The translational regulator FMRP controls lipid and glucose metabolism in mice and humans

Abstract

Objectives The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Methods Using metabolomics, in vivo metabolic phenotyping of the Fmr1- KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Results Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1- KO mice with reduced circulating glucose and insulin and increased free fatty acids. Conclusions Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.

Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome

“…Prior studies have focused on metabolic markers and have highlighted reduced levels of cholesterol [11][12][13] and abnormal abundances of the metabolic hormones leptin and adiponectin [14]. In a translational study addressing metabolic consequences of FMR1-deficiency both in a FXS mouse model and in FXS patients, we have recently shown that FXS patients display reductions in circulating glucose and increases in both free fatty acids and insulin, underlining metabolic anomalies in FXS [15]. Regarding possible immune dysfunctions in FXS, only a few studies have characterized FXS patients for immune biomarkers such as cytokines.…”

Fmr1-Deficiency Impacts Body Composition, Skeleton, and Bone Microstructure in a Mouse Model of Fragile X Syndrome

“…Murine Fmr1 -knock-out (KO) models of FXS have been generated, exhibiting CNS-related behavioral, and neuronal anomalies reminiscent of the human phenotypes (6, 7). The FMR1 gene is not only expressed in the central nervous system (CNS) but also in a variety of peripheral tissues, including adipose tissue, and liver (8–11). Adult skeletal and cardiac muscle are the only peripheral tissues tested so far not expressing FMRP, while both white adipose tissue (WAT) and brown adipose tissue (BAT) express FMRP (8–12).…”

“…This suggests that long-term pathological consequences of FMR1 -deficiency are not solely confined to the central nervous system disorders and more likely extend to physiological dysfunctions in peripheral systems. We have previously demonstrated in FXS mouse model how Fmr1- deficiency increased systemic utilization of lipids, reduced adiposity and provoked significant changes in metabolic homeostasis, some of which were also translatable to FXS patients (11). Besides presenting metabolic phenotypes, FXS is also accompanied by physical abnormalities (13).…”

Reduced serum levels of pro-inflammatory chemokines in Fragile X Syndrome

“…Prior studies have focused on metabolic markers and have highlighted reduced levels of cholesterol (11)(12)(13) and abnormal abundances of the metabolic hormones leptin and adiponectin (14). In a translational study addressing metabolic consequences of FMR1-deficiency both in a FXS mouse model and in FXS patients, we have recently shown that FXS patients display reductions in circulating glucose and increases in both free fatty acids and insulin, underlining metabolic anomalies in FXS (15) (n = 40 FXS with ASD; n = 64 FXS without ASD) and typically developping controls (n = 19) for the levels of 22 cytokines. Compared to healthy controls, the authors found that FXS patients exhibited higher plasma levels of the pro-inflammatory cytokine IL-1a and IL-12p40, and lower levels of the chemokines CCL2, CCL5, CCL11 and CXCL10 (17).…”