Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

Abstract

Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.

Keywords: Adipocyte hypertrophy; Adipose dysfunction; Insulin resistance; Obesity.

Fig. 1

Adipocyte hypertrophy-induced and metabolic dysregulations. With the increase of lipid accumulation, adipocyte hypertrophy is associated with, exacerbation of inflammation, adipocyte hypoxia, excessive collagen deposition, abnormal adipokine release, and impaired glucose metabolism, which finally contribute to dysregulated systemic energy metabolism

Fig. 2

Molecular mechanism of adipogenesis. During the process of mesenchymal stem cells (MSCs) commitment to adipose lineage, WNT1 inducible signaling pathway protein 2(WISP2) presented in the cytosol repressed transcriptional activator zinc finger protein-423 (ZFP423) through formation of a WISP2/ZFP423 complex in cytosol. Bone morphogenetic protein 4 (BMP4) phosphorylates SMAD1/5/8 to dissociate WISP2/ZFP423 complex, making ZFP423 enter into the nucleus and further activates peroxisome proliferator-activated receptor γ (PPARγ). BMP4 inhibitor Gremlin-1 suppresses MSCs by inhibiting BMP4. Likewise, extracellular WISP2 inhibits PPARγ by activating β-catenin. After committed differentiation to adipogenic lineage, EBF transcription factor 1(EBF1), a transcription factor activated by CCAAT-enhancer-binding proteins (C/EBPβ) and C/EBPδ, induces the activation of PPARγ. C/EBPα binds on the promoter region of PPARγ and forms the self-reinforcing regulatory loop to further stimulate adipogenesis. Activated PPARγ heterodimerizes with retinoid X receptor α (RXRα) and promotes transcription of genes involved in adipocyte differentiation and lipid transport