Figure 1.

The potential mechanisms underlying the anti-obesity effect of celastrol. Celastrol protects against obesity through both central and peripheral mechanisms. Mainly, in the hypothalamus, celastrol enhances leptin sensitivity by reducing ER stress via inhibition of PERK phosphorylation and possible GRP78, as well as activating IL1R and inhibiting PTP1B/TCPTP pathways. Celastrol can also attenuate food intake of obese mice by downregulating the levels of GAL, GALR1 and GALR3 in the brain. In terms of peripheral mechanisms, celastrol alleviates inflammatory responses by inhibiting both TLR3/NLRP3 inflammasome and NF-KB pathway. Celastrol also reduces inflammation and improves metabolic disorders by increasing Nur77/p62-mediated mitophagy. Celastrol activates HSF1/PGC1α, which results in the enhancement of energy expenditure and mitochondrial function in adipose tissues and muscles. Celastrol inhibits adipocyte differentiation and increases lipid metabolism by blocking PPARγ2- or C/EBPα-mediated transcriptional activity. Moreover, celastrol improves lipid metabolism by upregulating ABCA1, by reducing liver lipid synthesis, and by inhibiting gut lipid absorption by modulating gut microbiota. ABCA1—ATP-binding cassette transporter A1; C/EBPα—CCAAT/enhancer binding proteins-α; GAL—galanin; GALP—galanin-like peptides; GALR—galanin receptor; GRP78—78 kDa glucose-regulated protein; HSF1—heat shock factor 1; IL1R—interleukin-1 receptor; NF-κB—nuclear factor-κB; NLRP3—nucleotide-binding oligomerization domain—leucine-rich repeat—and pyrin domain containing 3; PGC-1α—peroxisome proliferator-activated receptor γ coactivator-1α; PERK—Protein kinase R-like ER kinase; PPARγ2—peroxisome proliferator-activated receptors-γ2; PTP1B—protein tyrosine phosphatase 1B; TCPTP—T-cell protein tyrosine phosphatase; TLR3—Toll-like receptor 3. Red arrows indicate “increase”, green arrows indicate “decrease”. Question marks mean “possible action and effect”.