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Ciliary Neurotrophic Factor Activates Leptin-Like Pathways and Reduces Body Fat, Without Cachexia or Rebound Weight Gain, Even in Leptin-Resistant Obesity

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Ciliary Neurotrophic Factor Activates Leptin-Like Pathways and Reduces Body Fat, Without Cachexia or Rebound Weight Gain, Even in Leptin-Resistant Obesity

P D Lambert et al. Proc Natl Acad Sci U S A.

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.

Figures

Figure 1
Figure 1
Treatment with leptin or CNTFAx15 in ob/ob and DIO mice [starting body weight ≈50 g]. Groups of ob/ob mice (n = 8) or DIO mice (n = 7) received a daily s.c. injection of vehicle (V), leptin (L; 1 mg/kg/day), or CNTFAx15 (C; 0.03, 0.1, 0.3 mg/kg/day). Body weight was measured daily and is shown as the percentage difference from body weight on the first day of injection (A1 and B1). A 24-h food intake was recorded and is shown as percentage of vehicle-treated control (A2 and B2). Body compositions were determined by carcass analysis at the end of the study, and data are shown as difference in fat and lean body mass (LBM) relative to vehicle-treated controls (A3 and B3). All data are mean ± SEM.
Figure 2
Figure 2
pSTAT3 and COX-2 immunostaining in the brain of ob/ob and DIO mice. The ob/ob mice (A) exhibited nuclear pSTAT3 immunostaining in neurons of the arcuate nucleus (arrowheads) 30 min after i.v. treatment with CNTFAx15 (0.1 mg/kg) or leptin (1.0 mg/kg). However, DIO mice showed STAT3-phosphorylation in response to CNTFAx15 but not leptin (B). No pSTAT immunostaining was seen in the arcuate nucleus of ob/ob (A) or DIO (B) mice 30 min after i.v. treatment with a dose of IL-1 (0.01 mg/kg) known to reduce body weight. Note that CNTFAx15 also induced pSTAT3 expression in the median eminence and in tanycytes and ependyma of the ventral part of the third ventricle. STAT3-phosphorylation was also noted within and adjacent to other circumventricular organs (area postrema, subfornical organ, and organum vasculosum of the lamina terminalis), which contain a fenestrated vasculature (data not shown). However, pSTAT3-immunoreactivity was not evident in other areas of the brain where CNTF receptor α is equally abundant, suggesting that peripherally administered CNTFAx15 does not freely cross the blood–brain barrier. The cortex of DIO mice (C) exhibited COX-2-immunostaining in blood vessels (arrowheads) 6 h after i.v. administration of IL-1 (0.01 mg/kg) but not CNTFAx15 (0.1 mg/kg). Arc, arcuate nucleus.
Figure 3
Figure 3
Evaluation of CTA, expressed as percentage of fluid intake as water after administration of CNTFAx15 (0.1, 0.5 mg/kg) or IL-1 (0.03 mg/kg) in C57BL/6 mice (n = 6, A). B illustrates changes in tibialis anterior (TA) muscle mass following a 10% reduction in body weight induced by CNTFAx15, IL-1, or food restriction (n = 5, B) in C57BL/6 mice (starting BW ≈24 g). The percentage difference in TA muscle weight from control (closed bar) is plotted alongside percentage change in body weight from day 0 to day 3 (open bar). Equivalent changes were observed in the relative weights of other muscles. Similarly distinct effects of IL-1 and CNTFAx15 on CTA response and muscle mass also were observed in AKR mice (data not shown).
Figure 4
Figure 4
Effect of CNTFAx15 and pair-feeding on hypothalamic markers of hunger in C57BL6 mice. Digitized images of pCREB immunostaining in the PVN after 3 days of s.c. treatment with vehicle, CNTFAx15 (C, 0.3 mg/kg/day) or pair-feeding (A). 3v, third ventricle. Histograms show mean number of pCREB-immunoreactive cells and NPY immunoreactivity (percentage of vehicle group) in the PVN after treatment (B and C; n = 4). ANOVA: pCREB, P < 0.01; NPY, P = 0.01. †, Difference from vehicle (veh); #, difference from pair-fed by Dunnett post hoc test. Northern blot analysis for Agrp, NPY, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA from hypothalamus of AKR mice after 4 days of treatment with CNTFAx15 (0.3 mg/kg/day), pair-feeding or a 48 h fast also is shown (D). Each lane represents pooled tissue from three mice.
Figure 5
Figure 5
Lack of rebound food intake in DIO mice after cessation of daily s.c. injection with CNTFAx15. DIO mice (n = 7; starting BW ≈50 g) were treated for 3 (A1 and B1) or 7 days (A2 and B2) with vehicle (V) or CNTFAx15 (C, 0.1, 0.3 mg/kg/day), or were pair-fed to the food intake of CNTFAx15-treated mice (P) after which all treatment was stopped and all animals were returned to ad lib feeding. The 24-h food intake (A1 and A2) and change in body weight (percentage from day 0; B1 and B2) was measured throughout both studies. The overeating and rapid return to prerestriction body weight seen after returning pair-fed mice to ad lib feeding was not seen after cessation of treatment with CNTFAx15.

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