FGF1: a novel regulator of metabolic homeostasis and insulin sensitization
Projectomschrijving
Suikerziekte (Type 2 diabetes) vormt een steeds groter probleem in onze samenleving. De toename van deze zogenaamde “metabole ziekte” hangt nauw samen met de Westerse levensstijl die gekenmerkt wordt door overmatige voedsel inname en te weinig lichaamsbeweging. Er zijn weliswaar effectieve medicijnen voor deze ziekte maar deze hebben ernstige bijwerkingen.
In ons onderzoek hebben wij ontdekt dat het hormoon FGF1 zeer gunstige effecten heeft op type 2 diabetes zonder de ernstige bijwerkingen die bij andere medicijnen gezien worden. FGF1 verlaagt langdurig de bloedsuikerspiegels en verhoogt tevens de gevoeligheid van het lichaam voor insuline. Hoewel FGF1 al meer dan 30 jaar geleden ontdekt is was de functie van dit hormoon nooit opgehelderd.
Het onderzoek in dit project is erop gericht om de mechanismen die ten grondslag liggen aan deze gunstige eigenschappen van FGF1 op te helderen en daarnaast om te onderzoeken of FGF1 ook in diabetespatiënten effectief en veilig te gebruiken is.
Producten
Titel: Fibroblast Growth Factor Signaling in Metabolic Regulation
Auteur: Nies, Vera J. M., Sancar, Gencer, Liu, Weilin, van Zutphen, Tim, Struik, Dicky, Yu, Ruth T., Atkins, Annette R., Evans, Ronald M., Jonker, Johan W., Downes, Michael Robert
Magazine: Frontiers in Endocrinology
Auteur: Nies, Vera J. M., Sancar, Gencer, Liu, Weilin, van Zutphen, Tim, Struik, Dicky, Yu, Ruth T., Atkins, Annette R., Evans, Ronald M., Jonker, Johan W., Downes, Michael Robert
Magazine: Frontiers in Endocrinology
Titel: Intestinal PPARd protects against diet-induced obesity, insulin resistance and dyslipidemia
Auteur: Doktorova, Marcela, Zwarts, Irene, Zutphen, Tim van, Dijk, Theo H. van, Bloks, Vincent W., Harkema, Liesbeth, Bruin, Alain de, Downes, Michael, Evans, Ronald M., Verkade, Henkjan J., Jonker, Johan W.
Magazine: Scientific Reports
Auteur: Doktorova, Marcela, Zwarts, Irene, Zutphen, Tim van, Dijk, Theo H. van, Bloks, Vincent W., Harkema, Liesbeth, Bruin, Alain de, Downes, Michael, Evans, Ronald M., Verkade, Henkjan J., Jonker, Johan W.
Magazine: Scientific Reports
Titel: Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease
Auteur: Liu, Weilin, Struik, Dicky, Nies, Vera J. M., Jurdzinski, Angelika, Harkema, Liesbeth, de Bruin, Alain, Verkade, Henkjan J., Downes, Michael, Evans, Ronald M., van Zutphen, Tim, Jonker, Johan W.
Magazine: Proceedings of the National Academy of Sciences USA
Auteur: Liu, Weilin, Struik, Dicky, Nies, Vera J. M., Jurdzinski, Angelika, Harkema, Liesbeth, de Bruin, Alain, Verkade, Henkjan J., Downes, Michael, Evans, Ronald M., van Zutphen, Tim, Jonker, Johan W.
Magazine: Proceedings of the National Academy of Sciences USA
Titel: Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
Auteur: Du L, Bergsneider M, Mirsadraei L, Young SH, Jonker JW, Downes M, Yong WH, Evans RM, Heaney AP.
Magazine: Proceedings of the National Academy of Sciences USA
Auteur: Du L, Bergsneider M, Mirsadraei L, Young SH, Jonker JW, Downes M, Yong WH, Evans RM, Heaney AP.
Magazine: Proceedings of the National Academy of Sciences USA
Titel: Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol
Auteur: Bertolini, Anna, van de Peppel, Ivo P., Doktorova-Demmin, Marcela, Bodewes, Frank A. J. A., de Jonge, Hugo, Bijvelds, Marcel, Verkade, Henkjan J., Jonker, Johan W.
Magazine: American Journal of Physiology - Gastrointestinal and Liver Physiology
Auteur: Bertolini, Anna, van de Peppel, Ivo P., Doktorova-Demmin, Marcela, Bodewes, Frank A. J. A., de Jonge, Hugo, Bijvelds, Marcel, Verkade, Henkjan J., Jonker, Johan W.
Magazine: American Journal of Physiology - Gastrointestinal and Liver Physiology
Titel: A PPARg-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.
Auteur: Jonker JW, Suh JM, Atkins AR, Ahmadian M, Li P, Whyte J, He M, Juguilon H, Yin YQ, Phillips CT, Yu RT, Olefsky JM, Henry RR, Downes M, Evans RM.
Magazine: Nature
Auteur: Jonker JW, Suh JM, Atkins AR, Ahmadian M, Li P, Whyte J, He M, Juguilon H, Yin YQ, Phillips CT, Yu RT, Olefsky JM, Henry RR, Downes M, Evans RM.
Magazine: Nature
Titel: Hepatic Farnesoid X-Receptor Isoforms a2 and a4 Differentially Modulate Bile Salt and Lipoprotein Metabolism in Mice
Auteur: Boesjes, Marije, Bloks, Vincent W., Hageman, Jurre, Bos, Trijnie, van Dijk, Theo H., Havinga, Rick, Wolters, Henk, Jonker, Johan W., Kuipers, Folkert, Groen, Albert K.
Magazine: PLoS ONE
Auteur: Boesjes, Marije, Bloks, Vincent W., Hageman, Jurre, Bos, Trijnie, van Dijk, Theo H., Havinga, Rick, Wolters, Henk, Jonker, Johan W., Kuipers, Folkert, Groen, Albert K.
Magazine: PLoS ONE
Titel: Short-Chain Fatty Acids Protect Against High-Fat Diet–Induced Obesity via a PPAR?-Dependent Switch From Lipogenesis to Fat Oxidation
Auteur: den Besten, Gijs, Bleeker, Aycha, Gerding, Albert, van Eunen, Karen, Havinga, Rick, van Dijk, Theo H., Oosterveer, Maaike H., Jonker, Johan W., Groen, Albert K., Reijngoud, Dirk-Jan, Bakker, Barbara M.
Magazine: Diabetes
Auteur: den Besten, Gijs, Bleeker, Aycha, Gerding, Albert, van Eunen, Karen, Havinga, Rick, van Dijk, Theo H., Oosterveer, Maaike H., Jonker, Johan W., Groen, Albert K., Reijngoud, Dirk-Jan, Bakker, Barbara M.
Magazine: Diabetes
Titel: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
Auteur: Suh, Jae Myoung, Jonker, Johan W., Ahmadian, Maryam, Goetz, Regina, Lackey, Denise, Osborn, Olivia, Huang, Zhifeng, Liu, Weilin, Yoshihara, Eiji, van Dijk, Theo H., Havinga, Rick, Fan, Weiwei, Yin, Yun-Qiang, Yu, Ruth T., Liddle, Christopher, Atkins, Annette R., Olefsky, Jerrold M., Mohammadi, Moosa, Downes, Michael, Evans, Ronald M.
Magazine: Nature
Auteur: Suh, Jae Myoung, Jonker, Johan W., Ahmadian, Maryam, Goetz, Regina, Lackey, Denise, Osborn, Olivia, Huang, Zhifeng, Liu, Weilin, Yoshihara, Eiji, van Dijk, Theo H., Havinga, Rick, Fan, Weiwei, Yin, Yun-Qiang, Yu, Ruth T., Liddle, Christopher, Atkins, Annette R., Olefsky, Jerrold M., Mohammadi, Moosa, Downes, Michael, Evans, Ronald M.
Magazine: Nature
Titel: Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells.
Auteur: Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Kläsener K, Ruf S, Sonntag AG, Maerz L, Grellscheid SN, Kremmer E, Nitschke R, Kuehn EW, Jonker JW, Groen AK, Reth M, Hall MN, Baumeister R.
Magazine: Cell
Auteur: Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Kläsener K, Ruf S, Sonntag AG, Maerz L, Grellscheid SN, Kremmer E, Nitschke R, Kuehn EW, Jonker JW, Groen AK, Reth M, Hall MN, Baumeister R.
Magazine: Cell
Titel: New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition
Auteur: van der Schoor, Lori WE, Verkade, Henkjan J, Kuipers, Folkert, Jonker, Johan W
Magazine: Expert opinion on drug metabolism & toxicology
Auteur: van der Schoor, Lori WE, Verkade, Henkjan J, Kuipers, Folkert, Jonker, Johan W
Magazine: Expert opinion on drug metabolism & toxicology
Titel: TUB gene expression in hypothalamus and adipose tissue and its association with obesity in humans
Auteur: Nies, V J M, Struik, D, Wolfs, M G M, Rensen, S S, Szalowska, E, Unmehopa, U A, Fluiter, K, van der Meer, T P, Hajmousa, G, Buurman, W A, Greve, J W, Rezaee, F, Shiri-Sverdlov, R, Vonk, R J, Swaab, D F, Wolffenbuttel, B H R, Jonker, J W, van Vliet-Ostaptchouk, J V
Magazine: International Journal of Obesity
Auteur: Nies, V J M, Struik, D, Wolfs, M G M, Rensen, S S, Szalowska, E, Unmehopa, U A, Fluiter, K, van der Meer, T P, Hajmousa, G, Buurman, W A, Greve, J W, Rezaee, F, Shiri-Sverdlov, R, Vonk, R J, Swaab, D F, Wolffenbuttel, B H R, Jonker, J W, van Vliet-Ostaptchouk, J V
Magazine: International Journal of Obesity
Titel: Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction
Auteur: van Zutphen, Tim, Ciapaite, Jolita, Bloks, Vincent W., Ackereley, Cameron, Gerding, Albert, Jurdzinski, Angelika, Allgayer de Moraes, Roberta, Zhang, Ling, Wolters, Justina C., Bischoff, Rainer, Wanders, Ronald J., Houten, Sander M., Bronte-Tinkew, Dana, Shatseva, Tatiana, Lewis, Gary F., Groen, Albert K., Reijngoud, Dirk-Jan, Bakker, Barbara M., Jonker, Johan W., Kim, Peter K., Bandsma, Robert H.J.
Magazine: Journal of Hepatology
Auteur: van Zutphen, Tim, Ciapaite, Jolita, Bloks, Vincent W., Ackereley, Cameron, Gerding, Albert, Jurdzinski, Angelika, Allgayer de Moraes, Roberta, Zhang, Ling, Wolters, Justina C., Bischoff, Rainer, Wanders, Ronald J., Houten, Sander M., Bronte-Tinkew, Dana, Shatseva, Tatiana, Lewis, Gary F., Groen, Albert K., Reijngoud, Dirk-Jan, Bakker, Barbara M., Jonker, Johan W., Kim, Peter K., Bandsma, Robert H.J.
Magazine: Journal of Hepatology
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Samenvatting van de aanvraag
Type 2 diabetes mellitus (T2DM) and obesity are leading causes of mortality and are associated with the Western lifestyle, which is characterized by excessive nutrient intake and lack of exercise. A central player in the pathophysiology of these diseases is the nuclear receptor PPARgamma (PPARg), a lipid sensor and master regulator of adipogenesis.
I have identified fibroblast growth factor 1 (FGF1) as a novel target of PPARg, critical for maintaining metabolic homeostasis and insulin sensitivity. My research demonstrates that FGF1 is specifically induced in visceral adipose tissue in response to high-fat diet (HFD) and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with HFD. Importantly, in diabetic patients, FGF1 expression in adipocytes was induced by the thiazolidinedione (TZD)-class of insulin sensitizers, which are ligands for PPARg, and this correlated with the efficacy of TZDs to lower fasting levels of glucose.
Basis for the current proposal is my finding that administration of recombinant FGF1 to diabetic mice has potent and long lasting beneficial metabolic effects, including lowering of blood glucose and insulin sensitization. These observations highlight the potency of FGF1 to prevent or treat the consequences of T2DM. The aim of this project is to characterize the metabolic and hormonal effects of FGF1 using genetic mouse models and in vivo tracer-based metabolomics and clamp studies. Elucidation of the molecular mechanisms will focus on the PPARg-FGF1-FGF receptor axis in FGF1-dependent signal transduction cascade and transcription. Studies will be done in normal and genetically modified mice with tissue-specific loss- and gain-of-function of FGF1.
The studies proposed here will establish the physiologic and pharmacologic mechanisms of action of FGF1 in maintaining metabolic homeostasis and prevention of T2DM. Therapeutic targeting of FGF1 or its receptor could serve as an improved strategy for the treatment of T2DM.