Ciliary neurotrophic factorAx15 alters energy homeostasis, decreases body weight, and improves metabolic control in diet-induced obese and UCP1-DTA mice.
Ciliary neurotrophic factor (CNTF) potently reduces appetite and body weight in rodents and humans. We studied the short- and long-term effects of CNTF(Ax15), a second-generation CNTF analog, in diet-induced obese C57BL/6J mice and brown adipose tissue (BAT)-deficient obese UCP1-DTA (uncoupling protein 1-diphtheria toxin A) mice. CNTF(Ax15) administration (0.1, 0.3, or 1.0 microg . g(-1) . day(-1) s.c.) for 3 or 7 days reduced food intake and body weight (mainly body fat mass). The effect of CNTF(Ax15) on food intake and body weight was more pronounced in CNTF(Ax15)-treated diet-induced obese C57BL/6J mice compared with pair-fed controls and was associated with suppressed expression of hypothalamic neuropeptide Y and agouti gene-related protein. Moreover, CNTF(Ax15) increased uncoupling protein 1 mRNA expression in BAT and energy expenditure in diet-induced obese C57BL/6J mice. Longitudinal observations revealed a sustained reduction in body weight for several days post-CNTF(Ax15) treatment of CNTF(Ax15)-treated but not pair-fed mice, followed by a gradual regain in body weight over 28 days. Finally, CNTF(Ax15) administration improved the metabolic profile in both diet-induced obese C57BL/6J and UCP1-DTA mice and resulted in a significantly improved glycemic response to oral glucose tolerance tests in CNTF(Ax15)-treated UCP1-DTA compared with pair-fed mice of similar body weight. These data suggest that CNTF(Ax15) may act through a pathway downstream of the putative point responsible for leptin resistance in diet-induced obese C57BL/6J and UCP1-DTA mice to alter food intake, body weight, body composition, and metabolism. CNTF(Ax15) has delayed and persistent effects in diet-induced obese C57BL/6J mice, which account for a reduction in body weight over and above what would be expected based on decreased foot intake alone.
Blüher
Susann
S
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215, USA. sblueher@caregroup.harvard.edu.
Moschos
Stergios
S
Bullen
John
J
Kokkotou
Efi
E
Maratos-Flier
Eleftheria
E
Wiegand
Stanley J
SJ
Sleeman
Mark W
MW
Sleemann
Mark W
MW
Mantzoros
Christos S
CS
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D002352:Carrier Proteins / Q000494:pharmacology*; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D004032:Diet; D004167:Diphtheria Toxin / Q000494:pharmacology; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007473:Ion Channels; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009765:Obesity / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000071256:Uncoupling Protein 1
D001786:Blood Glucose; D002352:Carrier Proteins; D020934:Ciliary Neurotrophic Factor; D004167:Diphtheria Toxin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C029795:diphtheria toxin fragment A