FGF21 protects from progressive metabolic syndrome after undernutrition refeeding

This application will study the effects of undernutrition on the development of the metabolic syndrome (MetS) after refeeding. Studies showed that undernutrition in childhood leads to obesity, malnutrition-related diabetes, insulin resistance, and metabolic abnormalities in adulthood. However, the causal factors and the progression of this etiology are fairly unknown. My initial observations in the mouse model suggest that several factors could be predetermining Mets progression after refeeding. These were characterized by impaired insulin signaling, adipogenesis, ectopic lipid accumulation, and a dysregulated FGF21 / adiponectin axis in the bone marrow. Since FGF21 prevents Mets and lipid accumulation, the hypothesis is that there is a FGF21 loss of function that predetermines progressive Mets after undemutrition refeeding. This study compares the clinical and metabolic consequences of refeedlng using wild type mice and FGF21 knockout mice. The first goal will be to mimic the food-addiction behaviors seen in populations suffering from both obesity and malnutrition. As a result, Aim 1 will determine whether the loss of FGF21 function is involved in either a) a sweet food preference or b) overeating a high fat diet, both of which are known drivers of Mets. Aim2, will evaluate if the central regulation from the bone marrow predetermines proclivity to progressive Mets after refeeding by establishing a) if FGF21 participates in the regulatory shift that determines either osteogenesis or adipogenesis from MSC precursors, or rather drives adipocyte browning; and b) if FGF21 engages in the mobilization of accumulated triglycerides, inhibiting ROS signaling and consequences (by multiparametric flow cytometry). Aim 3: will identify the transcriptional patterns imprinted in MSC and progeny during early malnutrition that persist later in life with negative consequences after refeeding. Also, it will identify the gene network driven by the nature of the diet and putative genes responsible for FGF21 and insulin dysfunction (by single cell-RNAseq). The four-year training for this career reorientation is geared toward the acquisition of knowledge that would contribute to my establishment as an independent researcher. First, academic studies specific to the orientation of the career are aimed at learning concepts about bone marrow plasticity and how to apply them to prevent Mets progression. Furthermore, for MSC and adipocyte metabolic reprograming strategies. Second, I will acquire skills for a deeper understanding of the regulatory role of the musculoskeletal system in metabolism and progressive Mets. As well, through training in cutting-edge technologies of single-cell sequencing and data integration to propel the discovery of molecular medicine targets for Mets prevention. Third, acquisition of skills to be involved in future collaborative studies and networking, including grant writing, ethics, and translational research as an overarching theme. These interdisciplinary studies will empower me to compete for funding as an independent investigator. Overall, the study will unravel the role of FGF21 sensitization in cellular and metabolic dysregulations in undernutrition and refeeding linked to the severity of Mets components.