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FGF21 is a link between reproduction and energy balance

English title FGF21 is a link between reproduction and energy balance
Applicant Pitteloud Nelly
Number 141960
Funding scheme Sinergia
Research institution Division d'endocrinologie, diabétologie et du métabolisme Département de médecine interne - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Endocrinology
Start/End 01.12.2012 - 31.05.2016
Approved amount 1'500'000.00
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Keywords (7)

circadian clock; structural biology; reproduction; human genetics; astrocytes; metabolism; fibroblast growth factor 21

Lay Summary (French)

Lead
L'objectif de ce projet est d'étudier le rôle du facteur de croissance des fibroblastes 21 (FGF21) en tant que lien entre le métabolisme et la reproduction.
Lay summary

Chez les humains comme chez les animaux, il existe un lien entre le métabolisme (la façon dont l’apport calorique est traité et utilisé) et la reproduction. Par exemple, la reproduction est altérée dans les états d’apport calorique excessif (obésité) ou insuffisant (malnutrition). D’une façon générale, l'objectif de ce projet est d'étudier le rôle du facteur de croissance des fibroblastes 21 (FGF21) en tant que lien entre le métabolisme et la reproduction.

Des études antérieures sur des animaux ont montré qu’administrer FGF21 a plusieurs effets: il améliore le métabolisme du sucre (sensibilité à l'insuline), diminue les taux de triglycérides (un type de cholestérol) et stimule la perte de poids. D'autres études indiquent que FGF21 est contrôlé par des rythmes biologiques naturels (horloge circadienne). De plus, nos travaux précédents ont identifié que les facteurs de croissance des fibroblastes jouent un rôle essentiel chez les patients souffrant d'infertilité secondaire à l’absence d'une hormone qui contrôle la reproduction, l’hormone de libération de la gonadotropine.

Dans ce projet, nous rassemblons des chercheurs en génétique humaine, biologie structurale, chronobiologie (horloge circadienne) et métabolisme, afin d'approfondir notre compréhension de la biologie de FGF21. L'objectif principal de ce projet est donc d'établir FGF21 comme un lien entre le métabolisme énergétique, le contrôle neuro-endocrinien de la reproduction (hormones cérébrales) et l'horloge circadienne et ce, au moyen d'études sur les cellules, les souris et les humains.

Les données obtenues par ces études nous permettront de mieux comprendre les effets de FGF21 sur le métabolisme et la reproduction. Ces domaines sont particulièrement importants parce que les troubles métaboliques (diabète) et de la reproduction (infertilité) affectent la santé individuelle en même temps qu’ils ont des conséquences économiques négatives pour la société. Ces études constituent la première étape dans le développement de nouvelles approches pour traiter ces pathologies.

Direct link to Lay Summary Last update: 14.08.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
Goetz R, Ohnishi M, Kir S, Kurosu H, Wang L, Pastor J, Ma J, Gai W, Kuro-o M, Razzaque MS, Mohammadi M (2012), Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor, in Journal of Biological Chemistry, 287(34), 29134-29146.
Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands
Goetz R, Ohnishi M, Ding X, Kurosu H, Wang L, Akiyoshi J, Ma J, Gai W, Sidis Y, Pitteloud N, Kuro-O M, Razzaque MS, Mohammadi M (2012), Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands, in Molecular & Cellular Biology, 32(10), 1944-1954.

Collaboration

Group / person Country
Types of collaboration
Albrecht/University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Mohammadi/New York University Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Pellerin/University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Society for Endocrinology & Diabetes Talk given at a conference KLB encoding the co-receptor of FGF21 is mutated in congenital hypogonadotropic hypogonadism 20.11.2015 Bern, Switzerland Somm Emmanuel; Mohammadi Moosa; Pitteloud Nelly; Miraoui Hichem;
54th Annual Meeting of the European Society for Paediatric Endocrinology Talk given at a conference KLB, encoding the co-receptor of FGF21, is mutated in congenital hypogonadotropic hypogonadism 01.10.2015 Barcelona, Spain Mohammadi Moosa; Miraoui Hichem; Pitteloud Nelly; Somm Emmanuel;
La journee de recherche du department de medecine, CHUV Talk given at a conference KLB, encoding the co-receptor for FGF21, is mutated in congenital hypogonadotropic hypogonadism 16.09.2015 Lausanne, Switzerland Miraoui Hichem; Pitteloud Nelly; Somm Emmanuel; Mohammadi Moosa;
Joint Scientific Meeting and Training School - COST Action BM1105 Talk given at a conference Links between the circadian clock and reproduction 27.04.2015 Prato, Italy Albrecht Urs Emanuel;
European society of endocrinology, basic course in reproductive endocrinology Talk given at a conference KLB, encoding a co-receptor for FGF21, is mutated in congenital hypogonadotropic hypogonadism 13.02.2015 Edinburgh, Great Britain and Northern Ireland Somm Emmanuel; Mohammadi Moosa; Miraoui Hichem; Pitteloud Nelly;
Center for Integrative Genomics Symposium 2014 “Rhythms in Biology" Poster FGF21: Link to reduced fertility in the Rev-Erbα -/- mice 12.06.2014 Lausanne, Switzerland Albrecht Urs Emanuel; Pitteloud Nelly;
Joint Meeting of the 16th International Congress for Endocrinology & the 96th Annual Meeting of the Endocrine Society Poster KLB, encoding the co-receptor for FGF21, is a novel locus underlies congenital GnRH deficiency 07.06.2014 Chicago, United States of America Somm Emmanuel; Miraoui Hichem; Pitteloud Nelly; Mohammadi Moosa;
COST Action BM1105 Scientific Meeting and Training School Poster KLB, encoding the co-receptor for FGF21, is mutated in congenital hypogonadotropic hypogonadism 06.03.2014 Berlin, Germany Miraoui Hichem; Somm Emmanuel; Mohammadi Moosa; Pitteloud Nelly;
Journée de Recherche du Département Médico-Chirurgical de Pédiatrie, Talk given at a conference KLB, encoding the co-receptor for FGF21, is mutated in congenital GnRH deficiency 30.01.2014 Lausanne, Switzerland Miraoui Hichem; Somm Emmanuel; Pitteloud Nelly; Mohammadi Moosa;


Awards

Title Year
Best oral presentation, European Society of Endocrinology, Basic Course in Reproductive Endocrinology. Edinburgh, UK, February 2015. 2015

Patents

Title Date Number Inventor Owner
Fibroblast growth factor 1 protein fragments and methods of use. 07.04.2015 U.S. Patent No. 8,999,929
Fibroblast growth factor proteins and methods of use. 11.12.2014 Australian Patent Application No. 2014274604
Chimeric fibroblast growth factor 21 proteins and methods of use. 06.06.2013 International Patent Application No. PCT/US2013/04
Chimeric fibroblast growth factor 21 proteins and methods of use. 06.06.2013 European Patent Application No. 13799858.9
Chimeric fibroblast growth factor 21 proteins and methods of use. 06.06.2013 Australian Patent Application No. 2013271471
Chimeric fibroblast growth factor 21 proteins and methods of use. 06.06.2013 China Patent Application No. 201380039848.9
Chimeric fibroblast growth factor 21 proteins and methods of use. 04.12.2012 U.S. Patent Application No. 14097116

Associated projects

Number Title Start Funding scheme
146265 Clock synchronization: From brain to periphery or periphery to brain? 01.04.2013 Project funding (Div. I-III)
153328 The Neuroendocrine Control of Human Reproduction 01.04.2014 Project funding (Div. I-III)
135648 The Neuroendocrine Control of Human Reproduction 01.04.2011 Project funding (Div. I-III)

Abstract

1. Summary of Research PlanFibroblast growth factor (FGF) signaling plays pleiotropic roles in mammalian development and metabolism as reflected by the fact that aberrant FGF signaling underlies several human diseases including reproductive syndromes such as congenital GnRH deficiency. FGF ligands (FGF1-10 and FGF16-23) signal in either paracrine or endocrine fashion through FGF receptors (FGFR1-4). Paracrine FGFs require heparan sulfate (HS) glycosaminoglycans to bind and dimerize their cognate receptors whereas the endocrine FGFs (FGF19, 21, and 23) rely on klotho proteins as co-receptors to activate their cognate receptors. FGF21 treatment enhances insulin sensitivity, decreases triglyceride concentrations, and induces weight loss in rodents and primates. Such actions identify FGF21 as a pharmaceutical target for metabolic disorders such as type 2 diabetes. FGF21 is also critical for the normal fasting response via hepatic peroxisome proliferator-activated receptor a (PPARa) activation. These combined actions identify FGF21 as a critical peripheral metabolic regulator. Interestingly, in contrast to other metabolic regulators such as insulin and leptin, the central role of FGF21 in largely uncharted. FGF21 crosses the blood-brain barrier and its action in the brain increases hepatic insulin sensitivity. These observations taken together with the existence of a link between metabolic state and reproductive fitness lead us to hypothesize that FGF21 signaling may tie metabolism and reproduction together. In support of this hypothesis, our structural and biochemical investigations of mutations identified in patients with GnRH deficiency have revealed a role for FGF21 signaling in the neuroendocrine control of reproduction. GnRH neurons, the pilot light of reproduction across mammals, interact closely with astrocytes in the hypothalamus. These cells provide metabolic fuels and growth factors to the GnRH neurons. Given the similarities between astrocytes and hepatocytes in terms of metabolic function, we propose that astrocytes also produce FGF21 in response to metabolic cues connecting reproduction to energy balance. In addition, both astrocytes and GnRH neurons display circadian rhythms. This is consistent with the growing evidence linking clock functions with metabolism, GnRH biology, and astrocyte function. Given this biologic complexity, we propose to utilize the Sinergia platform with lead investigators in the fields of human genetics, structural biology, chronobiology, and astrocytes metabolism to deepen our understanding of FGF21 biology. Thus, the main goal of this project is to establish FGF21 as a link between energy metabolism, the neuroendocrine control of reproduction, and the circadian clock. More specifically, we aim to :1) explore the role for FGF21 in mouse and human reproduction; 2) study the circadian/diurnal rhythm of FGF21 in reproductive disorders and its relationship to the circadian clock; 3) elucidate the structural basis for the endocrine mode of action of FGF21; and 4) determine the metabolic effects of FGF21 in astrocytes.
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