title: LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity.
abstract: LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Mylène
authors.initials: M
authors.lastname: Tajan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Batut
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Cadoudal
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Simon
authors.initials: S
authors.lastname: Deleruyelle
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Gonidec
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Céline
authors.initials: C
authors.lastname: Saint Laurent
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Maëlle
authors.initials: M
authors.lastname: Vomscheid
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Estelle
authors.initials: E
authors.lastname: Wanecq
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Karine
authors.initials: K
authors.lastname: Tréguer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Audrey
authors.initials: A
authors.lastname: De Rocca Serra-Nédélec
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Claire
authors.initials: C
authors.lastname: Vinel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Marie-Adeline
authors.initials: MA
authors.lastname: Marques
authors.affiliation: Cardiology Unit, University Hospital Center of Rangueil Toulouse, F-31432 Toulouse, France;
authors.forename: Joffrey
authors.initials: J
authors.lastname: Pozzo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Oksana
authors.initials: O
authors.lastname: Kunduzova
authors.affiliation: Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, F-31024 Toulouse, France;
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Salles
authors.affiliation: Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, F-31024 Toulouse, France;
authors.forename: Maithé
authors.initials: M
authors.lastname: Tauber
authors.affiliation: EA4568 Laboratoire Mécanismes des Cardiopathies et Résistances Hormonales dans le Syndrome de Noonan et les Syndromes Apparentés, Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France; and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Raynal
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S1131, Unité de Formation et de Recherche de Médecine Paris-Diderot-Institut Universitaire d'Hématologie Département de Génétique, Unité Fonctionnelle de Génétique Moléculaire Hôpital Robert Debré, F-75019 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, F-31024 Toulouse, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Edouard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, F-31432 Toulouse, France; Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Université Paul Sabatier, F-31432 Toulouse, France; armelle.yart@inserm.fr.
authors.forename: Armelle
authors.initials: A
authors.lastname: Yart
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001823:Body Composition; D002454:Cell Differentiation; D004032:Diet; D004195:Disease Models, Animal; D004734:Energy Metabolism; D007328:Insulin / Q000378:metabolism; D044542:LEOPARD Syndrome / Q000235:genetics*; D016086:Lentivirus / Q000378:metabolism; D008066:Lipolysis; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009765:Obesity / Q000517:prevention & control*; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D011995:Recombination, Genetic; D013851:Thinness / Q000235:genetics*
chemical_list: D007328:Insulin; D048728:MAP Kinase Kinase Kinase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: adipose tissue; energy metabolism; ras/MAPK; rasopathies