Leveraging the Bioenergetic Profile of Neurofibromatosis Type 1

Date

2021-05

Authors

Tritz, Rebekah

Journal Title

Journal ISSN

Volume Title

Publisher

Augusta University

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder resulting from mutations in the NF1 tumor suppressor gene. Genotype-phenotype correlations for NF1 are rare due to the large number of NF1 mutations and role of modifier genes in manifestations of NF1; however, emerging reports suggest that persons with NF1 display a distinct anthropometric and metabolic phenotype featuring short stature, low BMI, increased sensitivity to insulin, and protection from diabetes. Here, we sought to identify whether Nf1 heterozygous (Nf1+/-) mice recapitulate the anthropometric and metabolic features identified in persons with NF1 and whether these metabolic features may be leveraged to elucidate disease mechanisms of NF1. Littermate wildtype (WT) and Nf1+/- C57B/6J mice were subjected to anthropometrics using nuclear magnetic resonance (NMR), indirect calorimetry, and glucose/insulin/pyruvate tolerance testing at 16 weeks. Nf1+/- mice are leaner with reduced visceral and subcutaneous fat mass, which corresponds with an increased density of small adipocytes and reduced leptin levels. Additionally, Nf1+/- mice are highly reliant on carbohydrates as an energy substrate and display increased glucose clearance and insulin sensitivity and are protected from diet-induced hyperglycemia and insulin resistance. We leveraged these organismal observations to understand how neurofibromin promotes macrophage-mediated inflammation, a common observation in NF1-related tumors and manifestations. BMDM from neurofibromin deficient animals were more sensitive to LPS/INF-γ, resulting in higher levels of M1 cells and lower levels of M2 cells. Energy phenotype, glucose utilization (Seahorse) and uptake were measured in WT and neurofibromin-deficient macrophages. We found that neurofibromin-deficient macrophages experienced rapid glucose uptake with enhanced glycolysis that corresponded with over-expression of GLUT1 in neurofibromin-deficient tissues and cells. Incubation with a specific GLUT1 inhibitor (BAY-976) significantly reduced glucose uptake and utilization, and blunted neurofibromin-deficient macrophage capacity to respond to polarizing cytokines. These metabolic differences were mirrored when neurofibromin was knocked down in a human macrophage line (THP1). Altogether, our data suggests that Nf1+/- mice closely recapitulate the anthropometric and metabolic phenotype identified in persons with NF1 and that the enhanced glycolysis might be a driving factor in inflammation characteristic of NF1. These key metabolic findings will impact the interpretation of previous and future translational studies of NF1.

Description

Keywords

Biology, Glycolysis, Macrophage polarization , Metabolism, Neurofibromatosis Type 1, NF1

Citation

DOI