Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity
- 20 March 2001
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 98 (8) , 4652-4657
- https://doi.org/10.1073/pnas.061034298
Abstract
Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.Keywords
This publication has 35 references indexed in Scilit:
- Neuropeptide Y Counteracts the Anorectic and Weight Reducing Effects of Ciliary Neurotropic FactorJournal of Neuroendocrinology, 2000
- Anorectic Effects of the Cytokine, Ciliary Neurotropic Factor, Are Mediated by Hypothalamic Neuropeptide Y: Comparison with LeptinEndocrinology, 1998
- Leptin activation of Stat3 in the hypothalamus of wild–type and ob/ob mice but not db/db miceNature Genetics, 1996
- Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db MiceCell, 1996
- Identification and expression cloning of a leptin receptor, OB-RCell, 1995
- Recombinant Mouse OB Protein: Evidence for a Peripheral Signal Linking Adiposity and Central Neural NetworksScience, 1995
- Ciliary Neurotrophic Factor (CNTF) Induces Serum Amyloid A, Hypoglycaemia and Anorexia, and Potentiates IL-1 Induced Corticosterone and IL-6 Production in MiceCytokine, 1995
- Systemic administration of ciliary neurotrophic factor induces cachexia in rodents.Journal of Clinical Investigation, 1994
- Altered Expression of Hypothalamic Neuropeptide mRNAs in Food-Restricted and Food-Deprived RatsNeuroendocrinology, 1990
- Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleusPeptides, 1988