White adipose tissue achieves metabolic functions through the release of signaling molecules, such as adipokines, and hundreds of diverse factors, including classical hormones such as leptin, growth factors such as IGF-1 and PDGF, and cytokines such as IL-6, IL-8, or TNF-α acting as inflammatory mediators , comprehensively linked to appetite regulation and insulin sensitivity. Growing evidence supports the notion that chronic low-grade inflammation is a basic characteristic of obesity contributing to the establishment of insulin resistance into the target organs, including the adipose tissue, liver, and muscle, and the vascular system . Excess of nutrients, such as lipids and glucose, may simultaneously trigger inflammatory responses, which further disrupt metabolic function, enhancing stress and inflammation. Accordingly, the nutrition–immunity theory suggests that in the adipose tissue, overnutrition-induced obesity triggers low-level inflammatory processes . Anomalous fat accumulation has been shown to increase pathogenic risks since adipose tissue remains in a state of subclinical chronic inflammation . This condition is strictly related to a massive recruitment of macrophages and to an increased immune cell proliferation activation–infiltration connected to adipocyte hypertrophy and an impaired adipogenesis . The latter process is tightly controlled by a mixture of regulatory signals including endocellular transcription factors, extracellular circulating hormones , and additional post-transcriptional regulators of gene expression [60, 169,170,171,172].|
Adipogenesis is the process during which fibroblast-like pre-adipocytes differentiate into mature adipocytes, a complex mechanism involving cell commitment, clonal expansion, and terminal differentiation . More in detail, differentiation from pre-adipocytes into mature adipocytes is a key step orchestrated by several transcription factors such as the peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) that coordinately control expression of genes required for adipocyte phenotypes. C/EBPβ and C/EBPδ are induced by adipogenic stimuli and represent primary regulators of adipogenesis. Targets of C/EBPβ and C/EBPδ are the promoters of the genes encoding critical adipogenic factors such as C/EBPα and PPARγ, as well as the sterol regulatory element-binding protein (SREBP1), the key regulator of lipogenic genes. The protein encoded by the C/EBPα intronless gene is a leucine zipper transcription factor which can bind to specific promoters and enhancers as a homodimer or it can form heterodimers with the related proteins C/EBPβ and C/EBPγ. The C/EBPα protein has been shown to bind to the promoter and to also modify the expression of the leptin gene, playing a central role in body weight homeostasis. C/EBPα is sufficient to trigger differentiation of pre-adipocytes into mature adipocytes . Peculiarly, PPARγ directly triggers endogenous C/EBPα transcription. In turn, C/EBPα activates the PPARγ gene through a positive feedback loop, thereby promoting adipogenesis . Together, PPARγ and C/EBPα promote the expression of genes involved in insulin sensitivity, in lipogenesis and lipolysis, and, ultimately, in the terminal differentiation and mature functions of adipocytes. The complex series of events governing adipose cell commitment and differentiation also includes anti-adipogenic signaling cascade controlled by Wnt, BMPs, TGF-β, and hedgehog . As expected, an increase in size (hypertrophy) and number (hyperplasia) of adipocytes causes higher level of fat mass and energy storage in the adipose tissue, possibly ending in increased obesity risk.