LEPTIN: A NOVEL ROLE AS A NUTRITIONAL MODULATOR OF LIMB DEVELOPMENT AND REGENERATION  IN XENOPUS LAEVIES TADPOLES

Marietta Easterling

We tested the hypothesis that leptin, a nutritionally regulated hormone in post-natal vertebrates, plays a role in mediating nutrition-dependent morphogenesis in Xenopus laevis tadpoles. In limb development, we showed that leptin receptor and transcripts and protein were expressed primarily in the epidermis and neurons growing into the limb, and leptin administration activated JAK/STAT and MAPK/ERK pathways in these tissues. Potential endocrine sources of leptin at this stage were intestine, liver, and pituitary. Leptin injections activated leptin receptor in the hypothalamus, and administration of leptin in the brain accelerated limb development. Whole-body leptin mRNA expression was reduced with food restriction, confirming it is a nutritionally regulated hormone. This study supports the hypothesis that leptin is involved in epidermis differentiation and neurogenesis in limbs, and modulates limb development through paracrine, endocrine and neuroendocrine pathways. In an extensive review of the literature, we found that there is evidence for nutritional regulation of regeneration in other animals, but the mechanisms underlying this regulation are not understood. In this study we hypothesized that leptin is a factor that mediates nutrition-dependent regeneration. We showed that leptin and leptin receptor (long form) transcripts were highly expressed throughout regeneration and were expressed during wound epidermis and blastema formation. Leptin protein was also localized in the wound epidermis, in the epidermis of the forming blastema, and presumptive regenerating nerves. We also showed that leptin activates both JAK/STAT3 and MAPK/ERK signaling in these tissues. Our functional assays showed that food restriction caused a reduction in the amount and quality of limb regeneration, and both peripheral and intracerebroventricular leptin injections partially recovered this effect. Conversely, limb regeneration rate was reduced when leptin signaling was reduced via injection of leptin antibody. These data suggest that leptin signaling has pleiotropic roles during early stages of limb regeneration via paracrine/autocrine and could affect regeneration via endocrine or neuroendocrine actions that depend upon nutritional availability. This the first functional evidence supporting a role of leptin in regeneration, with roles in wound epidermis formation, blastema formation, and neural regeneration. These studies firmly support a role for leptin as a morphogen and growth factor during early development.

LEPTIN: A NOVEL ROLE AS A NUTRITIONAL MODULATOR OF LIMB DEVELOPMENT AND REGENERATION IN XENOPUS LAEVIES TADPOLES

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