Novel therapeutic perspectives in Noonan syndrome and RASopathies.

Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia).  Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. What is Known: • Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway. • This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known. What is New: • The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. • Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.

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

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.

Body composition and resting energy expenditure in a group of children with achondroplasia.

BACKGROUND: Persons with achondroplasia develop early obesity, which is a comorbidity associated with other complications. Currently, there are no validated specific predictive equations to estimate resting energy expenditure in achondroplasia. METHODS: We analyzed the influence of body composition on this parameter and determined whether predictive models used for children with standard height are adjusted to achondroplasia. In this cross-sectional study, we measured anthropometric parameters in children with achondroplasia. Fat mass was obtained using the Slaughter skinfold-thickness equation and resting energy expenditure was determined with a Fitmate-Cosmed calorimeter and with predictive models validated for children with average height (Schofield, Institute of Medicine, and Tverskaya). RESULTS: All of the equations yielded a lower mean value than resting energy expenditure with indirect calorimetry (1256±200 kcal/day [mean±SD]) but the closest was the Tverskaya equation (1017 ± 64 kcal/day), although the difference remained statistically significant. We conclude that weight and height have the greatest influence on resting energy expenditure. CONCLUSION: We recommend studying the relationship between body composition and energy expenditure in achondroplasia in more depth. In the absence of valid predictive models suitable for clinical use to estimate body composition and resting energy expenditure in achondroplasia, it is recommended to use the gold standard methods by taking into account certain anthropometric parameters.

The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2's molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation.

SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations.

Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.

Obesity in achondroplasia patients: from evidence to medical monitoring.

Achondroplasia is a rare genetic disease representing the most common form of short-limb dwarfism. It is characterized by bone growth abnormalities that are well characterized and by a strong predisposition to abdominal obesity for which causes are unknown. Despite having aroused interest at the end of the 20 h century, there are still only very little data available on this aspect of the pathology. Today, interest is rising again, and some studies are now proposing mechanistic hypotheses and guidance for patient management. These data confirm that obesity is a major health problem in achondroplasia necessitating an early yet complex clinical management. Anticipatory care should be directed at identifying children who are at high risk to develop obesity and intervening to prevent the metabolic complications in adults. In this review, we are regrouping available data characterizing obesity in achondroplasia and we are identifying the current tools used to monitor obesity in these patients.

Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia.

BACKGROUND: Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication. METHODS AND FINDINGS: To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals. CONCLUSION: This study demonstrate that achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.

Enhanced glucose metabolism is preserved in cultured primary myotubes from obese donors in response to exercise training.

CONTEXT: It was suggested that human cultured primary myotubes retain the metabolic characteristics of their donor in vitro. OBJECTIVES: The aim of the present study was to investigate whether the metabolic responses to endurance training are also conserved in culture. DESIGN AND VOLUNTEERS: Middle-aged obese subjects completed an 8-week supervised aerobic exercise training program in which vastus lateralis muscle biopsies were collected before and after training. MAIN OUTCOME MEASURES: Anthropometric and blood parameters, as well as aerobic capacity, were assessed before and after training. Muscle biopsies were either used for Western blot analysis or digested to harvest myogenic progenitors that were differentiated into myotubes. Glucose oxidation, palmitate oxidation, and glycogen synthesis assays were performed on myotubes before and after training. Gene expression was assessed by real-time quantitative PCR. RESULTS: Our data indicate that in parallel of in vivo improvement of whole-body aerobic capacity and glucose metabolism, biopsy-derived primary myotubes showed similar patterns in vitro. Indeed, glucose oxidation, glycogen synthesis, and inhibition of palmitate oxidation by glucose were enhanced in myotubes after training. This was associated with consistent changes in the expression of metabolism-linked genes such as GLUT1, PDK4, and PDHA1. Interestingly, no difference in myogenic differentiation capacity was observed before and after training. CONCLUSION: Aerobic exercise training is associated with metabolic adaptations in vivo that are preserved in human cultured primary myotubes. It can be hypothesized that skeletal muscle microenvironmental changes induced by endurance training lead to metabolic imprinting on myogenic progenitor cells.