Leptin signaling in the rainbow trout central nervous system is modulated by a truncated leptin receptor isoform.

Central leptin (Lep) signaling is important in control of appetite and energy balance in mammals, but information on Lep signaling and physiological roles in early vertebrates is still lacking. To elucidate fish Lep signaling activation and modulation, a long-form Lep receptor (LepRL) and a truncated LepR (LepRT) are functionally characterized from rainbow trout. The receptors generated in alternatively splicing events have identical extracellular and transmembrane domains but differ in the intracellular sequence, both in length and identity. Gene transfection experiments show that LepRL is expressed as a 125-kDa protein in rainbow trout hepatoma cell line RTH-149, whereas LepRT is 100 kDa; both receptors specifically bind Lep. Homogenous Lep induces tyrosine phosphorylation of Janus kinase 2 and signal transducer and activation of transcription 3 in LepRL-expressing RTH-149 cells. This response is diminished in cells coexpressing LepRL and LepRT, suggesting that the LepRT which lacks these kinase-associated motifs competes with the LepRL for Lep availability, thus attenuating the Lep signal. Both receptor genes are highly expressed in the central nervous system. The mRNA levels of LepRT in hypothalamus, but not LepRL, change postprandially, with decreased transcription at 2 hours postfeeding and then elevated at 8 hours, concomitant with changes in proopiomelanocortin-A1 transcription. However, both receptors have no change in mRNA levels during 3 weeks of fasting. These data indicate that LepRT transcription is more likely a mechanism for modulating Lep effects on short-term feed intake than in regulating energy balance in the long term. In vitro and physiological characterization of LepR isoforms indicates divergent Lep signaling modulation patterns among vertebrates with different life histories and metabolic profiles.