Lipid droplets (LDs), which largely found in adipocytes, are major organelles for energy storage and burndown. It is well known that ß-adrenergic signaling pathway liberates fatty acid from LDs to activate and fuel the thermogenesis program in mitochondria. However, the detailed events on the surface of LDs remain unclear. Here, we identified a novel hydrolase named Carboxylesterase 3 (Ces3) that targets LDs upon cold exposure by LC-MS/MS. We further found that translocation of Ces3 to LDs is cAMP-PKA pathway dependent. To investigate the function of Ces3 in β-adrenergic-activated adipocytes, we suppressed Ces3 with WWL229 (a specific Ces3 inhibitor) and small interfering RNA (siRNA) in 3T3-L1 and BAC (immortalized brown adipocytes) cells. We found that blockage of Ces3 by both methods dramatically attenuates ISO-induced lipolysis in cells. Furthermore, Ces3 inhibition leads to impaired mitochondrial respiratory function and attenuates ISO-induced thermogenic program in adipocytes by down-regulating Ucp1 and Pgc1α genes via PPARγ. Importantly, we further confirmed our findings by in vivo assays in mice. Specifically, our data showed that the thermogenic program in adipose tissue upon cold exposure is downregulated in WWL229 treated wild type mice and adipose tissue-specific Ces3 knockout mice. As the result, the mice exhibit dramatically impaired cold tolerance. Furthermore, we found that serum collected from cold-exposed wild type mice massively increase UCP1 levels in BAC cells while serum from Ces3 deficient mice fails to do so.
In conclusion, our study highlighted the Ces3-mediated lipolytic signaling as a unique process to regulate thermogenesis in adipose tissue.
L. Yang: None. X. Li: None. K. Sun: None.
National Institutes of Health