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Viktiga forskningsresultat - John-Olov Jansson


Den här informationen finns endast på engelska.

Findings 2002-2015

  •  In 2002, I was first to show that endogenous IL-6 prevents obesity and enhances glucose tolerance (Wallenius et al 2002, Nat Med 8:75, cited more than 500 times in WoS). We also showed evidence that this effect is exerted at the level of the CNS and involves increased leptin sensitivity.
     
  • We have shown that IL-6-/- mice have reduced endurance and energy expenditure during exercise (Fäldt et al 2004, Endocrinology 145:2680). These results suggest that the increase in muscle derived IL-6 observed in plasma of experimental animals and humans is necessary for normal exercise capacity.
     
  • We found that the levels of IL-6 in CSF differs in many ways from CSF leptin. I found evidence that CSF IL-6 is locally produced rather than serum derived. Moreover, body fat-regulating regions in the CNS may be exposed to insufficient IL-6 levels in more severely obese humans (Stenlöf et al 2003, J Clin Endocrinol Metab. 88:4579).
     
  • In 2006, I found that depletion of the only known biologically active IL-1 receptor, receptor I (IL-1RI) also causes mature onset obesity (Garcia et al 2006, Diabetes 55:1205) in a similar way as previously shown for mice with IL-6 gene knockout. Consistently, double IL-6 and IL-1 gene knockout (KO) in mice causes an earlier and more pronounced increase in fat mass. It has later been shown that several cytokines, such as IL-18 and GM-CSF, suppress obesity at the level of the hypothalamus in a similar way as IL-6 and IL-1(Reed et al 2005, J Clin Invest. 2005;115:3035; Netea et al 2006, Nat Med. 2006;12:650; Zorilla et al 2007, Proc Natl Acad Sci U S A 104:11097). Thus, we were the first to show that some endogenous cytokines can suppress obesity by increasing leptin sensitivity at the level of the brain, a now well established fact.
     
  • I later found evidence that IL-6 stimulates energy expenditure via stimulation of the sympathetic nerve system (Wernstedt et al 2006, Am J Physiol 291:R551). These effects that be mediated via a direct effects by IL-6 on neuronal circuits regulating energy balance in the paraventricular nucleus in the hypothalamus (Benrick et al 2009, J Neuroendo 21:620-628).
     
  • We have obtained ample evidence that polymorphisms of the IL-6 and IL-1 system genes are associated with body fat mass (e g Andersson et al 2009, Int J Obes 33:525; Sarwar N et al 2012, Lancet 379:1205-1213).
     
  • Using well characterized antibodies for immunohistochemistry, we have found that the ligand binding part of the IL-6 receptor IL-6Rα) is present in several nuclei and cell types of the mouse hypothalamus, known to regulate energy balance. These nuclei include the paraventricular nuclei (PVN), the arcuate nuclei (ARC) and the lateral hypothalamic area (LHA) ( Benrick A et al 2009, J Neuroendo 21:620; Schéle E et al 2012 J Neuroendo 24:930; Schéle E et al 2013 J Neuroendo 25:580). Intriguingly, IL-6Rα was onmly found in cells expressing melanin concentrating hormone (MCH) in humans (Schéle E et al 2012).
     
  • Very recently, we have found evidence that Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6 (Shirazi R et al 2013 Proc Natl Acad Sci USA 110:16199). This finding, done with Dr Karolina Skibicka, for the time suggest a mechanism of action for one of very few groups of pharmaceuticals on the market that can suppress obesity.

Earlier findings

  • Together with Olle Isaksson, I participated in the groundbreaking discovery that local injection of GH into the growth plate of long bones can stimulate growth independently of liver IGF-1 (Isaksson et al 1982, Science 216:1237).
     
  • The plasma GH pattern is sexually dimorphic in rodents as well as in humans with a more continuous secretion in females. I performed the first studies showing that the plasma GH pattern is a determinant for body growth, with a larger growth stimulation by pulsatile than by continuous GH exposure (Jansson et al 1985 Endo Rev 6:128, cited over 600 times).
     
  • I was the senior author of the first study showing that there is a larger stimulation of IGF-1 expression in cartilage and muscle by pulsatile compared to continuous GH exposure. As these are major target organs of anabolic effect GH , this provide mechanism for how pulsatile GH stimulates growth more effectively (Isgaard et al 1988, Endocrinology 123:2605). I also showed that the GH secretory pattern was of importance for epidermal growth factor receptors, providing another possible mechanism to affect body growth (Jansson et al 1988, J Clin Invest 82:1871; Ekberg et al 1989, Endocrinology 125:2158).
     
  • I clarified how the sexually dimorphic GH secretory pattern is regulated by sex steroids during adulthood in both sexes, as well as by neonatal programming by testicular androgens in male rodents.
     
  • When working with Larry Frohman, I was the first to provide clear evidence that the dwarf mouse little is GH deficient due to a defective GHRH receptor (Jansson et al 1986, Science 232:511; Frohman & Jansson 1986, Endocr Rev 7:223). It took almost 10 years before this hypothesis was proven to be correct, and that the little mouse has a point mutation of the GH releasing hormone (GHRH) receptor (Lin et al 1993, Nature 364:208; Godfrey et al 1993, Nat Genet 4:227-232). Later it has been shown that mutations of the GHRH gene also is a cause of dwarfism in humans (Wajnrajch et al 1996, Nat Genet 12:88). Our article in Science was to our knowledge the first descriptions of a disease caused by defective GPCR. The GPCR associated disease found next was rhodopsin dysregulation in retinitis pigmentosa described by Drya TP et al in 1990 (N Engl J Med 323:1302, 1990). GPCR related diseases is now a large area of research (Thompson MD et al 2008, Methods Mol Biol 448:109).


    Fig 1
  • Using a sophisticated iv infusion system for freely moving rats, I obtained evidence that a delayed negative feedback effect of GH on hypothalamic somatostatin release contributes to the pulsatile GH secretion rhythm in male rats (Carlsson & Jansson 1990, Endocrinology 126:6-10). Remarkably, the same conclusion was reached at about the same time by professor Chihara in Japan, after using a completely different experimental approach (Sato et al 1989, Neuroendocrinology 50:139-151).
     
  • I have shown evidence that amplification and over-expression of the hepatocyte growth factor (HGF) receptor gene can contribute to the development and growth of various tumours (Helou et al 1999, Oncogene 18:3226; Wallenius et al 2000, Am J Pathol 156:821).
     
  • I found evidence that normal liver growth is dependent on the tumour necrosing factor α (TNFα)- TNFreceptor1- IL-6 axis. This was based on the finding that both IL-6 knockout mice and TNF recptor1 knockout mice have a selective decrease in liver growth (Wallenius et al 2001, Endocrinology 142:2953).
     
  • For several years, I have participated in several studies with Olle Isaksson And Claes Ohlsson investigating the biological effects of liver-derived IGF-1. By using a unique model for inducible liver specific deletion of the IGF-1 gene developed in Gothenburg, we have got evidence that liver derived endogenous IGF-1 is not important for body growth, but exerts several other biological functions (Sjögren et al 1999, Proc Natl Acad Sci USA 96:7088; for review see Ohlsson et al 2009, Endo Rev 30: 494).
     
  • I provided convincing evidence that liver derived endogenous IGF-1 contributes to the suppression of GH, using our model for inducible liver specific deletion of the IGF-1 gene (Wallenius et al 2001, Endocrinology 142: 4762).
     
  • I was the first to hypothesize and prove that ghrelin replacement can reverse symptoms, including decreased appetite and weight loss after gastrectomy (Patent EP1553969/WO 2004/032952; Dornonville de la Cour et al 2005, Gut 54:907).



    Fig 2. Proposed model for hypothalamicpituitary-liver feedback axis of GH secretionand how it is affected by liver-specific IGF-Ideletion

    Fig 2. Proposed model for hypothalamicpituitary-
    liver feedback axis of GH secretion
    and how it is affected by liver-specific IGF-I
    deletion
    (Adapted from Ohlsson C, Mohan S, Sjögren K, et al. The Role of Liver-Derived Insulin-Like Growth Factor-I. Endocrine Reviews. 2009;30(5):494-535. doi:10.1210/er.2009-0010.)

    Mice with liver-specific IGF-I KO (right panel) have increased GH secretion. Increased GH levels in turn enhance the liver weight. In male mice with depletion of liver-derived IGF-I, the enhanced GH trough levels feminize liver functions regulated by the sexual dimorphism of GH secretion in rodents. The mechanism for how lack of liver-derived IGF-I increases GH secretion seems to involve increased expression of GHRH and Ghrelin receptors (right panel) and
    augmented responsiveness to these ligands at the level of the pituitary. There is no evidence that lack of liver-derived IGF-I enhances GH secretion via an effect on the hypothalamus, possibly because enhanced pituitary GH and
    local hypothalamic IGF-I secretion partly counteract the effects of lack of liver-derived IGF-I on the hypothalamus.
     

 

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