USE OF INTERLEUKIN-6 IN TREATMENT OF OBESITY AND/OR OBESITY ASSOCIATED DISORDERS

Abstract: Use of a substance that upon administration to a patient will lead to an increased level of an interleukin-6 (IL-6) receptor agonist, preferably IL-6, for the production of a medicinal product for treatment of obesity and/or obesity associated disorders is disclosed. Also a method for treatment of obesity and/or obesity associated disorders wherein a pharmaceutically effective amount of a substance that upon administration to a patient will lead to an increased level of an interleukin-6 receptor agonist is disclosed.

Description: USE OF INTERLEUKIN-6 IN TREATMENT OF OBESITY AND/OR OBESITY ASSOCIATED DISORDERS Technical field of the invention The present invention relates to a new medicinal product and a new method for treatment of pathological disturbances of regulation of body fat tissue mass and/or obesity associated disorders. Background art Understanding obesi ty- Obesity is a large problem m the Western world since both severe and moderate obesity is associated with increased health risks. Obesity is associated with diseases such as diabetes, hypertension and heart disease, whose incidence increases with body-mass index (BMI, body mass m kg/square of height in meters) . A study based on information on 18-year-old Swedish military conscripts show a 1. -fold increase m prevalence of overweight (BMI >25) and a 1.7-fold increase m obesity (BMI >30) from the year 1971 to 1993 (Rasmussen F, Johansson M and Han- sen HO, 1999) . Generally, obesity is due to energy intake that exceeds energy expenditure. This can be caused by overeating, i.e. higher food intake than necessary for maintenance of body mass. In addition, low mobility and low metabolic rate may predispose for obesity (see Flier, J. S. and Foster D. W. (1998) Eating disorders: obesity, anorexia nervosa, and bulimia nervosa. In: Williams Textbook of Endocrinology, 9th Ed, Saunders Co.) . However, the general opinion that obesity is largely the result of a lack of willpower is unsatisfactory. In- tense research efforts are therefore made to reveal the genetic and environmental factors of importance for development of obesity (Friedman JM and Halaas JL, 1998) . Obesi ty m humans and mice Animal models can be used for investigation of which genes that are causing development of obesity. Of particular importance is the information that can be gained from mouse strains that develop obesity because of gene knockouts. These mouse strains can provide evidence that a certain gene product is of crucial importance for regulation of body fat. This m turn may facilitate the development of new treatment paradigms. There are mdica- tions that there are gender differences regarding the genetic ethiology of obesity (see e.g. Costet, P. et al . (1998) Peroxisome Proliferator-activated receptor α- lsoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis . J. Biochem. Chem. 273,29577-29585). Obesi ty and blood fats m relation to cardiovascular disease It is recognized that obesity, especially visceral obesity, and deranged lipid-lipoprotem profile, including hypertriglyceπdemia and hypercholesteolemia are associated with larger risk of cardiovascular disease (Lamarche B, et al . (1998), Visceral obesity and the risk of lschemic heart disease: insights from the Quebec car- diovascular study. Growth hormone and IGF research 8, (suppl. B) 1-8.) . So far, a lot of the research on the ethiology of this syndrome has dealt with neuroendocπne, i.e. hypothalamohypophyseal , and endocrine disturbances, focusing on the effects of the hypothalamus-pituitary- adrenal (HPA) axis regulating glucocorticoid, sex steroids and growth hormone (see e.g. Bjόrntorp, P. (1996) The regulation of adipose tissue distribution m humans, Int. J. Obesity 20, 291-301.) Leptm and obesi ty Following the cloning of leptm 6 years ago (see Zhang et al . (1994), Positional cloning of the mouse ob (obesi ty) gene and its human homologue. Nature 372, 425- 432) , there were great hopes that this would mean new possibilities to treat obesity and overeating. However, later it was found that obesity m humans very seldom is due to leptm deficiency, but rather is associated with increased leptm levels. Moreover, it has been shown that both mice and humans often are resistant to the anti- obesity effect of leptm (see e.g. Flier, J. S. (1998), What's m a name? In search of lept 's physiological role, J Clm. Endocr . Metab 83, 1407-1413, and references therein) . The 16 kDa protein leptm is almost only produced white adipocytes from which leptm is then released to circulation. Leptm production by fat and plasma leptm levels is highly correlated with adipose tissue mass (Flier JS, 1997). Leptm acts through specific receptors m the hypothalamus to create a feedback loop for body weight regulation. Therefore, the pathophysiology of obesity was assumed to be partly endocrine. Leptm does not rise significantly after a meal and does not result the termination of a meal . Instead leptm appears largely to exert long-term effects on food consumption and energy expenditure (Flier JS , 1998; Friedman JM and Halaas JL, 1998) . Leptin as a starvation signal Obese ( ob) mice which lack leptm show many of the abnormalities seen m starved animals, including hyper- phagia, decreased body temperature, decreased energy ex- penditure, decreased immune function, and infertility. Leptin replacement corrects all of these abnormalities implying that ob mice live m a state of "perceived starvation" due to lack of leptin and that the biological response m the presence of food leads to obesity. These observations led to speculation that leptm' s mam physiological role is to signal nutritional status during periods of food deprivation (Flier JS , 1998; Friedman JM and Halaas JL, 1998) . The leptin receptors The leptin receptor (Ob-R) is normally expressed at high levels m hypothalamic neurons and m other cell types, including T cells and vascular endothelial cells. In si tu hybridisation was used to identify the hypothalamic arcuate nucleus, and also dorsomedial hypothalamic nucleus (DMH) , paraventπcular nucleus (PVN) , ventrome- dial hypothalamic nucleus (VMH) and lateral hypothalamic nucleus (LH) as principal sites of Ob-R expression the central nervous system. Each of these nuclei, such as the arcuate nucleus, express one or more neuropeptides and neurotransmitters such as neuropeptide Y (NPY) and mela- nocyte-stimulating hormone alpha ( -MSH) , that regulate food intake and/or body weight, probably by actions downstream of leptin (Friedman JM and Halaas JL, 1998; Flier JS and Maratos-Flier E, 1998) . Leptin and human obesi ty The role of leptm m the pathogenesis of obesity may be inferred by measurement of plasma leptin. An increase m plasma leptin suggests that obesity is the re- suit of resistance to leptin. A low or normal plasma concentration of leptin suggests that obesity is due to decreased production of leptin. This interpretation is similar to that used m studies of msulm and the pathogenesis of type I and type II diabetes. As is the case with msulm and its receptor diabetes, mutations of leptin and its receptor are rare m human obesity, but most obese individuals still have higher levels of leptin than do non-obese individuals, an indication of leptin resistance that might be receptor-independent (Flier JS, 1997) . Many genes involved m development of obesity have recently been found and most of them seem to act down- stream of leptin at the hypothalamic level. Other genes that are involved m development of obesity encode neuro- peptides, e.g. leukocyte adhesion receptors, which are important cell -cell adhesion molecules the mflamma- tory and immune systems (Dong ZM et al . , 1997), and neu- rocytokmes like ciliary neurotrophic factor, whose receptor subumts share sequence similarity with the leptin receptor (Gloaguen I et al . . , 1997) . The identification of anti-obesity mechanisms that act independently or to- gether with the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance . Leptin has immuno- regulatory activi ty Exogenous leptin up-regulates both phagocytosis and the macrophage production of promflammatory cytokmes such as tumor necrosis factor (TNF- ) and mterleukm-6 (Loffreda S et al . , 1998) . It has been suggested that the up-regulation of inflammatory immune responses by leptin may contribute to several of the major complications of obesity such as increased incidence of infection, diabetes and cardiovascular disease (Loffreda S et al . , 1998; McCarty MF, 1999) . This hypothesis is attractive since it would implicate a common pathogenic mechanism (lack of leptin action) for both obesity and some of its major complications. However, an alternative possibility is that regulatory mechanisms usually connected to e.g. immune functions also are of importance for the regulation of body fat . In t erl eukin - 6 The cytokmes act as hormonal regulators of the immune system and m the body's reactions during trauma and inflammation. The cytokme mterleukm-6 (IL-6) is known to be important the development of B-lymphocytes and m the change of plasma protein production of the liver during trauma and inflammation, the so-called acute phase response. In line with this, IL-6 levels are markedly increased during acute phase response. It has been shown that IL-6-type cytokme receptors share functional specificity with the long form of the leptin receptor (Baumann H et al., 1996) . The role of the cytokmes including IL-6 m healthy animals and humans is not well known and they are suggested to have little effect, partly because circulating levels often are low m the absence of illness (Hirano T, 1998) . Structures of mterleukm- 6 and i ts receptor Interleukm-6 (IL-6) exerts its biological effects through the ligand-specifIC IL-6 receptor, which belongs to the cytokme receptor superfamily. The multisubunit IL-6 receptor complex consists of the IL-6Rα subunit which binds to IL-6 and the membrane associated glycopro- tem gpl30 which s a signal transducer. Unlike most other cytokme receptors, the IL-6R subunit can be activated by ligand binding m both its membrane bound and its soluble form. IL-6 induces heterodimeπzation between IL-δRα and gpl30, which m turn leads to homodimeπzation of gpl30 to a second gpl30 molecule (see e.g. Hirano, T. (1998), Interleukm 6 and its receptor: ten years later. Int. Rev. Immunol. 16, 249-284). Actually, IL-6/lL-6Rα complexes can be potent activators of gpl30, including cells that lack membrane bound IL-6R . Since gpl30 can be activated by several other ligand-receptor complexes, these effects may not reflect the physiological role of IL-6 (see e.g. Schirmacher, P., et al . (1998), Hepatocel- lular hyperplasia, plasmacytoma formation, and extramed- ullary hematopoiesis m interleukm (IL) -6/soluble IL-6 receptor double-transgenic mice. Am. J. Pathol . 153, 639- 648) . On the other hand, the fact that several different types of cytokme receptors can activate gpl30 opens the possibility that different cytokmes may potentiate each others actions thereby exerting synergistic effects. One example of receptors belonging to the IL-6Rα family is the leptin receptor (Tartaglia, L. A. et al . , (1995), Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263-1271) but the leptin receptor is not acting via gpl30 (see e.g. Baumann, H., (1996), The full-length leptin receptor has signaling capabilities of interleukm 6-type receptors. Proc Natl . Acad. Sci . USA 93, 8374-8378) . Most patents issued regarding IL-6 have described methods to get beneficial effects of suppression of IL-6 action. One exception is a recent patent claiming that IL-6 can suppress demyelmation, e.g. during multiple sclerosis (see US Pat. No. 5,863,529) Methods have been developed for production of human IL-6 in large quantities (see e.g. US Pat. No. 5,641,868). Interleukin- 6 agonists Several IL-6 have been described previous patent applications. For instance, possible superagonists made from wild type human IL-6 with various ammo acid substi- tutions have been described (see e.g. US Pat. No. 5,914,106, US Pat. No .5 , 506 , 107 , and US No. 5,891,998). Interleukm- 6 and obesi ty It has recently been discovered that knockout of the IL-6 gene m mice surprisingly induces "middle age onset" obesity (Wallenius V and Jansson JO, unpublished results) . There is little data m the literature indicating that IL-6 has any effect on metabolic parameters the absence of acute phase reaction and inflammation. How- ever, there are recent reports indicating that IL-6 is released from normal adipose tissue m humans. In addition, the IL-6 levels m blood are proportional to body fat mass (Mohamed-Ali V et al . , (1997), Subcutaneous adipose tissue releases mterleukm-6, but not tumor necrosis factor-alpha, m vivo. J Clin Endocrinol Metab 82, 4196-200) . If 11-6 prevents obesity, this finding suggest that obese individual could be IL-6 resistant, and therefore benefit from treatment with a factor that enhances the effect of IL-6 m addition to IL-6 itself. In addition, it is well known that IL-6 is released from immune cells including macrophages, as well as endothe- lial cells and various other cell types (Hirano T, 1998) . Moreover, both IL-6 and IL-6 receptors have been found m hypothalamic nuclei known to be important m the regulation of food intake and body weight (Schδbitz B et al . . 1993, see Fig. 1) . These observations have drawn our at- tention to IL-6's potential role m the regulation of body weight . IL- 6 and acute phase reaction (APR) IL-6 plays a role for different parts of the immune response (see e.g. Hirano, T. (1998) , supra) . It is well known that production of IL-6 as well as the circulating levels of this cytokme is enhanced during so-called acute phase reaction (APR) . Moreover, IL-6 is considered a key mediator of APR, especially after infection with gram positive bacteria (see e.g. Kopf, M., et al . (1994), Impaired immune and acute-phase responses m mterleukm- 6-defιcιent mice. Nature 368, 339-342) . The APR is characterized by changes m the composition of the proteins released into plasma from the liver. APR is seen m pathological conditions with an inflammatory component such as trauma, infections, autoimmune disease, and tumors. These conditions are also associated with catabo- lism, i.e. decreased growth and increased degradation of tissues belonging to the fat free mass m the body. IL- 6 and ageing Aging is associated with several somatic changes including increased body fat mass m general and visceral fat mass m particular (see e.g. Rudman, D., et al . , (1990) , Effects of human growth hormone m men over 60 years old. N. Engl . J. Med. 323, 1-6; Flier, J. S. and Foster D. W. (1998) supra) . The proportion of the popula- tion that have disturbances of blood fats such as pathologically elevated serum triglyceπdes also increase with age and is higher middle aged than m young adult persons (Brown, M. S., and Goldstein, J. L. (1983) Disorders of lipid metabolism, Harrison's principle of internal medicine, 10th Ed, 547-559. It has been suggested that several age-associated diseases are caused by enhanced IL-6 (see e.g. Ershler, W. B., et al . , (1994), The role of mterleukm-6 m certain age-related diseases. Drugs Agmg 5, 358-365) . In humans there is an epidemiological connection between high IL-6 levels m peripheral blood mononuclear cells (PBMC) (see e.g. O'Mahony, L., et al . , (1998), Quantitative mtracellular cytokme measurement: age-related changes promflammatory cytokme produc- tion. Clm. Exp . Immunol. 113, 213-219) as well as m serum (see e.g. Mysliwska, J. , et al . , (1998), Increase of interleukm 6 and decrease of interleukm 2 production during the agmg process are influenced by the health status. Mech. Agmg Dev. 100, 313-328) . Effects of low, normal levels of IL- 6 mice of differ- en t age There is much information about the effects of high levels of IL-6, e.g. m connection with inflammation (see e.g. Kopf, M. , et al , supra) . However, little is known about the importance of the low, basal levels of IL-6 m animals and humans without inflammation. One reason could be that it has been difficult to measure the low IL-6 levels healthy mice with the assays available today. However, it can not be excluded that there still is a biologically significant effect of IL-6 these animals. Moreover, IL-6 that is produced locally tissues may exert autocrine or paracrme effects on cells m the same tissue, without being transported to other organs via blood circulation. There have been few reports of differences between mice with complete IL-6 deficiency due to targeted dis- ruption of the IL-6 gene, and normal wild type mice m the absence of provocations (see e.g. Hirano, T. (1998), supra) . It is known that these mice develop normally to adulthood and they are fertile (see e.g. Kopf, M. , et al , supra, and Poll, V., et al . , (1994) . Interleukm-6 deficient mice have been reported to be protected from bone loss caused by estrogen depletion. EMBO J. 13, 1189- 1196) . It has also been reported that IL-6 mice might have a defective fever response (see e.g. Hirano, T. (1998) , supra) . However, very little has been published about the effects of IL-6 deficiency m mice that are older than a couple of months. This could be due to the fact that it is expensive and laborious to keep mice for longer time. Since the normal life span of a mouse is about two years, there are few publications about a large part of the adult life of mice. Regulation of IL-6 production and release As mentioned above, IL-6 is released during acute phase reaction. Therefore, it is not surprising that IL-6 production is enhanced by gram-positive as well as by gram-negative bacteria. The latter seem to release IL-6 via production of an antigen called lipopolysacchaπde (LPS) (see e.g. Kopf, M. , et al . (1994), supra). The pro- duction of IL-6 is enhanced by tumor necrosis factor-α, TNF-α, a cytokme that is thought to play a role for the induction of type 2 diabetes, an illness associated with visceral obesity and cardiovascular disease. TNF-α production is enhanced from adipocytes that have accumulated fat (see e.g. Hotamisligil G. S. and Spiegelman B. M. , (1994) , Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43, 1271-1278; Flier, J. S. and Foster D. W. (1998), supra). Several other hormones have also been shown to en- hance IL-6 production. These include parathyroid hormone (PTH) , 1 , 25-dιhydroxyvιtamm D3 , thyroid hormone, platelet-derived growth factor, insulin-like growth factor I, and IL-1 (see e.g. Swolm, D., et al . , (1996), Growth hormone increases mterleukm-6 produced by human osteo- blast-like cells. J. Clin. Endocrinol. Metab. 81, 4329- 4333, and references therein) . In addition, it has been shown that nicotine, a well known suppresser of obesity, can enhance IL-6 production and plasma IL-6 levels (see e.g. Song, D-K.,et al . , (1999), Central injection of nicotine increases hepatic and splenic mterelukm-6 (IL- 6) mRNA expression mice: involvement of the peripheral sympathetic nervous system. FASEB J13 : 1259-1267) . It has also been reported that corticosteroids , which are well known mducers of visceral obesity, can suppress IL-6 expression (see e.g. Swolm-Eide, D., et al . , (1998), Effects of cortisol on the expression of mterleukm-6 and mterleukm-1 beta m human osteoblast-like cells. J. Endocrinol. 156, 107-114) . IL- 6 and body fat during APR IL-6 is a major mediator of APR, a condition associ- ated with wasting and decreased appetite. However, it is still by no means certain that IL-6 also causes these an- orectic and wasting effects. In fact, there are data indicating that this is not the case, although lipopolysac- charides (LPS) were reported to induce weight loss mice and that this effect can be significantly prevented by treatment with antι-IL-6 monoclonal antibodies. However, m the same study the antι-IL-6 antibodies did not prevent the hypertnglyceridemia induced by LPS, possibly suggesting that IL-6 is less important for changes m fat metabolism during APR (Strassman, G. et al . (1993), The role of mterleukm-6 m lipopolysacchaπde- induced weight loss, hyperglycemia and flbrmogenproduction. Cytokme 5, 285-290) . It has been reported that IL-6 treatment can de- crease lipoprotem lipase (LPL) activity m adipose tissue of mice and m murme adipocyte cell lines m vitro. This effect has been seen as an indication of a lipolytic effect of IL-6 during cancer cachexia, a condition associated with APR (see Greenberg, A. S., (1992), Interleu- kιn-6 reduces lipoprotem lipase activity m adipose tissue of mice m vivo and m 3T3-L1 adipocytes : a possible role for mterleukm-6 m cancer cachexia, Cancer Res. 52, 4113-4116) . On the other hand, there are indications e.g. from studies of gene knockout mice that LPL activity does not affect fat accumulation (Zechner, R (1997) , The tissue specific expression of lipoprotem lipase: impli- cations for energy and lipoprotem metabolism, Curr. Op- pin. Lipidol. 877-88). IL- 6 and body fat during normal condi tions It has been speculated that that IL-6, like leptin, could have an adipostatic activity also m patients without APR. However, this assumption was based only on the finding that subcutaneous fat releases IL-6 m patients without acute phase reaction. Not surprisingly, there was also a correlation between high BMI, presumably reflect- ing fat mass, and levels of circulating IL-6 (Mohamed- Ali, V., et al . (1997) Subcutaneous adipose tissue releases mterleukm-6, but not tumor necrosis factor-α, vivo, J. Clm. Endocrinol. Metab. 82,4196-4200). However, the finding that IL-6 is released by adipose tissue, does m no way prove that this factor would regulate fat tissue mass. As noted above, it is by no means clear that IL-6 is of importance for lipolysis even during APR. In the absence of APR, the available data has suggested that long term treatment with IL-6 m low, physiological doses is not lipolytic by itself. Although a single injection of IL-6 m a dose of 50 μg/kg body weight has been shown to enhance release of free fatty acids into blood circulation (Nonogagi K, et al . (1995), Interelukm-6 stimulates hepatic triglyceπde secretion m rats, Endocrinol - ogy 136, 2143-2149) , there is no obvious loss of fat mass m transgenic mice with very high levels of circulating IL-6 (see e.g. Peters, M. (1997), Extramedullary expan- sion of hematopoietic progenitor cells m interleukm (IL) -6-SIL-6R double transgenic mice. J. Exp . Med. 185,755-766), although such mice display growth impairment (De Benedetti, F. et al . (1997), Interleukm-6 causes growth impairment m transgenic mice through a decrease msulm-like growth factor-1. J. Clin. Invest. 99, 643-650) as well as muscle atrophy (Tsu mak, T et al . (1996), Interleukm 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems m mter- leukin 6 transgenic mice. J. Clin. Invest. 97, 244-249). Moreover, there have been few indications m the literature that long term absence of the low physiological amounts of endogenous IL-6 that are produced an animal or human without APR, would have consequences for fat me- tabolism, especially fat mass and blood fat levels. The best way to investigate the consequences of long term absence is probably the study of mice with IL-6 gene knock out. In 1998 one of the worlds leading experts on IL-6 concluded m a review that the results of IL-6 knock out m mice had shown "that IL-6 is critical m only a limited range of biological reactions such as APR, the muco- sal IgA response, the fever response, and estrogen deficiency-induced bone loss." (see e.g. Hirano, T. (1998), supra, p 252) . No effects of fat mass IL-6 knock-out mice have been reported. As noted above, IL-6 can suppress LPL (see Greenberg, A. S., (1992), supra), and it has also been suggested that LPL can increase predisposition for obesity and fat accumulation. On the other hand, this theory is challenged by the fact that fat specific deletion of LPL activity does not affect fat mass (Zech- ner, R (1997) , The tissue specific expression of lipoprotem lipase: implications for energy and lipoprotem metabolism, Curr. Oppm. Lipidol . 8,77-88). The general opinion by well renowned researchers today is that IL-6 does not affect fat mass essentially, especially not during normal life without APR. IL- 6 and ethanol Under certain circumstances, alcohol can suppress the concentration of circulating IL-6 (see e.g. Akerman, P. A., et al . (1993), Long-term ethanol consumption al- ters the hepatic response to the regenerative effects of tumor necrosis factor-alpha. Hepatology 17, 1066-1073). It is also well known that ethanol can cause visceral obesity as well as deranged blood fats including enhanced serum triglyceride levels (Brown, M. S., and Goldstein, J. L. (1983), supra) . TNF- and regula tion of body fat As mentioned above, TNF-α is a stimulator of IL-6 production. This effect of TNF-α is exerted via the type 1 (p55) receptor, since it has been shown that IL-6 levels are decreased m mice with TNF receptor 1, but not TNF receptor 2, gene knock out (Yamada, Y., et al . (1998), Analysis of liver regeneration m mice lacking type 1 or type 2 tumour necrosis factor receptor: re- quirement for type 1 but not type 2 receptor. Hepatology 28,959-970). The role of TNF-α for development of obesity is not clear. Mice lacking the TNF-α ligand have not been reported to be obese (Uysal, K. T., et al (1997), Protection from obesity induced msulm resistance m mice lacking TNF-α, Nature 389,610-614), and there was no obesity mice deficient m the both of the two receptors, type 1 (ρ55) and type 2 (p75) , that are thought to mediate the biological effects of TNF-α. Actually, mice deficient the type 2 (p75) receptor ga less weight when given high fat diet, suggesting that TNF-α might even stimulate obesity via this receptor type (Schreyer, S. A. (1998), Obesity and diabetes m TNF-α receptor deficient mice. J. Cl . Invest. 102,402-411). Furthermore, no increase body weight was found m mice with TNF re- ceptor 1 gene knock out even when they were fed high fat diet (Schreyer, S. A. (1998), supra). Obesity db/db (diabetes/diabetes) mice with a defective leptin recep- tor, was not affected by lack of the TNF receptor 1 (Schreyer, S. A. et al (1998), supra) or by lack of the ligand TNF-α which activates both receptor 1 and receptor 2 (Uysal, K. T., et al . , (1997), supra). Another finding that argues against beneficial effects of TNF-α m obesity is that TNF-α often enhances msulm resistance, a symptom often associated with obesity (see Flier, J. S. and Foster D. W. (1998) , supra) . Cytokmes and atherosclerosis Although the interest m the possible associations between cytokmes and atherosclerosis has increased during recent years, it has mostly concerned the possible deleterious effects of cytokmes and inflammation m de- velopment of atherosclerosis The cytokmes have been assumed to stimulate the development of the atherosclerotic plaques by local effects (see e.g. Rus , H. G., et al . , (1996) Interleukm- 6 and interleukm- 8 protein and gene expression m human arterial atherosclerotic wall. Ath- erosclerosis 127,263-271). In addition, as mentioned above, IL-6 has been reported to increase circulating triglyceπdes by release of triglyceπdes from the liver (Nonogagi K, et al . (1995), Interleukm-6 stimulates hepatic tπglyceride secretion m rats, Endocrinology 136, 2143-2149) . Summary of the invention The object of the present invention is to provide new medicinal products and methods for treatment of obe- sity and/or obesity associated disorders. The invention relates to the use of a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist for the production of a medicinal product for the treat - ment of obesity and/or obesity associated disorders. Furthermore, the invention relates to a method for treatment of obesity and/or obesity associated disorders wherein a pharmaceutically effective amount of a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist is administered to said patient. The characterizing features of the invention will be evident from the following description and the appended claims . Detailed description of the invention In the research work leading to the present invention it was found that endogenous IL-6 can inhibit development of "middle-aged" -onset obesity as well as obesity associated disorders, e g the metabolic syndrome. The metabolic syndrome (also called syndrome X) comprises obesity (m particular abdominal obesity) , disturbances of blood fats (e g triglyceπdes) , and diabetes type II. The invention thus relates to medicinal products comprising a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist. Said substance may be an IL-6 receptor agonist . A preferred example of such an agonist is IL-6. It is possible to use a naturally occurring agonist, such as IL-6, as well as a synthetically produced agonist, such as an IL-6 mimetic. Examples of syntheti- cally produced IL-6 receptor agonists are given m US 550 61 07 (Cunningham et al) , US 589 19 98 (Rocco et al) , and US 591 41 06 (Gennaro et al) . Said substance may also be a substance that upon administration will lead to the release of an endogenous occurring IL-6 receptor agonist, preferably IL-6, from different cells, such as endothe- lial cells, or organs, such as the liver. The expression "IL-6 receptor agonist" used herein relates to all substances that bind to and activate the same receptor proteins as IL-6. The term "patient" used herein relates to any human or non-human mammal m need of treatment with the medicinal product or method according to the invention. The term "treatment" used herein relates to both treatment m order to cure or alleviate a disease or a condition, and to treatment m order to prevent the development of a disease or a condition. The treatment may either be performed m an acute or m a chronic way. As mentioned above, the invention is suitable for treatment of high levels of triglyceπdes . The expressions "high levels of triglyceπdes" relates to amounts of this compound that are higher than for a normal, healthy person. The medicinal product and the method according to the invention are suitable for treatment of different pathological disturbances of regulation of body fat tissues, leading to obesity and/or obesity associated disor- ders. One example is visceral or general obesity that is due to genetic predisposition, a condition sometimes described as the thrifty genotype. Another example is diet- mduced obesity, a condition that often is resistant to leptin treatment . The medicinal product and the method according to the invention are e.g. suitable for treatment of cardiovascular disease, since obesity and obesity associated disorders are associated with an increased risk of cardiovascular disease. The medicinal product and the method according to the invention are also suitable for treatment of persons that have been exposed to high doses of glucocorticoid hormone, e.g. due to tumours producing such hormones, due to treatment with glucocorticoids against certain dis- eases, or due to abuse of glucocorticoids. It is known that high levels of glucocorticoids cause visceral obesity and disturbed blood fats. It has been shown that glucocorticoids under certain circumstances can decrease IL-6 production. Other patients which may be treated with the medicinal product or the method according to the invention are persons with obesity, obesity associated disorders, and/or low endogenous production of IL-6 during normal state, i.e., m the absence of APR. Also persons with obesity and/or obesity associated disorders m combination with msensitivity to IL-6 may be treated with the medicinal product and the method according to the invention. The IL-6 msensitivity could e.g. be caused by low levels of the receptor protein IL-6Rα on the cell surface or low levels of the glycoprotem gpl30 which normally mediates the effects of IL-6. In these persons, the IL-6 produced by the patients themselves may not be sufficient to inhibit development of obesity and/or obesity associated disorders. Another example of a group of patient which may be treated according to the invention are patients suffering from normal agmg. In some cases, the production of IL-6 m important tissues could be insufficient although the circulating levels often are increased. A possible IL-6 insufficiency m agmg may also be due in part to msensitivity to IL-6. It is also possible to treat patients with obesity and/or obesity associated disorders m combination with low concentrations of growth hormone (GH) receptors or defective GH receptors. It is known that GH has lipolytic effects . It is also possible to treat obese patients with low concentrations of leptin or leptm receptors, or patients with defective leptin receptors. More often, it would be beneficial to treat patients with obesity and/or obesity associated disorders combination with leptin resis- tance due to unknown reasons. Also patients abusing alcohol may suffer from conditions treatable according to the present invention. It has been shown that alcohol may decrease IL-6 levels (Ak- erman, P. A., et al . (1993), supra) and that patients abusing alcohol often display increase visceral obesity and enhanced serum triglyceπde levels man (Flier, J. S. and Foster D. W. (1998), supra). It may be advantageous to combine the substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist used according to the invention with a factor that will intensify the effect of said mterleukm-6 (IL-6) receptor agonist, and the medicinal product according to the invention may thus also comprise such a factor. An example of such a factor is a soluble IL-6 binding protein. However, a problem may be that IL-6 m combination with soluble IL-6Rα may exert unspecific effects, including even on cells that do not have membrane bound IL-6Rα (see e.g. Peters, M. (1997), supra). The medicinal product according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled the art . The medicinal product according to the invention may be formulated for enteral (e.g. oral or per oral) or par- enteral administration. The invention also relates to use of a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist for a medicinal product for treatment of the above speci- fied conditions. Furthermore, the invention relates to a method for treatment of pathological disturbances of fat metabolism wherein a pharmaceutically effective amount of a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist is administered to said patient. Preferably, said substance is administered together with a factor that will intensify the effect of said mterleukm-6 (IL-6) receptor agonist. Since these effects of IL-6 on fat metabolism were first seen m the work leading to the present invention after removal of endogenous IL-6, it seems appropriate to use IL-6 according to the invention m doses that previously have been used to substitute for IL-6 deficiency. Such a dose would be about 1 mg/kg body weight given as a subcutaneous injection to mice (se e.g. e.g. Cressman, D. E., et al . , (1996), Liver failure and defective hepa- tocyte regeneration m mterleukm-6-deflcient mice. Science 274, 1379-1383) . However, the dose of IL-6 m humans could be quite different. The dose may be higher m older individuals, since it has been shown that IL-6 levels m- crease with age. The dose may be lower than those doses that would result IL-6 levels found during APR, to avoid side effects similar to the symptoms of APR. The invention will now be further explained m the following examples. These examples are only intended to illustrate the invention and should m no way be considered to limit the scope of the invention. Brief description of the drawings In the examples below reference is made to the ac- companymg drawing on which: Fig 1 A shows the effect of mterleukm-6 gene knock out m male mice on mean body weight at different ages. Fig 1 B shows the physical appearance of IL-6 knock out male mice at 9-10 months of age. The photo shows repre- sentative body shapes of IL-6 -/- and IL-6 +/+ male mice. The computerized tomography (CT) shows transverse sections of the abdomen of representative IL-6 -/- and IL-6 Fig 2 A, B and C illustrates the effects of mter- leukm-6 gene knock out on mean body weight at different ages m female mice (Fig 2 A) and the effect of mterleukm-6 gene knock out on mean body mass index (Fig 2 B) (BMI, body weight/ (crown-rump length) 2 ) and mean visceral transversal width (mm) (Fig 2 C) were also investigated m 9 month-old female mice. Fig 3 Shows the measured daily food intake during three consecutive days m 11 month-old female IL-6 +/+ and IL-6 -/- mice. Fig 4 A and B illustrates the effects of mterleu- km- 6 gene knock out m female mice on serum triglyceride levels (Fig 4 A) and serum leptin levels (Fig 4 B) . Fig 5 shows the possible sources of IL-6 that could be of importance for body composition and leptin sensitivity. Fig 6 shows the effect of vehicle and leptin administration on food intake 15 month-old wild-type and IL- 6 knockout (IL-6 _/ ) male mice. 8 A shows vehicle treated mice, wild-type n = 5, IL-6 " _ n = 4. 8 B shows leptin at 120 μg/day, n = 5 per genotype. 8 C shows leptin at 240 μg/day, wild-type n = 5, IL-6 _/" n = 3. Thick black bars represent leptin treatment period. Vehicle or leptin was injected mtrapeπtoneally twice daily. Values are indicated as mean ± SEM. # P<0.05, ## P<0.01, ### P<0.001 vs. study day 0, paired t test with the Bonferroni correc- tion. * P<0.05, ** P<0.01 vs. wild-type, independent t test . Fig 7 shows the effect of vehicle and leptin administration on body weight m 15 month-old wild-type and IL- 6 knockout (IL-6 ) male mice. 9 A shows vehicle treated mice, wild-type n = 5, IL-6 _/~ n = 4. 9 B shows leptin at 120 μg/day, n = 5 per genotype. 9 C shows leptin at 240 μg/day, wild-type n = 5 , IL-6 _,~ n = 3. Thick black bars represent leptin treatment period. Vehicle or leptin was injected mtrapeπtoneally twice daily. Values are mdi- cated as mean ± SEM. # P<0.05, ## P<0.01, ### P<0.001 vs. study day 0, paired t test with the Bonferroni correction. * P<0.05, ** P<0.01, *** P<0.001 vs. wild-type, independent t test . Fig 8 shows relative weights of different fat depots (% fat weight/body weight) m IL-6 + + and IL-6 _ ~ mice. Three mtra-abdommal fat pads (gonadal, retroperitoneal and mesenteric) and the femoral fat pad (a subcutaneous fad pad on the outer thigh) were dissected and weighed 18-month-old male (A) and female (B) IL-6+/+ and IL-6-/- mice. There were 4-10 mice each group. * P < 0.05, ** P < 0.01 and *** P<0.001, vs. corresponding IL-6+/+ mice. Fig 9 shows comparison of the effect of IL-6 treatment m IL-6 + + and IL-6 ~ _ mice. The mice were treated with gradually increasing doses of IL-6 (40 ng/day, days 0-4; 80 ng/day, days 5-12; 160 ng/day, days 13-18). Changes m body weight (g) during the IL-6 treatment period compared to before start of treatment (A) . Figures 11 B and C compare values at day 0 before initiation of IL-6 treatment with day 18 after IL-6 treatment m IL-6 +/ + and IL-6 " _ mice. The total abdominal area was calculated from the CT scans (B) . The mtraperitoneal area containing fat was measured separately by calculating the darker areas with attenuation similar to subcutaneous fat (C) . Both the total mtraperitoneal and mtraperitoneal fat areas were calculated blindly by two different people, with no connection to the study. There were 5 mice in each group. All animals were 12 -month-old at the start of the treatment. * P < 0.05, ** P < 0.01 and *** P<0.001, vs. corresponding control mice. # P <0.05, vs. the corresponding group before initiation of IL-6 treatment. Examples The IL-6 knock out mice (i.e. IL-6 -/- mice) and the corresponding controls used m these examples were kindly provided by Dr. Manfred Kopf at Basel Institute of Immu- nology, Basle, Switzerland (see e.g. Kopf, M. (1994), supra) . The IL-6 -/- mice were back crossed 7-8 times with C57B1/6 mice to ga a strain of mice genetically consisting of more than 95 % C57B1/6. As controls to the IL-6 -/- mice, wild type C57B1/6 mice (i.e. IL-6 +/+ mice) (Bomholtgard Breeding & Research Centre A/S) were used m examples 1-4. These mice were kept at standardized conditions with standard low fat chow and water freely available. Food intake was measured keeping two female mice per cage. The amount of chow was recorded once per day. In example 5 age-matched normal C57BL/6 male mice from B&K Universal AB (Sollen- tuna, Sweden) were used as wild-type controls. All male mice were housed separately (due to aggressiveness) m standard cages under standardised environmental conditions, i.e. 24-26°C, 50-60% relative humidity, artificial lightning at 05:00-19:00 hours, with water and pelleted food (Beekay Feeds, Rat and mouse standard diet, B&K Universal AB, Sollentuna, Sweden) ad libi tum . In examples 6 and 7, mice with IL-6 gene knock-out (IL-6 ' mice) were generated as described by Kopf et ai (12) . To reduce genetic heterogeneity, the IL-6 _ geno- type was moved onto C57BL/6 background by eight successive back crosses. The resulting strain of mice consists genetically of more than 99.5% C57BL/6. Normal C57BL/6 mice from B&K Universal (Sollentuna, Sweden) were used as wild-type controls for the IL-6 _ ~ mice. The animals were maintained under standardized environmental conditions, i.e. 24-26°C, 50-60% relative humidity, artificial lighting at 05.00-19.00 h, with water and pelleted food ad li bi tum . All procedures regarding the mice were conducted accordance with protocols approved by the institutions (Goteborg and Lund) and the local ethical committees on animal care . Measurements of body weight and food intake In examples 1-4 the body weight of the IL-6 -/- mice and wild type control female mice were recorded regularly. The crown-rump length and the transversal abdominal diameter were measured m anesthetized animals by dual x-ray absorptiometry (DEXA) using the Norland pDEXA Sabre (Fort Atkinson, WI , USA) . Body mass index was then calculated for each mouse as body weight/crown-rump length 2 . Visceral and subcutaneous obesity was also evaluated by computerized tomography (CT) at a level 5 mm cranially of the junction between the L6 and SI vertebras . In example 5 body weight was measured using a weighing scale (A S D Instruments, EK-200G) . Food consumption was measured daily by weighing the food left over 24 h after the previous fillup. Basal food intake was measured during pre-treatment with saline injections before onset of the leptin treatment. Body weight and food intake was measured for 3 days after the end of leptin treatment. Leptm measurement Plasma leptin was determined with a recently described radioimmunoassay (Ahren, B. et al . (1997) Regulation of plasma leptin m mice: Influence of age, high-fat diet and fasting, Am. J. Physiol. 273, R113-R120; Lmco Research, St Charles, Mo, USA) . The method uses a poly- clonal rabbit antibody raised against recombmant mouse leptin, 125 I -labeled tracer prepared with recombmant mouse leptin and mouse leptin as standard. Rabbit anti- rabbit IgG was used for separation of bound and free leptin. In example 5 tail blood samples were collected from young (4 months) and old (12 months) wild-type and IL-6 1 male mice. Differences between IL-6 -/- and IL-6 +/+ control mice were determined by Student's t-test. When more than two groups were compared, statistics were calculated by one-way ANOVA followed by Student-Newman-Keuls multiple range test . Example 1 IL-6 -/- knock-out male mice were not heavier than their wild type littermates at 2-5 months of age. However, the body weight of 9 months old IL-6 -/- male mice was higher than that of the corresponding wild type animals, as evident from Fig. 1 A. The physical appearance of male mice at 9-10 months of age clearly showed that the IL-6 -/- mouse was considerably fatter than a wild type control of the same age, as shown Fig. 1 B) . Computerized tomography (CT) of the abdomen clearly indicated that both visceral (mtraabdommal) and subcutane- ous fat mass were markedly increased m the IL-6 -/- mice compared to the wild type control, as evident from Fig. 1 C. Example 2 In this example the effects of IL-6 knock-out on body weight was studied at different ages m female mice. The body weight did not differ between wild type and knock-out female mice between two and five months of age, but between seven and nine months of age the body weight was significantly higher m IL-6 -/- than m wild type +/+ mice, as seen m Fig. 2 A. The body mass index of 9- 10 months old IL-6 knock-out female mice was higher than that of the corresponding wild type females, which is illustrated m Fig. 2B. The transversal abdominal diameter, as measured by DEXA, was also larger m IL-6 knock-out female mice than wild type controls at 9-10 months of age (Fig. 2C) . Example 3 Thereafter the daily food intake for three consecu- tive days was studied for 11 months old IL-6 -/- female mice compared to wild type IL-6 +/+ controls. From the results shown m Fig. 3 it is clearly evident that the food intake was increased m the L-6 -/- mice compared to the controls. Example 4 Serum triglyceride and cholesterol levels of 11 months old female IL-6 -/- mice were compared to wild type IL-6 +/+ controls. As can be seen m Fig. 4 A the serum triglyceride was considerably higher m the IL-6 - /- mice. Also the circulating levels of leptin were mark- edly higher, i.e., about three times, compared to those of wild type mice, as seen m Fig. 4 B. Example 5 15-month-old IL-6 and wild-type males received mtraperitoneal dp) injections of leptin at doses of 120 μg/day or 240 μg/day or vehicle twice daily (at 08:30 and 17:00) for 3 consecutive days. Human leptin was obtained from PeproTech (Rocky Hill, NJ, USA) and dissolved m sterile PBS, 0.1% BSA. In order to get the animals used to injections, mice were given saline injections twice daily before the start of the leptin treatment. The descriptive statistical results are presented as means ± SEM. Independent t test was used to test between- group differences. Withm-group differences were analysed using paired t test followed by the Bonferroni correction. P < 0.05 was considered significant. Effects of leptin treatment on food intake Vehicle treatment (PBS, 0.1% BSA) showed no effect on food intake compared to baseline levels m wild-type and IL-6 ' mice (Fig. 6 A) . In contrast, treatment with leptin at a dose of 120 μg/day to wild-type male mice led to a 40% decrease m food intake during the first two treatment days compared to baseline levels (baseline level: 4.91 ± 0.08 g) . Food intake was not significantly decreased m IL-6 _ mice during treatment with leptin m this dose (Fig 6 B) . The decrease m food intake was significantly larger m wild-type mice than m IL-6 ~ _ mice on day 1-3 of leptin treatment (Fig 6 B) . At the end of the leptin treatment, food intake was normalised within 2 days m wild-type mice. Leptin treatment at a larger dose (240 μg/day) led to a reduction of food intake m wild-type males with the largest decrease (50%) from baseline level during the third treatment day (baseline level: 4.46 ± 0.30 g, Fig 8 C) . There was no decrease food intake m the IL-6 mice (Fig 6 C) . Three days after the end of the leptin treatment, food intake increased significantly to above baseline levels wild-type mice and there was a similar tendency m IL-6 -/ mice (Fig 6 C) . Effects of leptin treatment on body weight Vehicle treatment (PBS, 0.1% BSA) showed no effect on body weight compared to baseline levels m wild-type and IL-6 _/ mice (Fig 7 A) . However, body weights were markedly reduced during and after leptin treatment (120 μg/day) wild-type mice, while the effect was less pronounced m the IL-6 mice (Fig 7 B) . The reduction m body weight was signifi- cantly larger m wild-type mice than IL-6 _ ~ mice day 1-4 after initiation of leptin treatment. Body weights were significantly reduced m wild-type mice both for three days during and for three days after a higher dose of leptin treatment (240 μg/day, Fig 9 C) . There was a tendency towards decreased body weights leptin treated IL-6 mice, but this decrease was not significant tested with paired t test followed by the Bonferroni correction for five comparisons. On day 3 of leptm treatment, the decrease m body weight was sig- nificantly smaller m IL-6 ~/_ mice than m wild-type Discussion In has thus been shown that IL-δ "7'" mice have de- creased responsiveness to leptin treatment compared to wild type mice. These findings indicate that presence of endogenous IL-6 is of importance for normal leptin responsiveness. Leptin treatment induced a significant reduction m food intake m the wild-type mice, but not the IL-6 _ mice. In addition, the suppressive effect of leptin on body weight was less pronounced m IL-6 mice than wild-type mice. These effects of IL-6 may be re- lated to the IL-6 receptor structure, since it has been shown that IL-6 type cytokme receptors share functional specificity with the long form of the leptm receptors (Ob-Rb, Baumann H et al . , 1996) . The receptor subunits for ciliary neurotrophic factor (CNTF) have been shown to share sequence similarities with Ob-Rb, Gloaguen I et al . , 1997) and IL-6 receptors. When administered systemi- cally, CNTF can reverse obesity m various animal models, including db mice lacking leptin receptors (Gloaguen I et al . , 1997) . All three of these systems, leptin, IL-6 and CNTF, signals through the JAK-STAT pathway to regulate gene expression (Flier JS , 1997; Hirano T, 1998; Gloaguen I et al . , 1997) . Cross-reactivity between the three systems at the receptor or post -receptor level may serve as an explanation for the link between regulation of body weight by leptin and IL-6 (as well as CNTF) . It has also been shown that the body weights of the IL-6 ~f ~ mice m this study were significantly higher compared with the body weights of wild-type mice. This re- suit is supported by the recent finding that IL-6 _ ~ mice develop "middle age onset" obesity (Wallenius V and Jans- son JO, unpublished results) . There may be several possible reasons why the obese phenotype of these mice has not been noticed previously. IL-6 _/ mice are commonly used to investigate the role of IL-6 m various infectious and inflammatory models (Kopf et al . 1994), but the weight gam m the IL-6 mice was not observed until they were "middle aged", that is about 4 months of age. Younger animals are preferred for studying infection and mflam- mation. Moreover, the IL-6 mice m this study were back-crossed for 8 generations to a 99.5% pure C57BL/6 background, which may be of importance for the development of the obese phenotype. If so, this raises the question whether the obese phenotype is exclusive for IL-6 _ ~ mice with a C57BL/6 background or if it also would be seen m other mice strains deficient for IL-6. The weight gam m the IL-6 ~ _ mice could be secondary to the development of leptin resistance indicated by this study. If this is the case, one could expect the IL- 6 /_ mice to have a higher level of basal food intake compared to wild-type mice. So far, studies on basal food intake m IL-6 _/ mice have not shown such results. There are also indications m the literature, suggesting that IL-6 affects energy expenditure rather than feeding (Chrousos GP, 1995) . If IL-6 acts mainly on the regula- tion of energy expenditure relative to the regulation of appetite/food intake, the finding this study that endogenous IL-6 may potentiate the suppressive effect of leptm on food intake is a bit surprising (Friedman JM and Halaas JL, 1998) . It is common knowledge that food intake and appetite is reduced during infectious diseases and inflammation, conditions which are associated with increased levels of circulating IL-6 (Hirano T, 1998) . However, there have been few earlier indications that the low basal production of IL-6 m healthy animals would af- feet food intake or fat mass. So far, the reason for the weight gam m the IL-6 mice is not clear and needs further investigation. Measurement of plasma leptm levels m male IL-6 mice and wild-type male mice showed no significant dif- ference between old IL-6 _/~ mice and old wild-type mice. This is surprising for two reasons. Firstly, the IL-6 _/~ mice were heavier than the wild-type mice because of increased body fat mass (Wallemus V and Jansson JO, unpublished results) . Since plasma leptm levels are highly correlated with adipose tissue mass (Friedman JM and Halaas JL, 1998), the plasma leptin levels of the IL-6 '/ mice were expected to be higher than m the wild-type mice. Secondly, leptin resistance m the IL-6 ~/_ mice, as indicated by this study, is associated with increased plasma leptin levels. For instance, elevation of plasma leptin is seen m most obese humans with leptin resistance (Flier JS and Foster DW, Williams textbook of endo- crmology 9 th edition) . Other measurements of plasma leptin levels m female mice have shown increased levels m the IL-6 " _ mice compared to wild-type mice (Wallenius V and Jansson JO, unpublished results) . It is known that the levels of circulating leptm are higher m females than m males (Flier JS and Foster DW, Williams textbook of endocrinology 9 th edition) , and there are several gender differences m the regulation of fat mass (Vettor R et al . , 1997) . Therefore, the preliminary results of the measurements of plasma leptin levels m male IL-6 ' ! ' mice need to be repeated and investigated further. Example 6 In this example, the increase m body fat caused by IL-6 deficiency was confirmed by fat dissections 18- month-old male (shown Fig. 8 A) and female (shown m Fig. 8 B) mice. Four different fat pads were dissected from these mice. The male and female IL-6 ~/_ and IL-6 + + mice were first weighed and then three mtra-abdominal fat pads (gonadal, retroperitoneal and mesenteric) and the femoral fat pad (subcutaneous pad m the groin of the thigh) were dissected and weighed. All investigated fat pads, except the male mesenteric fat pad (Fig. 8 A) , were significantly larger m the IL-6 " _ mice compared to IL- 6 + + mιce. In both males and females the total weight of all dissected fat pads was increased by 50-60 % IL-6 _ ~ compared to IL-6 mice (not shown) . Example 7 In this example female IL-6 " _ and IL-6 + + mice were treated with IL-6 to see if it was possible to reverse some of the phenotypical changes observed m the IL-6 mice. Figure 9 A shows that 18 days of IL-6 treatment reduced body weight to a larger extent m IL-6 mice than m IL-6 + + mice. Quantification of several CT scans performed before the start of IL-6 treatment showed that the mtraperitoneal area was significantly higher m the IL- 6 _/~ mice compared to the IL-6 + + (Fig. 9 B) . After 18 days of IL-6 treatment the total abdominal area had decreased significantly m the IL-6 _ mice while there was no such effect m the IL-6 + + mice (Fig. 9 B) . Intraperitoneal ar- eas were also measured, and they had a similar attenuation on the CT scans as subcutaneous fat. This quantification, excluding non-fat tissues, indicated an even larger increase m the fat content m IL-6 "/" mice compared to the IL-6 + + mice (Fig. 9 C) . There was a signifi- cant decrease the mtraperitoneal areas with fat-like attenuation after IL-6 treatment to the IL-6 _ " mice (Fig. 9 C) . Before IL-6 treatment, leptin levels were almost three times higher m the IL-6 _ ~ mice compared to the IL- 6 + + mice. IL-6 replacement for 18 days to the IL-6 _ ~ mice caused a significant decrease m leptin levels compared to before treatment . The computerized tomographies (CTs) m this example were performed with the Stratec peripheral quantitative computerized tomography (pQCT) XCT Research M (software version 5.4B; Norland Medical Systems Inc., Fort Atkinson, WI) operating at a resolution of 70 μm. The section was made at the same point all mice, i.e. 5 mm proxi- mally of the cri sta illiaca .

Claims: CLAIMS 1. Use of a substance that upon administration to a patient will lead to an increased level of an mterleu- km-6 (IL-6) receptor agonist for the production of a medicinal product for treatment of obesity and/or obesity associated disorders. 2. Use according to claim 1, wherein said substance is an IL-6 receptor agonist. 3. Use according to claim 2, wherein said substance 4. Use according to any one of the claims 1-3, wherein said obesity and/or obesity associated disorders is caused by a pathological disturbance of fat metabo- lism. 5. Use according to claim 4, wherein said obesity is mainly visceral or mtraabdom al . 6. Use according to any one of the claims 1-5, wherein said obesity is observed despite high levels of circulating leptin. 7. Use according to any one of the claims 1-6, wherein said obesity is accompanied by leptin msensitivity. 8. Use according to any one of the claims 1-3, wherein said disorder is a pathological increase of serum triglyceπdes . 9. Use according to any one of the claims 1-8, wherein said medicinal product is suitable for treatment of a cardiovascular disease. 10. Use according to any one of the claims 1-8, wherein said medicinal product is suitable for treatment of the metabolic syndrome. 11. Use according to any one of the claims 1-8 or 10, wherein said medicinal product is suitable for treat - ment of diabetes type II. 12. Use according to any one of the claims 1-11, wherein said medicinal product is suitable for treatment of a condition due to ageing. 13. Use according to claim 12, intended for a human patient of the age 30 years or older. 14. Use according to any one of the claims 1-13, wherein said medicinal product further comprises a factor that will intensify the effect of said mterleukm-6 (IL- 6) receptor agonist. 15. Use according to claim 14, wherein said factor is a factor acting via gpl30. 16. Use according to claim 14, wherein said factor is leptm. 17. A method for treatment of obesity and/or obesity associated disorders wherein a pharmaceutically effective amount of a substance that upon administration to a patient will lead to an increased level of an mterleukm-6 (IL-6) receptor agonist is administered to said patient. 18. A method according to claim 17, wherein said substance is an IL-6 receptor agonist. 19. A method according to claim 18, wherein said substance is IL-6. 20. A method according to any one of the claims 17- 19, wherein said obesity and/or obesity associated disor- ders is caused by a pathological disturbance of fat metabolism. 21. A method according to claim 20, wherein said obesity is mainly visceral or mtraabdommal . 22. A method according to according to any one of the claims 17-21, wherein said obesity is observed despite high levels of circulating leptin. 23. A method according to according to any one of the claims 17-22, wherein said obesity is accompanied by leptin msensitivity. 24. A method according to any one of the claims 17- 19, wherein said condition is a pathological increase of serum triglyceπdes . 25. A method according to any one of the claims 17- 24, wherein said medicinal product is suitable for treatment of a cardiovascular disease. 26. A method according to any one of the claims 17- 25, wherein said medicinal product is suitable for treatment of a condition due to ageing. 27. A method according to claim 26, wherein said patient is a human of the age 30 years or older. 28. A method according to any one of the claims 17- 27, wherein said IL-6 receptor agonist is administered combination with a factor that will intensify the effect of said IL-6 receptor agonist. 29. A method according to claim 28, wherein said factor is a factor acting via gpl30. 30. A method according to claim 28, wherein said factor is leptin.

Inventors: JANSSON JOHN-OLOV, WALLENIUS VILLE, JANSSON, JOHN-OLOV, WALLENIUS, VILLE
Applicants: JANSSON JOHN OLOV, SAHLTECH AB, WALLENIUS VILLE, JANSSON, JOHN-OLOV, SAHLTECH I GOETEBORG AB, WALLENIUS, VILLE
Application year: 2000
Main classification: A61K38
IPC codes: A61K38, A61P3