Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice - Relationship with body weight change

H. Dhillon, Y. L. Ge, R. M. Minter, V. Prima, L. L. Moldawer, N. Muzyczka, S. Zolotukhin, P. S. Kalra, S. P. Kalra

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (βOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-βOb (6 x 109 particles) was ineffective, the middle dose (6 x 1010 particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6 x 1011 particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-βOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, α-melanocyte stimulating hormone and cocaine-and- amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-βOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders. (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalRegulatory Peptides
Volume92
Issue number1-3
DOIs
StatePublished - Aug 25 2000

Keywords

  • AgrP
  • Gene Therapy
  • Hypothalamus
  • Leptin
  • NPY
  • POMC

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Clinical Biochemistry
  • Cellular and Molecular Neuroscience

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