González Olmedo, Carmen

Universitat Autònoma de Barcelona. Facultat de Biociències

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       	   IL-6: Inflammatory Marker with Controversial Role in Metabolism  CARMEN GONZÁLEZ OLMEDO Final Project of  Degree in Biomedical Sciences, 2011-2015   Faculty of  Biosciences, Universitat Autònoma de Barcelona, Spain          The interleukin-6 (IL-6) is a well-known inflammatory cytokine with pleiotropic action throughout the body.   Lately, several studies have reported an IL-6 METABOLIC ROLE suggesting that this cytokine: 1.  Can directly act on its membrane receptor (IL-6Rα), extensively distributed in different hypothalamus sites, regulating fat mass. 2.  Mediates the expression of  some neuropeptides involved in energy homeostasis in a GENDER-DEPENDENT-MANNER. 3.  Leads to body weight decrease mainly through ENERGY EXPENDITURE, rather than controlling food-intake. Since IL-6 mechanism of  action in the central nervous system is currently unclear, much more research on this matter is required in order to provide NOVEL TREATMENT TARGETS for some diseases with a remarkable impact on population, as it is OBESITY.         The discussion carried out in this review, about the IL-6 role in the energy balance, was basically based on:  1.  Bibliographic revision: 51 original and review articles read, 22 CITED.  2.  Online databases: mainly PUBMED. 3.  Scientific journals of  high impact as: Journal of  Neuroendocrinology.  	     1.  Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 75–79 (2002). 2.  Wallenius, K., Wallenius, V., Sunter, D., Dickson, S. L. & Jansson, J.O. Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem. Biophys. Res. Commun. 293, 560–5 (2002). 3.  Ferrer, B. et al. Muscle-specific interleukin-6 deletion influences body weight and body fat in a sex-dependent manner. Brain. Behav. Immun. 40, 121–30 (2014).  4.  Schéle, E. et al. Inter-relation between Interleukin (IL)-1, IL-6 and Body Fat Regulating Circuits of  the Hypothalamic Arcuate Nucleus. J. Neuroendocrinol. 25, 580–589 (2013).    IntroductionReferencesMethodologyIL-6 and obesityIL-6 in the CNSIL-6 and exerciseContradictory IL-6 OVER-EXPRESSION observed either in physiological or pathological conditions EXERCISE High levels of  IL-6 have been found during skeletal muscle contraction 	  OBESITY Up-regulated IL-6 correlates the adipose tissue mass with the adipokine-dose released Fig. 1. a) Changes in body weight during two weeks of  i.c.v treatment with IL-6 in comparison with saline. b) IL-6 -/- (IL-6-KO) mice developed mature-onset obesity.Results from Wallenius, K. et al., and Wallenius, V.  et al. see References1,2.Fig. 2. a) Body weight gain in IL-6-KO and floxed mice fed the control diet and the HFD with sex-specific differences.  b) Gender-dependent quantification for the main neuropeptides involved in food intake and energy expenditure in specific hypothalamic nuclei: corticotrophin-releasing hormone (CRH), prepro-orexin (ppOx), agouti-related peptide (AgRP), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC).  Results from	  B. Ferrer et al., see References3. Control IL-6-/-a) b) The general believed of  obesity as  PRO-INFLAMMATORY STATE, involving high IL-6 levels, could seem inconsistent with results shown in  a) and b). However, these results demonstrate a metabolic role of  the IL-6 in the energ y ba lance regulat ion (see Conclusions).   a) Intra-cerebro-ventricular (i.c.v) administration decreases body weight. b) Mice lacking the IL-6 gene (IL-6-KO) developed later-onset obesity. ConclusionsContracting muscle is considered an IMPORTANT SOURCE of  IL-6 since this cytokine is over-expressed during exercise.  a) b) Muscle IL-6 has a role in a sex-specific fashion decreasing body weight, as shown in Fig.2. a. Adittionally, neuropeptides related with fat mass regulation seemed to be mediated by muscle IL-6, as shown in Fig.2. b   1.  Since the adipose-derived hormone leptin correlates with adipose tissue mass during obesity, the IL-6 might correlate with the pro-inflammatory state of  obese patients as well as with their adipose tissue mass in a similar way as leptin. Thus, it is suggested that IL-6 could signal the CNS to regulate fat mass in analogous form as leptin does. 2.  The IL-6 influence on homeostasis is exerted via some energy balance-related nuclei and neuropeptides in the hypothalamus and hindbrain, regulating body weight mainly through increased energy expenditure rather than controlling food intake. 3.  Deletion of  cell-specific IL-6 seems to have similar repercussions on energy balance. Development of  gender-cell-specific IL-6 knockout mice is, indeed, an efficient tool suggested for future studies. (see Conclusions). Rodent-vs-Human	  	  NPY AgRPPOMC CART OrexinMCHCRHOxytocinARCPVNLHANTSHYPOTHALAMUSHINDBRAIN     ENERGY EXPENDITURE	  	      BODY FATIL-6 and IL-1 Fig. 3. a) Cells with co-localised IL-6Rα-and NPY in the ARC. Hypothalamic NPY, AgRP and POMC mRNA levels in IL-1 receptor type I deficient (IL-1R1-/-) mice (b) and IL-6 deficient (IL-6-/-) mice(c) .  Results from Schéle et al., see References4. b) a) c) Graphic 1. Rodent-vs-Human: Different central IL-6Rα distribution. Main areas where the IL-6 membrane receptor was found by current studies and principal neuropeptides which expression was altered by IL-6: lateral hypothalamic area (LHA), paraventricular nucleus (PVN), arcuate nucleus (ARC) and melanin-concentrating hormone (MCH).            SYMPATHETIC NERVOUS STIMULATIONIL-6RαHUMANPresentLHA: MCH complete overlaps AbsentPVNInfundibular area (ARC in rodents) MOUSEIntensively stainedPVN: CRH, OXYTOCIN ARC: NPYScattered LHA: MCH and OREXIN  ²  COOPERATIVE FUNCTION of  IL-6 with IL-1 appears to be important for obesity development. ²  I n f l u e n c e o n f a t r e g u l a t i n g neuropeptides was observed in IL-6 and IL-1R1-KO mice, as shown in  Fig. 3. b and c. ²  Both cytokines might exert anti-obesity effect acting on the GLP-1 receptor in the HINDBRAIND.  IL-6IL-6-IL-6R-gp130 complexImage modified from Schéle et al.. 

IL-6 : inflammatory marker with controversial role in metabolism

http://ddd.uab.cat/pub/tfg/2015/144642/TFG_carmengonzalezolmedo.pdf

IL-6 : inflammatory marker with controversial role in metabolism

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