Coordinated metabolic transitions and gene expression by NAD+ during adipogenesis

Author:

Sánchez-Ramírez Edgar1,Ung Thi Phuong Lien2,Alarcón del Carmen Alejandro1,del Toro-Ríos Ximena1ORCID,Fajardo-Orduña Guadalupe R.1ORCID,Noriega Lilia G.3ORCID,Cortés-Morales Victor A.4ORCID,Tovar Armando R.3,Montesinos Juan José4ORCID,Orozco-Solís Ricardo5ORCID,Stringari Chiara2ORCID,Aguilar-Arnal Lorena1ORCID

Affiliation:

1. Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico 1

2. Laboratory for Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau, France 2

3. Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico 3

4. Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, Mexico City, Mexico 4

5. Laboratorio de Cronobiología y Metabolismo, Instituto Nacional de Medicina Genómica, Mexico City, Mexico 5

Abstract

Adipocytes are the main cell type in adipose tissue, which is a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells (hMSCs) through adipogenesis, a tightly controlled differentiation process involving close interplay between metabolic transitions and sequential programs of gene expression. However, the specific gears driving this interplay remain largely obscure. Additionally, the metabolite nicotinamide adenine dinucleotide (NAD+) is becoming increasingly recognized as a regulator of lipid metabolism, and a promising therapeutic target for dyslipidemia and obesity. Here, we explored how NAD+ bioavailability controls adipogenic differentiation from hMSC. We found a previously unappreciated repressive role for NAD+ on adipocyte commitment, while a functional NAD+-dependent deacetylase SIRT1 appeared crucial for terminal differentiation of pre-adipocytes. Repressing NAD+ biosynthesis during adipogenesis promoted the adipogenic transcriptional program, while two-photon microscopy and extracellular flux analyses suggest that SIRT1 activity mostly relies on the metabolic switch. Interestingly, SIRT1 controls subcellular compartmentalization of redox metabolism during adipogenesis.

Funder

Human Frontier Science Program

Agence Nationale de la Recherche

Universidad Nacional Autónoma de México

Consejo Nacional de Ciencia y Tecnología

Publisher

Rockefeller University Press

Subject

Cell Biology

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