Ciliary neurotrophic factor infused intracerebroventricularly shows reduced catabolic effects when linked to the TAT protein transduction domain.
Ciliary neurotrophic factor (CNTF) regulates the differentiation and survival of a wide spectrum of developing and adult neurons, including motor neuron loss after injury. We recently described a cell-penetrant recombinant human CNTF (rhCNTF) molecule, formed by fusion with the human immunodeficiency virus-1 transactivator of transcription (TAT) protein transduction domain (TAT-CNTF) that, upon subcutaneous administration, retains full neurotrophic activity without cytokine-like side-effects. Although the CNTF receptor is present in hypothalamic nuclei, which are involved in the control of energy, rhCNTF but not TAT-CNTF stimulates signal transducers and activators of transcription 3 phosphorylation in the rat hypothalamus after subcutaneous administration. This could be due limited TAT-CNTF distribution in the hypothalamus and/or altered intracellular signaling by the fusion protein. To explore these possibilities, we examined the effect of intracerebroventricular administration of TAT-CNTF in male adult rats. TAT-CNTF-induced weight loss, although the effect was smaller than that seen with either rhCNTF or leptin (which exerts CNTF-like effects via its receptor). In contrast to rhCNTF and leptin, TAT-CNTF neither induced morphological changes in adipose tissues nor increased uncoupling protein 1 expression in brown adipose tissue, a characteristic feature of rhCNTF and leptin. Acute intracerebroventricular administration of TAT-CNTF induced a less robust phosphorylation of signal transducers and activators of transcription 3 in the hypothalamus, compared with rhCNTF. The data show that fusion of a protein transduction domain may change rhCNTF CNS distribution, while further strengthening the utility of cell-penetrating peptide technology to neurotrophic factor biology beyond the neuroscience field.
Vieira
André S
AS
Department of Genetics, Evolution and Bioagents, State University of Campinas, Campinas, SP, Brazil. vieira.as@gmail.com
Rezende
Alexandre C S
AC
Grigoletto
Jessica
J
Rogério
Fabio
F
Velloso
Lício A
LA
Skaper
Stephen D
SD
Negro
Alessandro
A
Langone
Francesco
F
D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015696:Gene Products, tat / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014161:Transduction, Genetic / Q000379:methods*
D020934:Ciliary Neurotrophic Factor; D015696:Gene Products, tat; D011993:Recombinant Fusion Proteins