Regulatory mechanisms of the early phase of white adipocyte differentiation: an overview

Abstract

The adipose organ comprises two main fat depots termed white and brown adipose tissues. Adipogenesis is a process leading to newly differentiated adipocytes starting from precursor cells, which requires the contribution of many cellular activities at the genome, transcriptome, proteome, and metabolome levels. The adipogenic program is accomplished through two sequential phases; the first includes events favoring the commitment of adipose tissue stem cells/precursors to preadipocytes, while the second involves mechanisms that allow the achievement of full adipocyte differentiation. While there is a very large literature about the mechanisms involved in terminal adipogenesis, little is known about the first stage of this process. Growing interest in this field is due to the recent identification of adipose tissue precursors, which include a heterogenous cell population within different types of adipose tissue as well as within the same fat depot. In addition, the alteration of the heterogeneity of adipose tissue stem cells and of the mechanisms involved in their commitment have been linked to adipose tissue development defects and hence to the onset/progression of metabolic diseases, such as obesity. For this reason, the characterization of early adipogenic events is crucial to understand the etiology and the evolution of adipogenesis-related pathologies, and to explore the adipose tissue precursors' potential as future tools for precision medicine.

Keywords: Adipogenesis; Cytoskeleton; Epigenome modifications; Obesity; Transcriptional control of differentiation.

Fig. 1

Schematic representation of adipogenesis and of main mechanisms involved in adipose tissue stem cell commitment. In the first phase of adipogenesis, adipose tissue stem cells undergo adipogenic commitment in the presence of specific chemical and physical cues (step 1, green area), while in the second phase white preadipocytes build up lipids as energy storage and express adipokines (step 2, blue area). These steps are mainly controlled by several transcription factors that are finely coordinated in a time-dependent fashion [, –119]. Notably, adipose tissue stem cell transition to preadipocytes is not associated to significant morphological changes, rather to biochemical, genetic, and metabolic rearrangements; these include F-actin fibers breakdown and F-actin rearrangement to preadipocyte periphery (step 3), mitochondrial biogenesis and fusion associated to increased metabolic performance (step 4), and epigenetic events occurring on both DNA, histones and RNA (step 5). Among the main epigenetic modification, histone phosphorylation, acetylation, methylation and ubiquitination together with DNA and RNA methylation have been demonstrated as important regulatory steps of adipogenesis [72, 120, 121]