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Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4494-503. doi: 10.1073/pnas.1406107111. Epub 2014 Oct 6.

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity.

Author information

1
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;
2
Cardiology Unit, University Hospital Center of Rangueil Toulouse, F-31432 Toulouse, France;
3
Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, F-31024 Toulouse, France;
4
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.
5
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.
6
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.

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.

KEYWORDS:

adipose tissue; energy metabolism; ras/MAPK; rasopathies

PMID:
25288766
PMCID:
PMC4210352
DOI:
10.1073/pnas.1406107111
[Indexed for MEDLINE]
Free PMC Article

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