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

Abstract

BackgroundAchondroplasia 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 findingsTo 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.ConclusionThis 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.

Current knowledge of medical complications in adults with achondroplasia: A scoping review

“…However, BMI and other anthropometric measurements are poor predictors of body fat and fat distribution, and even more in individuals of disproportionate short stature, such as achondroplasia . In a recently published paper, the authors found an atypical obesity with preferential abdominal obesity in achondroplasia children . The obesity was not associated with classical complications, such as diabetes or hypercholesterolemia, suggesting an uncommon energy metabolism in achondroplasia .…”

“…32,60,65 In a recently published paper, the authors found an atypical obesity with preferential abdominal obesity in achondroplasia children. 66 The obesity was not associated with classical complications, such as diabetes or hypercholesterolemia, suggesting an uncommon energy metabolism in achondroplasia. 66 This corresponds with previous findings by Owen et al, who found normal triglycerides and no incidents of diabetes in a cohort of adults with achondroplasia with abdominal obesity.…”

“…66 The obesity was not associated with classical complications, such as diabetes or hypercholesterolemia, suggesting an uncommon energy metabolism in achondroplasia. 66 This corresponds with previous findings by Owen et al, who found normal triglycerides and no incidents of diabetes in a cohort of adults with achondroplasia with abdominal obesity. 32 More research is needed to explore body composition and fat distribution in adults with achondroplasia, including clinical and metabolic implications.…”

Characterisation of endogenous players in fibroblast growth factor‐regulated functions of hypothalamic tanycytes and energy‐balance nuclei

“…By contrast, a significant number of achondroplasia patients that carry activating FGFR3 mutations also manifest atypical obesity. 55 Difficulties that prevent drawing firm conclusions from human patients include: the germline nature of these mutations, which would additionally impact peripheral organs or indeed multiple brain regions; their rareness, which may preclude statistically valid associations with metabolic/neuroendocrine defects or diet; and their varied molecular mode of function, with some mutant receptors operating in a FGF ligand-independent manner.…”

Anthropometrics, diet, and resting energy expenditure in Norwegian adults with achondroplasia

“…The arms and legs are short, while the trunk has an almost normal size (Merker et al, ). Previous studies have reported that individuals with achondroplasia have an increased risk of obesity starting from childhood, cardiovascular disease (CVD), and mortality (Hecht et al, ; Hecht, Francomano, Horton, & Annegers, ; Paajanen, Oksala, Kuukasjarvi, & Karhunen, ; Saint‐Laurent et al, ; Wynn, King, Gambello, Waller, & Hecht, ). The reasons for this are currently unknown (Hecht et al, ; Paajanen et al, ; Wynn et al, ), but both genetic and lifestyle factors are likely involved (Hecht et al, ; Saint‐Laurent et al, ; Trenkwalder, Kessler, Schunkert, & Erdmann, ).…”