Adipocyte differentiation, termed adipogenesis, (the development of fat cells from preadipocytes) is a complicated process in which pluripotent mesenchymal stem cells differentiate into mature adipocytes. The process of adipocyte differentiation is tightly regulated by a number of transcription factors, hormones and signaling pathway molecules. Adipogenesis from preadipocytes into mature adipocyte is precisely coordinated by transcription factors such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), cytokines, and hormones.Adipose-derived mesenchymal stem cells (MSCs) have the capacity to differentiate into a variety of cell types, including adipocytes, osteoblasts, chondrocytes and myocytes. Adipogenic induction rapidly induces expression of the C/EBPβ and C/EBPδ. These are key early regulators of adipogenesis, and the anti-adipogenic preadipocyte factor 1 (PREF1) acts through SOX9 in the direct regulation of the promoters for the genes encoding C/EBPβ and C/EBPδ. Among the targets of C/EBPβ and C/EBPδ are the promoters of the genes encoding the key adipogenic transcription factors C/EBPα and PPARγ and the regulator of lipogenic genes SREBP1. PPARγ activates the promoter of the gene encoding C/EBPα and vice versa, creating a positive-feedback loop. In addition, PPARγ and C/EBPα induce the expression of genes that are involved in insulin sensitivity, lipogenesis and lipolysis.
Many factors influencing adipogenesis ultimately affect the activity of PPARγ. The sirtuin (Sirt) SIRT2, inhibits PPARγ indirectly by reducing the amount of forkhead box O1 (FOXO1) acetylation and phosphorylation. Phosphorylation of PPARγ provides another means of regulation. The kinase submodule of general transcription factor IIH (GTFIIH, also known as TFIIH), which contains both the RING finger protein menage a trois homolog 1 (MNAT1) and cyclin-dependent kinase (CDK) 7, phosphorylates PPARγ at Ser112.
Other factors affecting adipogenesis include Wnt signaling, a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator- activated receptor γ (PPARγ).
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) influence adipogenic transcription factor activity. MicroRNAs (miRNAs) provide an additional newly discovered mechanism for controlling adipogenic gene expression. These small noncoding RNAs are processed from longer precursor primary transcripts. Increased autophagosome levels in differentiating adipocytes suggest a potential role for autophagy in adipogenesis. Studies have demonstrated that loss of Atg5 or Atg7 in mice results in impaired white adipose tissue development in vitro and in vivo. Several molecules that are involved in the regulation of circadian rhythm have also been shown to influence adipogenesis, including nocturnin, PER2 and RevERBα, a target of the complex of CLOCK.
A considerable number of molecules or pathways that have been identified from cellular models of adipogenesis have yet to be validated in vivo or in human cells. The ability of adipose tissue to influence whole-body metabolism makes it attractive for pharmacological therapy.