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Alberico L. Catapano
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Nico Mitro
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Emma De Fabiani
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Maurizio Crestani
Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy
Share:

Abstract

Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT.
Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS.
Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P<0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P<0.0001). No difference was observed following HDAC3 silencing in mature adipocytes.
We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation.
Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype.
[FONDAZIONE CARIPLO 2015-0641]

Send mail to Author


Send Cancel

Custom technologies based on your needs

  • MongoDB
  • ElasticSearch
  • Redis
  • Solr
  • Memcached