Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus

Celastrol is a natural pentacyclic
triterpene used in traditional
Chinese medicine with significant weight-lowering effects. Celastrol-administered
mice at 100 μg/kg decrease food consumption and body weight
via a leptin-dependent mechanism, yet its molecular targets in this
pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced
weight loss is largely mediated by the inhibition of leptin negative
regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell
PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show
in vitro that celastrol binds reversibly and inhibits noncompetitively
PTP1B and TCPTP. NMR data map the binding site to an allosteric site
in the catalytic domain that is in proximity of the active site. By
using a panel of PTPs implicated in hypothalamic leptin signaling,
we show that celastrol additionally inhibited PTEN and SHP2 but had
no activity toward other phosphatases of the PTP family. These results
suggest that PTP1B and TCPTP in the ARC are essential for celastrol’s
weight lowering effects in adult obese mice.