Posted by Adipocytes are known to store a significant amount of non-esterified cholesterol in their lipid droplets. It has been hypothesized that adipose tissue serves as a cholesterol sink, and cholesterol levels can comprise from 25% of the total body cholesterol content in lean individuals up to 50% in obese individuals. The abundant amount and the unique storage form of cholesterol in adipocytes suggest its role in modulating adipocyte function. Moreover, studies have shown that cholesterol levels are elevated in hypertrophied adipocytes in obesity, and cellular cholesterol distribution is altered in hypertrophied adipocytes. Therefore, cholesterol imbalance may have an impact on adipocyte function during obesity or other diseases. To clarify this the cholesterol level in adipocytes was modulated to examine its effect on the secretion of adiponectin, an important hormone specifically secreted by adipocytes. Treating differentiated 3T3-L1 adipocytes with 4 mM methyl-β-cyclodextrin (MβCD), a molecule with a high affinity for cholesterol, rapidly depleted cholesterol in adipocytes. Interestingly, MβCD treatment increased adiponectin in the medium without affecting its intracellular level, suggesting a modulation of secretion. By contrast, cholesterol addition did not affect adiponectin secretion, suggesting that cholesterol-depletion-induced intracellular cholesterol trafficking, but not reduced cholesterol level, accounted for MβCD-induced adiponectin secretion. MβCD-induced adiponectin secretion was reduced after 10 μg/mL U18666A treatment that suppressed cholesterol transport out of late endosomes/lysosomes. Depleting Niemann–Pick type C1 (NPC1) or NPC2 proteins, which mediate endosomal/lysosomal cholesterol export, consistently reduced MβCD-induced adiponectin secretion. Furthermore, treatment with 1 μM bafilomycin A1, which neutralized acidic endosomes/lysosomes, also attenuated MβCD-induced adiponectin secretion. Finally, MβCD treatment redistributed cellular adiponectin to lower-density fractions in sucrose gradient fractionation. The results show that MβCD-mediated cholesterol depletion elevates the secretion of adiponectin, highlighting the involvement of endosomes and lysosomes in adiponectin secretion in adipocytes.
Chiang, Y.-T.; Wu, Y.-Y.; Lin, Y.-C.; Huang, Y.-Y.; Lu, J.-C. Cyclodextrin-Mediated Cholesterol Depletion Induces Adiponectin Secretion in 3T3-L1 Adipocytes. Int. J. Mol. Sci. 2023, 24, 14718. https://doi.org/10.3390/ijms241914718