Ciliary Neurotrophic Factor Ax15 Alters Energy Homeostasis, Decreases Body Weight, and Improves Metabolic Control in Diet-Induced Obese and UCP1-DTA Mice
Susann Blüher 1 ,
Stergios Moschos 1 ,
John Bullen, Jr. 1 ,
Efi Kokkotou 2 ,
Eleftheria Maratos-Flier 2 ,
Stanley J. Wiegand 3 ,
Mark W. Sleeman 3 and
Christos S. Mantzoros 1
1 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
2 Joslin Diabetes Center, Harvard Medical School, Research Division, Boston, Massachusetts
3 Regeneron Pharmaceuticals, Tarrytown, New York
Address correspondence and reprint requests to Susann Blüher, Beth Israel Deaconess Medical Center, Harvard Medical School,
99 Brookline Ave., Boston, MA 02215. E-mail: sblueher{at}caregroup.harvard.edu
Abstract
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 μg · 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.
AgRP, agouti gene–related protein
BAT, brown adipose tissue
CNTF, ciliary neurotrophic factor
NPY, neuropeptide Y
OGTT, oral glucose tolerance test
POMC, proopiomelanocortin
UCP1, uncoupling protein 1
Footnotes
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
Accepted July 8, 2004.
Received February 11, 2004.
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Ciliary Neurotrophic FactorAx15 Alters Energy Homeostasis, Decreases Body Weight, and Improves Metabolic Control in Diet-Induced Obese and UCP1-DTA Mice

10.2337/diabetes.53.11.2787