FABP4 Controls Fat Mass Expandability (Adipocyte Size and Number) through Inhibition of CD36/SR-B2 Signalling.

Adipose tissue hypertrophy during obesity plays pleiotropic effects on health. Adipose tissue expandability depends on adipocyte size and number. In mature adipocytes, lipid accumulation as triglycerides into droplets is imbalanced by lipid uptake and lipolysis. In previous studies, we showed that adipogenesis induced by oleic acid is signed by size increase and reduction of FAT/CD36 (SR-B2) activity. The present study aims to decipher the mechanisms involved in fat mass regulation by fatty acid/FAT-CD36 signalling. Human adipose stem cells, 3T3-L1, and its 3T3-MBX subclone cell lines were used in 2D cell cultures or co-cultures to monitor in real-time experiments proliferation, differentiation, lipolysis, and/or lipid uptake and activation of FAT/CD36 signalling pathways regulated by oleic acid, during adipogenesis and/or regulation of adipocyte size. Both FABP4 uptake and its induction by fatty acid-mediated FAT/CD36-PPARG gene transcription induce accumulation of intracellular FABP4, which in turn reduces FAT/CD36, and consequently exerts a negative feedback loop on FAT/CD36 signalling in both adipocytes and their progenitors. Both adipocyte size and recruitment of new adipocytes are under the control of FABP4 stores. This study suggests that FABP4 controls fat mass homeostasis.

Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots?

TBC1D4 (AS160) and TBC1D1 are Rab GTPase-activating proteins that play a key role in the regulation of glucose and possibly the transport of long chain fatty acids (LCFAs) into muscle and fat cells. Knockdown (KD) of TBC1D4 increased CD36/SR-B2 and FABPpm protein expressions in L6 myotubes, whereas in murine cardiomyocytes, TBC1D4 deficiency led to a redistribution of CD36/SR-B2 to the sarcolemma. In our study, we investigated the previously unexplored role of both Rab-GAPs in LCFAs uptake in human adipocytes differentiated from the ADMSCs of subcutaneous and visceral adipose tissue origin. To this end we performed a single- and double-knockdown of the proteins (TBC1D1 and TBC1D4). Herein, we provide evidence that AS160 mediates fatty acid entry into the adipocytes derived from ADMSCs. TBC1D4 KD resulted in quite a few alterations to the cellular phenotype, the most obvious of which was the shift of the CD36/SR-B2 transport protein to the plasma membrane. The above translated into an increased uptake of saturated long-chain fatty acid. Interestingly, we observed a tissue-specific pattern, with more pronounced changes present in the adipocytes derived from subADMSCs. Altogether, our data show that in human adipocytes, TBC1D4, but not TBC1D1, deficiency increases LCFAs transport via CD36/SR-B2 translocation.