Abstract
Recent findings show that ciliary neurotrophic factor (CNTF) and leptin have similar effects on food intake and body weight, suggesting possible overlapping mechanisms. Intracerebroventricular (icv) injection of leptin results in adipose tissue apoptosis. To determine if CNTF has similar activity, male Sprague Dawley rats implanted with lateral cerebroventricular cannulas were randomly assigned to four treatment groups (N = 8), including control (aCSF), 10 μg/day leptin, 1 μg/day CNTF, and 5 μg/day CNTF. Rats received daily icv injections for 4 successive days. Both leptin and CNTF (5 μg) decreased BW (8.6% and 11.77%, respectively, p < .05) and cumulative food intake was decreased 43% by leptin (p < .05). Leptin and CNTF (5 μg) reduced adipose tissue mass in epididymal adipose (Epi) by 30 and 33.5%, (p < .05), in inguinal adipose (Ing) by 51 and 55% (p < .05), in retroperitoneal adipose (Rp) by 65 and 64% (p < .05), and in intrascapular brown adipose (iBAT) by 34 and 25% (p < .05), respectively. Gastrocnemius muscle was not affected. Leptin and CNTF (5 μg) increased apoptosis in Epi by 84 and 150%, respectively (p < .05) and in Rp by 121 and 146%, respectively (p < .05). Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following CNTF treatments.
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Manthorpe M, Louis JC, Hagg T, Varon, S. In: Loughlin SE, Fallon JH, eds. Neurotrophic Factors. San Diego: Academic Press 1993: 443–473.
Ip NY, Yancopoulos GD. Annu Rev Neurosci 1996; 19: 491–515.
Bazan JF. Neuropoietic cytokines in the hematopoietic fold. Neuron 1991; 7: 197–208.
Martin D, Merkel E, Tucker KK, et al. Cachectic effect of ciliary neurotrophic factor on innervated skeletal muscle. Am J Physiol 1996; 271: R1422–R1428.
Shapiro L, Zhang XX, Rupp RG, Wolff SM, Dinarello CA. Ciliary neurotrophic factor is an endogenous pyrogen. Proc Natl Acad Sci USA 1993; 90: 8614–8618.
Henderson JT, Seniuk NA, Richardson PM, Gauldie J, Roder JC. Systemic administration of ciliary neurotrophic factor induces cachexia in rodents. J Clin Invest 1994; 93: 2632–2638.
Espat NJ, Auffenberg T, Rosenberg JJ, et al. Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. Am J Physiol 1996; 271: R185–R190.
Lambert PD, Anderson KD, Sleeman MW, et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 2001; 98: 4652–4657.
Xu B, Dube MG, Kalra PS, et al. Anorectic effects of the cytokine, ciliary neurotropic factor, are mediated by hypothalamic neuropeptide Y: Comparison with leptin. Endocrinology 1998; 139: 466–473.
Kalra SP, Xu B, Dube MG, Moldawer LL, Martin D, Kalra PS. Leptin and ciliary neurotropic factor (CNTF) inhibit fastinginduced suppression of luteinizing hormone release in rats: Role of neuropeptide Y. Neurosci Lett 1998; 240: 45–49.
Sahu A.Leptin decreases food intake induced by melaninconcentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat. Endocrinology 1998; 139: 4739–4742.
Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546–549.
Gloaguen I, Costa P, Demartis A, et al. Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin defi-ciency and resistance. Proc Natl Acad Sci USA 1997; 94: 6456–6461.
Ziotopoulou M, Erani DM, Hileman SM, Bjorbaek C, Mantzoros CS. Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling. Diabetes 2000; 49: 1890–1896.
Marsh DJ, Hollopeter G, Huszar D, et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 1999; 21: 119–122.
Gullicksen PS, Hausman DB, Dean RG, Hartzell DL, Baile CA. Adipose tissue cellularity and apoptosis after intracerebroventricular injections of leptin and 21 days of recovery in rats. International Journal of Obesity 2003; 27: 302–312.
Qian H, Azain MJ, Compton MM, Hartzell DL, Hausman GJ, Baile CA. Brain administration of leptin causes deletion of adipocytes by apoptosis. Endocrinology 1998; 139: 791–794.
Wang MY, Lee Y, Unger RH. Novel form of lipolysis induced by leptin. J Biol Chem 1999; 274: 17541–17544.
Fruhbeck G, Aguado M, Martinez JA. In vitro lipolytic effect of leptin on mouse adipocytes: Evidence for a possible autocrine/paracrine role of leptin. Biochem Biophys Res Commun 1997; 240: 590–594.
Kalra SP. Circumventing leptin resistance for weight control. Proc Natl Acad Sci USA 2001; 98: 4279–4281.
ChoiYH,Li CL, Page KA, et al. Melanocortin receptors mediate leptin effects on feeding and body weight, but not adipose apoptosis. Physiol Behav 2003; 79: 795–801.
Gullicksen PS, Dean RG, Baile CA. Detection of DNA fragmentation and apoptotic proteins, and quantification of uncoupling protein expression by Real-Time RT-PCR in Adipose Tissue. J Biochem Biophys Methods 2004; 58: 1–13.
Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540–543.
Della-Fera MA, Qian H, Baile CA. Adipocyte apoptosis in the regulation of body fat mass by leptin. Diabetes Obes Metab 2001; 3: 299–310.
Inui A. Feeding and body-weight regulation by hypothalamic neuropeptides-Mediation of the actions of leptin. Trends Neurosci 1999; 22: 62–67.
Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD, Wiegand SJ. The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv 2000; 74: 265–272.
Hansen MJ, Ball MJ, Morris MJ. Enhanced inhibitory feeding response to alpha-melanocyte stimulating hormone in the dietinduced obese rat. Brain Res 2001; 892: 130–137.
Jang M, Romsos DR. Neuropeptide Y and corticotropinreleasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding. J Nutr 1998; 128: 2520–2525.
Yokosuka M, Xu B, Pu S, Kalra PS, Kalra SP. Neural substrates for leptin and neuropeptide Y (NPY) interaction: Hypothalamic sites associated with inhibition of NPY-induced food intake. Physiol Behav 1998; 64: 331–338.
Kotz CM, Briggs JE, Pomonis JD, Grace MK, Levine AS, Billington CJ. Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein. Am J Physiol 1998; 275: R478–R484.
Gong HX, Guo XR, Fei L, Guo M, Liu QQ, Chen RH. Lipolysis and apoptosis of adipocytes induced by neuropeptide Y-Y5 receptor antisense oligodeoxynucleotides in obese rats. Acta Pharmacol Sin 2003; 24: 569–575.
Margareto J, Aguado M, Oses-Prieto JA, et al. A new NPYantagonist strongly stimulates apoptosis and lipolysis on white adipocytes in an obesity model. Life Sci 2000; 68: 99–107.
Shiraishi T, Sasaki K, Niijima A, Oomura Y. Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats [In Process Citation]. Nutrition 1999; 15: 576–579.
Egawa M, Yoshimatsu H, Bray GA. NeuropeptideYsuppresses sympathetic activity to interscapular brown adipose tissue in rats. Am J Physiol 1991; 260: R328–R334.
Page KA, Hartzell DL, Li C, et al. Beta-Adrenergic Receptor Agonists Increase Apoptosis of Adipose Tissue In Mice. Domest Anim Endocrinol 2004; 26: 23–31.
Prima V, Tennant M, Gorbatyuk OS, Muzyczka N, Scarpace PJ, Zolotukhin S. Differential modulation of energy balance by leptin, CNTF, and LIF gene delivery: Microarray DNAchip analysis of gene expression. Endocrinology 2004; 145: 2035–2045.
Suzuki S, Li AJ, Ishisaki A, et al. Feeding suppression by fibroblast growth factor-1 is accompanied by selective induction of heat shock protein 27 in hypothalamic astrocytes. Eur J Neurosci 2001; 13: 2299–2308.
Aly KB, Pipkin JL, Hinson WG, et al. Chronic caloric restriction induces stress proteins in the hypothalamus of rats. Mech Ageing Dev 1994; 76: 11–23.
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Duff, E., Li, C.L., Hartzell, D.L. et al. Ciliary neurotrophic factor injected icv induces adipose tissue apoptosis in rats. Apoptosis 9, 629–634 (2004). https://doi.org/10.1023/B:APPT.0000038042.31683.7b
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DOI: https://doi.org/10.1023/B:APPT.0000038042.31683.7b