- Email: [email protected]
On the site and mechanism of action of the anti-obesity effects of interleukin-6
Growth Hormone & IGF Research 13 (2003) S28–S32 www.elsevier.com/locate/ghir
On the site and mechanism of action of the anti-obesity effects of interleukin-6 John-Olov Jansson a,*, Kristina Wallenius a, Ingrid Wernstedt a, Claes Ohlsson a, Suzanne L. Dickson b, Ville Wallenius a a
Division of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden b Department of Physiology, University of Cambridge, United Kingdom
Abstract We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus. Ó 2003 Elsevier Science Ltd. All rights reserved. Keywords: Obesity; Interleukin-6
1. Interleukin-6 (IL-6) in the immune system
2. IL-6 in non-immune organs
IL-6 has widespread actions in many systems in the body, playing physiological and even pathophysiological roles. Perhaps its best known role relates to its effects on immune function. IL-6 is released from immune cells during inflammation and elicits pro-inflammatory effects, such as induction of the acute-phase reaction, and also proliferation of B lymphocytes [1,2]. In one of the first articles describing IL-6 knockout mice, Kopf and co-workers [3] showed that endogenous IL-6 is essential for survival from certain infections. However, IL-6 also has important anti-inflammatory properties, such as down-regulation of the inflammatory cytokines tumor necrosis factor a (TNFa) and interferon during acutephase reaction [4].
In the absence of inflammation, a large proportion of the circulating IL-6 is derived from adipose tissue [5], and IL-6 levels in blood correlate with adipose tissue mass [5,6] in a manner similar to that of leptin. Both short-term and long-term changes in food intake influence the amount of IL-6 in both fat tissue and in the circulation [7,8]. Circulating levels of IL-6, but not of TNFa and interleukin 1b (IL-1b), increase 100-fold during exercise. This finding reflects increased expression of IL-6 in skeletal muscle, but does not seem to be related to muscle damage [9,10]. Furthermore, IL-6 and its receptor are expressed in discrete hypothalamic nuclei that have an established role in the regulation of metabolism and body composition [11,12]. In summary, several nonimmune organs that have an established role in the regulation of metabolism and body composition also produce IL-6.
*
Corresponding author. Tel.: +46-7-3901-1122; fax: +46-3182-1524. E-mail address: [email protected] (J.-O. Jansson).
1096-6374/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1096-6374(03)00051-0
J.-O. Jansson et al. / Growth Hormone & IGF Research 13 (2003) S28–S32
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3. Endogenous IL-6 suppresses body fat in mice Recently, we demonstrated that IL-6-deficient mice develop mature-onset obesity and obesity-related metabolic disorders. Administration of low-dose IL-6 replacement therapy partly reversed many of these disorders, indicating that the phenotypical changes were indeed due to the IL-6 deficiency [13]. However, the low doses of IL-6 that partly reversed the obesity seen in IL-6-deficient mice did not induce acute-phase reaction and did not affect body weight or the amount of fat mass in the lean wild-type mice, suggesting that the change was not the result of a pharmacological effect, but rather a replacement effect.
4. IL-6 and obesity-related metabolic disturbances Older IL-6 knockout mice displayed leptin insensitivity and decreased glucose tolerance, and older females displayed increased circulating triglyceride levels [13]. These metabolic perturbations and the leptin insensitivity may be secondary to obesity [14]. Moreover, our findings show that the obese mice lacking IL-6 still develop impaired glucose tolerance. This suggests that IL-6 from adipose tissue is not an essential mediator of obesity-associated glucose intolerance in mice, a hypothesis put forward previously based on epidemiologic data in humans [15].
5. Central nervous system (CNS) IL-6 treatment suppresses obesity To investigate a possible site of action for the anti-obesity action of endogenous IL-6 in rodents, we investigated the effects of long-term central IL-6 treatment. Rats were administered daily intracerebroventricular (ICV) injections of either IL-6 or saline. The results showed that the IL-6 injections suppressed body weight between days 5–10 of treatment, and this difference was maintained throughout the 14-day study. In contrast, saline injections had no effect on body weight by the end of the study (Fig. 1A), as reported previously [16]. At the end of the 2-week ICV IL-6 injection study, fat pads were dissected and weighed. The total weight of all dissected fat pads was significantly lower among IL-6-treated rats compared with those of the salinetreated controls (Fig. 1B). In line with the decreased weight of dissected fat pads, circulating leptin levels were decreased by 40% in the IL-6-treated group at the end of the study compared with pretreatment baseline levels. Leptin levels in the saline-treated rats were not significantly decreased during the study [16].
Fig. 1. Effects of ICV treatment with IL-6 (0.4 lg/day) or saline to male rats fed a high fat diet. (A) Changes in body weight during the 2-week treatment period. (B) The total weight of the dissected fat pads after 2 weeks of treatment. Three intra-abdominal fat pads and the inguinal subcutaneous fat pad were dissected (Reprinted, with permission, from Academic Press).
6. Effects of IL-6 on the hypothalamus Results of our study indicate that IL-6 suppresses obesity via an effect on the CNS. The exact site of action for IL-6 is unknown. However, it seems reasonable to assume that, at least in part, it is exerted on the hypothalamus, which is an important centre for the regulation of body fat [14,17]. Several lines of evidence indicate that the action of both IL-6 and its receptor are expressed in the hypothalamus. Possibly, the site of action is found in hypothalamic nuclei involved in the regulation of appetite and other metabolic functions [11,18–20]. Moreover, acute systemic injection of IL-6 has been shown to induce markers of neuronal activation and to activate signal transducers in the hypothalamus [21,22].
7. Effects of central IL-6 on food intake In our study, average daily food intake was decreased in rats treated with IL-6 ICV for 2 weeks compared with that of animals in the saline-treated group, although the food intake was not consistently decreased on all days
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during the treatment period. Moreover, daily food intake per unit of body weight was not significantly lower in the IL-6 treated group compared with the salinetreated group [16]. Recently, Li et al. [21] confirmed that chronic exposure of the hypothalamus to an IL-6-expressing adenovirus-associated viral vector decreased body weight and body fat mass in rats. These investigators did not find any effect of centrally administered IL-6 on food intake [21]; in contrast, Plata-Salaman [23] found that IL-6 administration to the CNS can suppress food intake. In one study, we found an inconsistent and barely significant decrease in food intake, although the decrease we noted in body weight was clear cut [16], and in another study we saw no effect at all on food intake [13].
8. Effects of central IL-6 on energy expenditure To investigate the site and mechanism of action of IL-6, we compared the effect of a single low dose of IL-6 given centrally or peripherally on energy expenditure and food intake in rats. A single ICV IL-6 injection in the lateral ventricle increased oxygen consumption ðVO2 Þ and carbon dioxide production ðVCO2 Þ in male rats. The respiratory exchange ratio (RER), which is a measure of nutrient partitioning of fat and carbohydrates, was not changed. Saline treatment did not affect ðVO2 Þ, ðVCO2 Þ or RER. Intraperitoneal injections at the same comparatively low doses of IL-6 (100 and 200 ng) had no effect on ðVO2 Þ or ðVCO2 Þ, supporting the hypothesis that the anti-obesity effect of IL-6 is exerted at the level of the CNS. These results do not at all exclude the possibility that IL-6 can decrease body fat mass when given peripherally in higher doses. In conclusion, our results are in line with those of work by Nancy Rothwell et al. [24] and which are confirmed in the recent study by Li et al. [21] that IL-6 decreases body fat by enhancing energy expenditure at the level of the CNS. In rodents, at least, this may then lead to stimulation of the sympathetic nerve system, which in turn induces production of uncoupling protein 1, and thereby increases thermogenesis in brown adipose tissue [21] (Fig. 2). The effect of IL-6 on food intake is less consistent and might only be seen at higher IL-6 doses than those needed to decrease fat mass and enhance energy expenditure.
Fig. 2. Summary of the possible sites and mechanisms of action of the inhibition of body fat by IL-6. UCP-1, uncoupling protein-1; BAT, brown adipose tissue; WAT, white adipose tissue.
and energy expenditure via the CNS [13,16,25,26], it was of interest to study the correlation between IL-6 levels in the cerebrospinal fluid (CSF) and obesity in humans. We found that in obese subjects, CSF IL-6 levels correlated negatively with total body weight, subcutaneous body fat, and total body fat [27]. In contrast, CSF leptin levels were positively correlated with body weight, subcutaneous body fat and total body fat in line with earlier results [25,26], and with the postulation that CSF leptin is derived from serum. The finding that CSF IL-6 levels are negatively correlated with fat mass in obese/overweight individuals suggests that CSF IL-6 is regulated independently of serum IL-6, possibly produced locally in the brain, as depicted in Fig. 2. Moreover, these results are in line with the assumption that, in individuals with more severe obesity, body fat-regulating regions in the CNS are exposed to insufficient IL-6 levels.
10. A comparison between IL-6 and ciliary neurotrophic factor (CNTF) Recently, the cytokine ciliary neurotrophic factor (CNTF), which shares many properties with IL-6, has been demonstrated to decrease obesity in mice [28,29]. Subsequently, clinical phase 2 studies also showed CNTF to have the same effect in humans [30]. Consequently, clinical phase 3 studies are now being conducted with CNTF for treatment of obesity.
9. IL-6 in the CNS of humans As mentioned above, serum IL-6 is, to a large extent, like leptin, released from adipose tissue in individuals without inflammation. Not surprisingly, the levels of IL6 correlate positively with body mass index [5,6], in a way that is similar to that shown for leptin [14]. However, as our results indicate that IL-6 can affect body fat
11. Conclusion Some of our present knowledge about the metabolic effects of IL-6 is summarized in Fig. 2. IL-6 seems to increase energy expenditure and decrease fat mass via effects at the CNS level [13,16], possibly the hypothala-
J.-O. Jansson et al. / Growth Hormone & IGF Research 13 (2003) S28–S32
mus [11,12]. The stimulatory effect on energy expenditure may be exerted, at least in rodents, via stimulation of the sympathetic nervous system that in turn induces increased expression of uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT) and thereby increased heat production [21]. Fig. 2 shows possible sources of IL-6 for this effect. Comparatively low levels of IL-6 are released from white adipose tissue (WAT) and may reach the CNS [5]. Higher amounts of IL-6 are released from skeletal muscle during exercise [9,10], and it seems more likely that during these peaks IL-6 could penetrate and exert effects in the CNS. Finally, there are indications from experimental and human studies that substantial amounts of IL-6 are produced in the CNS itself [11,12,27], suggesting that locally produced IL-6 participates in regulation of metabolic function.
Acknowledgements We thank the Swedish Medical Research Council (9894), the Bergvall Foundation, the Swedish Medical Society, the Swedish Society for Medical Research, the Novo-Nordisk Foundation and the European Commission (Framework 5, QLRT-1999-02038).
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[9] M.A. Febbraio, B.K. Pedersen, Muscle-derived interleukin-6: mechanisms for activation and possible biological roles, FASEB J. 16 (2002) 1335–1347. [10] I.H. Jonsdottir, P. Schjerling, K. Ostrowski, S. Asp, E.A. Richter, B.K. Pedersen, Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles, J. Physiol. 528 (2000) 157–163. [11] B. Schobitz, E.R. de Kloet, W. Sutanto, F. Holsboer, Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain, Eur. J. Neurosci. 5 (1993) 1426–1435. [12] K. Shizuya, T. Komori, R. Fujiwara, S. Miyahara, M. Ohmori, J. Nomura, The expressions of mRNAs for interleukin-6 (IL-6) and the IL-6 receptor (IL-6R) in the rat hypothalamus and midbrain during restraint stress, Life Sci. 62 (1998) 2315–2320. [13] V. Wallenius, K. Wallenius, B. Ahren, M. Rudling, H. Carlsten, S.L. Dickson, C. Ohlsson, J.O. Jansson, Interleukin-6-deficient mice develop mature-onset obesity, Nat. Med. 8 (2002) 75–79. [14] J.M. Friedman, J.L. Halaas, Leptin and the regulation of body weight in mammals, Nature 395 (1998) 763–770. [15] J.P. Bastard, M. Maachi, J.T. Van Nhieu, C. Jardel, E. Bruckert, A. Grimaldi, J.J. Robert, J. Capeau, B. Hainque, Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro, J. Clin. Endocrinol. Metab. 87 (2002) 2084–2089. [16] K. Wallenius, V.W. Wallenius, D. Sunter, S.L. Dickson, J.-O. Jansson, Intracerebroventricular interleukin-6 treatment decreases body fat in rats, Biochem. Biophys. Res. Commun. 293 (2002) 560–565. [17] M.W. Schwartz, S.C. Woods, D. Porte Jr., R.J. Seeley, D.G. Baskin, Central nervous system control of food intake, Nature 404 (2000) 661–671. [18] W. Wang, C. Lonnroth, E. Svanberg, K. Lundholm, Cytokine and cyclooxygenase-2 protein in brain areas of tumor-bearing mice with prostanoid-related anorexia, Cancer Res. 61 (2001) 4707–4715. [19] S. Miyahara, T. Komori, R. Fujiwara, K. Shizuya, M. Yamamoto, M. Ohmori, Y. Okazaki, Effects of repeated stress on expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat hypothalamus and midbrain, Life Sci. 66 (2000) PL93–PL98. [20] Y. Gao, Y.K. Ng, J.Y. Lin, E.A. Ling, Expression of immunoregulatory cytokines in neurons of the lateral hypothalamic area and amygdaloid nuclear complex of rats immunized against human IgG, Brain Res. 859 (2000) 364–368. [21] G. Li, R.L. Klein, M. Matheny, M.A. King, E.M. Meyer, P.J. Scarpace, Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats, Neuroscience 115 (2002) 879–889. [22] M. Niimi, Y. Wada, M. Sato, J. Takahara, K. Kawanishi, Effect of continuous intravenous injection of interleukin-6 and pretreatment with cyclooxygenase inhibitor on brain c-fos expression in the rat, Neuroendocrinology 66 (1997) 47–53. [23] C.R. Plata-Salaman, Anorexia induced by activators of the signal transducer gp 130, NeuroReport 7 (1996) 841–844. [24] N.J. Rothwell, N.J. Busbridge, R.A. Lefeuvre, A.J. Hardwick, J. Gauldie, S.J. Hopkins, Interleukin-6 is a centrally acting endogenous pyrogen in the rat, Can. J. Physiol. Pharmacol. 69 (10) (1991) 1465–1469. [25] J.F. Caro, J.W. Kolaczynski, M.R. Nyce, J.P. Ohannesian, I. Opentanova, W.H. Goldman, R.B. Lynn, P.L. Zhang, M.K. Sinha, R.V. Considine, Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance, Lancet 348 (1996) 159–161. [26] M.W. Schwartz, E. Peskind, M. Raskind, E.J. Boyko, D. Porte Jr., Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans, Nat. Med. 2 (1996) 589–593. [27] K. Stenl€ of, I. Wernstedt, T. Fj€allman, V.K.W. Wallenius, J.-O. Jansson, Interleukin-6 levels in the central nervous system are
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[29] P.D. Lambert, K.D. Anderson, M.W. Sleeman, V. Wong, J. Tan, A. Hijarunguru, T.L. Corcoran, J.D. Murray, K.E. Thabet, G.D. Yancopoulos, S.J. Wiegand, 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 98 (2001) 4652–4657. [30] G.A. Bray, L.A. Tartaglia, Medicinal strategies in the treatment of obesity, Nature 404 (2000) 672–677.
On the site and mechanism of action of the anti-obesity effects of interleukin-6 John-Olov Jansson a,*, Kristina Wallenius a, Ingrid Wernstedt a, Claes Ohlsson a, Suzanne L. Dickson b, Ville Wallenius a a
Division of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden b Department of Physiology, University of Cambridge, United Kingdom
Abstract We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus. Ó 2003 Elsevier Science Ltd. All rights reserved. Keywords: Obesity; Interleukin-6
1. Interleukin-6 (IL-6) in the immune system
2. IL-6 in non-immune organs
IL-6 has widespread actions in many systems in the body, playing physiological and even pathophysiological roles. Perhaps its best known role relates to its effects on immune function. IL-6 is released from immune cells during inflammation and elicits pro-inflammatory effects, such as induction of the acute-phase reaction, and also proliferation of B lymphocytes [1,2]. In one of the first articles describing IL-6 knockout mice, Kopf and co-workers [3] showed that endogenous IL-6 is essential for survival from certain infections. However, IL-6 also has important anti-inflammatory properties, such as down-regulation of the inflammatory cytokines tumor necrosis factor a (TNFa) and interferon during acutephase reaction [4].
In the absence of inflammation, a large proportion of the circulating IL-6 is derived from adipose tissue [5], and IL-6 levels in blood correlate with adipose tissue mass [5,6] in a manner similar to that of leptin. Both short-term and long-term changes in food intake influence the amount of IL-6 in both fat tissue and in the circulation [7,8]. Circulating levels of IL-6, but not of TNFa and interleukin 1b (IL-1b), increase 100-fold during exercise. This finding reflects increased expression of IL-6 in skeletal muscle, but does not seem to be related to muscle damage [9,10]. Furthermore, IL-6 and its receptor are expressed in discrete hypothalamic nuclei that have an established role in the regulation of metabolism and body composition [11,12]. In summary, several nonimmune organs that have an established role in the regulation of metabolism and body composition also produce IL-6.
*
Corresponding author. Tel.: +46-7-3901-1122; fax: +46-3182-1524. E-mail address: [email protected] (J.-O. Jansson).
1096-6374/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1096-6374(03)00051-0
J.-O. Jansson et al. / Growth Hormone & IGF Research 13 (2003) S28–S32
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3. Endogenous IL-6 suppresses body fat in mice Recently, we demonstrated that IL-6-deficient mice develop mature-onset obesity and obesity-related metabolic disorders. Administration of low-dose IL-6 replacement therapy partly reversed many of these disorders, indicating that the phenotypical changes were indeed due to the IL-6 deficiency [13]. However, the low doses of IL-6 that partly reversed the obesity seen in IL-6-deficient mice did not induce acute-phase reaction and did not affect body weight or the amount of fat mass in the lean wild-type mice, suggesting that the change was not the result of a pharmacological effect, but rather a replacement effect.
4. IL-6 and obesity-related metabolic disturbances Older IL-6 knockout mice displayed leptin insensitivity and decreased glucose tolerance, and older females displayed increased circulating triglyceride levels [13]. These metabolic perturbations and the leptin insensitivity may be secondary to obesity [14]. Moreover, our findings show that the obese mice lacking IL-6 still develop impaired glucose tolerance. This suggests that IL-6 from adipose tissue is not an essential mediator of obesity-associated glucose intolerance in mice, a hypothesis put forward previously based on epidemiologic data in humans [15].
5. Central nervous system (CNS) IL-6 treatment suppresses obesity To investigate a possible site of action for the anti-obesity action of endogenous IL-6 in rodents, we investigated the effects of long-term central IL-6 treatment. Rats were administered daily intracerebroventricular (ICV) injections of either IL-6 or saline. The results showed that the IL-6 injections suppressed body weight between days 5–10 of treatment, and this difference was maintained throughout the 14-day study. In contrast, saline injections had no effect on body weight by the end of the study (Fig. 1A), as reported previously [16]. At the end of the 2-week ICV IL-6 injection study, fat pads were dissected and weighed. The total weight of all dissected fat pads was significantly lower among IL-6-treated rats compared with those of the salinetreated controls (Fig. 1B). In line with the decreased weight of dissected fat pads, circulating leptin levels were decreased by 40% in the IL-6-treated group at the end of the study compared with pretreatment baseline levels. Leptin levels in the saline-treated rats were not significantly decreased during the study [16].
Fig. 1. Effects of ICV treatment with IL-6 (0.4 lg/day) or saline to male rats fed a high fat diet. (A) Changes in body weight during the 2-week treatment period. (B) The total weight of the dissected fat pads after 2 weeks of treatment. Three intra-abdominal fat pads and the inguinal subcutaneous fat pad were dissected (Reprinted, with permission, from Academic Press).
6. Effects of IL-6 on the hypothalamus Results of our study indicate that IL-6 suppresses obesity via an effect on the CNS. The exact site of action for IL-6 is unknown. However, it seems reasonable to assume that, at least in part, it is exerted on the hypothalamus, which is an important centre for the regulation of body fat [14,17]. Several lines of evidence indicate that the action of both IL-6 and its receptor are expressed in the hypothalamus. Possibly, the site of action is found in hypothalamic nuclei involved in the regulation of appetite and other metabolic functions [11,18–20]. Moreover, acute systemic injection of IL-6 has been shown to induce markers of neuronal activation and to activate signal transducers in the hypothalamus [21,22].
7. Effects of central IL-6 on food intake In our study, average daily food intake was decreased in rats treated with IL-6 ICV for 2 weeks compared with that of animals in the saline-treated group, although the food intake was not consistently decreased on all days
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during the treatment period. Moreover, daily food intake per unit of body weight was not significantly lower in the IL-6 treated group compared with the salinetreated group [16]. Recently, Li et al. [21] confirmed that chronic exposure of the hypothalamus to an IL-6-expressing adenovirus-associated viral vector decreased body weight and body fat mass in rats. These investigators did not find any effect of centrally administered IL-6 on food intake [21]; in contrast, Plata-Salaman [23] found that IL-6 administration to the CNS can suppress food intake. In one study, we found an inconsistent and barely significant decrease in food intake, although the decrease we noted in body weight was clear cut [16], and in another study we saw no effect at all on food intake [13].
8. Effects of central IL-6 on energy expenditure To investigate the site and mechanism of action of IL-6, we compared the effect of a single low dose of IL-6 given centrally or peripherally on energy expenditure and food intake in rats. A single ICV IL-6 injection in the lateral ventricle increased oxygen consumption ðVO2 Þ and carbon dioxide production ðVCO2 Þ in male rats. The respiratory exchange ratio (RER), which is a measure of nutrient partitioning of fat and carbohydrates, was not changed. Saline treatment did not affect ðVO2 Þ, ðVCO2 Þ or RER. Intraperitoneal injections at the same comparatively low doses of IL-6 (100 and 200 ng) had no effect on ðVO2 Þ or ðVCO2 Þ, supporting the hypothesis that the anti-obesity effect of IL-6 is exerted at the level of the CNS. These results do not at all exclude the possibility that IL-6 can decrease body fat mass when given peripherally in higher doses. In conclusion, our results are in line with those of work by Nancy Rothwell et al. [24] and which are confirmed in the recent study by Li et al. [21] that IL-6 decreases body fat by enhancing energy expenditure at the level of the CNS. In rodents, at least, this may then lead to stimulation of the sympathetic nerve system, which in turn induces production of uncoupling protein 1, and thereby increases thermogenesis in brown adipose tissue [21] (Fig. 2). The effect of IL-6 on food intake is less consistent and might only be seen at higher IL-6 doses than those needed to decrease fat mass and enhance energy expenditure.
Fig. 2. Summary of the possible sites and mechanisms of action of the inhibition of body fat by IL-6. UCP-1, uncoupling protein-1; BAT, brown adipose tissue; WAT, white adipose tissue.
and energy expenditure via the CNS [13,16,25,26], it was of interest to study the correlation between IL-6 levels in the cerebrospinal fluid (CSF) and obesity in humans. We found that in obese subjects, CSF IL-6 levels correlated negatively with total body weight, subcutaneous body fat, and total body fat [27]. In contrast, CSF leptin levels were positively correlated with body weight, subcutaneous body fat and total body fat in line with earlier results [25,26], and with the postulation that CSF leptin is derived from serum. The finding that CSF IL-6 levels are negatively correlated with fat mass in obese/overweight individuals suggests that CSF IL-6 is regulated independently of serum IL-6, possibly produced locally in the brain, as depicted in Fig. 2. Moreover, these results are in line with the assumption that, in individuals with more severe obesity, body fat-regulating regions in the CNS are exposed to insufficient IL-6 levels.
10. A comparison between IL-6 and ciliary neurotrophic factor (CNTF) Recently, the cytokine ciliary neurotrophic factor (CNTF), which shares many properties with IL-6, has been demonstrated to decrease obesity in mice [28,29]. Subsequently, clinical phase 2 studies also showed CNTF to have the same effect in humans [30]. Consequently, clinical phase 3 studies are now being conducted with CNTF for treatment of obesity.
9. IL-6 in the CNS of humans As mentioned above, serum IL-6 is, to a large extent, like leptin, released from adipose tissue in individuals without inflammation. Not surprisingly, the levels of IL6 correlate positively with body mass index [5,6], in a way that is similar to that shown for leptin [14]. However, as our results indicate that IL-6 can affect body fat
11. Conclusion Some of our present knowledge about the metabolic effects of IL-6 is summarized in Fig. 2. IL-6 seems to increase energy expenditure and decrease fat mass via effects at the CNS level [13,16], possibly the hypothala-
J.-O. Jansson et al. / Growth Hormone & IGF Research 13 (2003) S28–S32
mus [11,12]. The stimulatory effect on energy expenditure may be exerted, at least in rodents, via stimulation of the sympathetic nervous system that in turn induces increased expression of uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT) and thereby increased heat production [21]. Fig. 2 shows possible sources of IL-6 for this effect. Comparatively low levels of IL-6 are released from white adipose tissue (WAT) and may reach the CNS [5]. Higher amounts of IL-6 are released from skeletal muscle during exercise [9,10], and it seems more likely that during these peaks IL-6 could penetrate and exert effects in the CNS. Finally, there are indications from experimental and human studies that substantial amounts of IL-6 are produced in the CNS itself [11,12,27], suggesting that locally produced IL-6 participates in regulation of metabolic function.
Acknowledgements We thank the Swedish Medical Research Council (9894), the Bergvall Foundation, the Swedish Medical Society, the Swedish Society for Medical Research, the Novo-Nordisk Foundation and the European Commission (Framework 5, QLRT-1999-02038).
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