Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

Peroxisome proliferator-activated receptor-γ (PPARγ) expression can be regulated at the transcriptional level by tumour-necrosis factor-α (TNFα) (arrow 1) through the activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP1), which negatively regulate PPARγ expression–. Recent data indicate rapid turnover of PPARγ mRNA in adipocytes and treatment of cultured adipocytes with TNFα might enhance PPARγ mRNA degradation (dashed arrow 2). Translational control of PPARγ that is mediated by MAP4K4 (mitogen-activated protein kinase kinase kinase kinase-4), a protein kinase that is upregulated by TNFα, can also occur (arrow 3). Furthermore, activation of caspases by TNFα signalling might trigger PPARγ protein degradation in adipocytes (dashed arrow 4). Regulation of PPARγ activity and stability are also negatively regulated by kinase-mediated phosphorylation and ubiquitylation, which promote PPARγ protein degradation through a proteasome-dependent pathway (arrow 5). TNFα action at multiple levels might therefore result in decreased PPARγ activity. Precise regulation of PPARγ expression and function can contribute to the control of triglyceride biosynthesis, hydrolysis and deposition in the lipid droplet — the lipid storage organelle of adipocytes. This can occur through the regulation of the expression of triglyceride metabolism enzymes such as phosphoenolpyruvate carboxykinase (PEPCK), fatty acid synthase (FAS), Acyl-CoA synthetase (ACS), lipoprotein lipase (LPL) and lipid-droplet proteins including CIDEA, FSP27 and perilipin (arrow 6). Dashed arrows that emanate from PPARγ mRNA (step 2) and protein (step 4) indicate hypotheses that await definitive testing.

Publication

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. () Adilson Guilherme, et al. Nat Rev Mol Cell Biol. ;9(5):367-377. Figure: F3. All organisms Homo sapiens Danio rerio

Disease mentions