Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats

The centrally-projecting Edinger-Westphal nucleus (EWcp) hosts a large population of neurons expressing urocortin 1 (Ucn1) and about half of these neurons also express the leptin receptor (LepRb). Previously, we have shown that the peripheral adiposity hormone leptin signaling energy surfeit modulates EWcp neurons' activity. Here, we hypothesized that Ucn1/LepRb neurons in the EWcp would act as a crucial neuronal node in the brain white adipose tissue (WAT) axis modulating efferent sympathetic outflow to the WAT. We showed that leptin bound to neurons of the EWcp stimulated STAT3 phosphorylation, and increased Ucn1-production in a time dependent manner. Besides, retrograde transneuronal tract-tracing using pseudorabies virus (PRV) identified EWcp Ucn1 neurons connected to WAT. Interestingly, reducing EWcp Ucn1 contents by ablating EWcp LepRbpositive neurons with leptin-saporin, did not affect food intake and body weight gain, but substantially (+26%) increased WAT weight accompanied by a higher plasma leptin level and changed plasma lipid profile. We also found that ablation of EWcp Ucn1/LepRb neurons resulted in lower respiratory quotient and oxygen consumption one week after surgery, but was comparable to sham values after 3 and 5 weeks of surgery. Taken together, we report that EWcp/LepRb/Ucn1 neurons not only respond to leptin signaling but also control WAT size and fat metabolism without altering food intake. These data suggest the existence of a EWcp-WAT circuitry allowing an organism to recruit fuels without being able to eat in situations such as the fight-or-flight response.

Automated summary

This study reveals that the centrally-projecting Edinger-Westphal nucleus (EWcp) plays a role in controlling white adipose tissue (WAT) size and fat metabolism, in response to leptin signaling. The existence of a circuitry between EWcp and WAT allows the organism to recruit energy without being able to eat, in situations such as the fight-or-flight response.