Neurofibromatosis type 1 (NF1) is a heritable multi-system disease resulting from mutations in the NF1 tumor suppressor gene. The NF1 gene is large, containing 60 exons with a high mutation rate and more than 2,800 unique mutations identified to date. The dispersion and variety of mutations across the NF1 gene supports the clinical observation that genotype-phenotype correlations for NF1 are largely absent and explains why disease presentation and burden vary between individuals with similar NF1 mutations and between family members.

Apart from the common manifestations, persons with NF1 display a unique body composition characterized by short stature and thin body habitus (i.e., low body mass index or BMI). The unusual association of short stature with low BMI suggests that energy storage or utilization is altered in persons with NF1. In support of this hypothesis, emerging evidence from large cohorts of NF1 and matched controls suggest that persons with NF1 are resistant to diabetes and obesity. In fact, a recent study of 2,500 persons with NF1 identified a much lower rate of hospitalization for endocrine-related diseases, including diabetes and obesity, than in the general population. In fact, endocrine-related hospitalization was the only one of 12 categories to demonstrate a reduced hospitalization rate for persons with NF1. Additionally, persons with NF1 have lower fasting glucose values and enhanced glucose clearance after glucose administration when compared with controls. Interestingly, hormones that control glucose uptake and utilization (i.e., insulin and glucagon) did not differ between groups; however, hormones secreted by fat cells, termed adipocytes, were significantly different between groups. Persons with NF1 have lower leptin levels and higher adiponectin values along with reduced fat mass when compared with matched controls. Based on the well-recognized role of adipocytes in glucose utilization and energy storage, these human observations strongly point to alterations in adipocyte development or function in persons with NF1.

Recently, we demonstrated that mice harboring a single Nf1 mutation (Nf1 heterozygous) display a similar reduction in fat mass and abnormal lipid deposition in tissues as observed in persons with NF1. Close inspection of these fat samples revealed that fat depots from Nf1 heterozygous mice are densely packed with small, early adipocytes when compared with littermate controls. These smaller adipocytes are more metabolically active and influence local and systemic processes and suggests that loss of neurofibromin promotes the formation of primitive adipocytes and reduced fat mass. Further, Nf1 heterozygous mice also had lower leptin and higher adiponectin levels as seen in humans with NF1. Clearly, Nf1 heterozygous mice mimic the metabolic and body composition phenotype observed in humans with NF1. Unfortunately, the role of neurofibromin in adipocyte maturation and function has never been explored and is a critical barrier to understanding the mechanisms underlying NF1-related manifestations. Given the widespread presence of adipocytes within every human tissue and influence over hormone activity, metabolism, and immune cell function, these mouse and human observations have tremendous implications for understanding why heterogeneity within the NF1 community exists.

The long-term goal of our laboratory is to develop new insights and therapies for NF1. Our goal in this Exploration-Hypothesis Development Award application is to identify how loss of neurofibromin alters adipocyte maturation and whether loss of neurofibromin induces the synthesis and release of growth factors and metabolites that promote NF1 tumor growth and transformation. At the conclusion of the funding period, we will have (1) developed two animal models with loss of neurofibromin in adipocytes alone that can be easily transitioned to interrogate the role of adipocytes in preclinical models of NF1, (2) described how neurofibromin controls adipocyte maturation and function, and (3) identified multiple proteins, pathways, and metabolites that are dysregulated in adipocytes carrying Nf1 mutations. Many of these outputs are highly translational and may be quickly utilized to generate new biomarkers or treatment targets for persons with NF1. More importantly, these experiments will provide direct insight into why persons with NF1 clearly demonstrate a consistent metabolic phenotype and body type despite the wide distribution of genetic mutations and how these metabolic features may influence manifestations of NF1.

While the purpose of the Exploration-Hypothesis Development Award mechanism is intended to be “high-risk, high-gain,” our preliminary animal data demonstrate a clear phenotype that mimics humans with NF1 that has never been explored. Thus, we believe this proposal represents a “low-risk, high-gain” opportunity to understand how adipocytes and fat depots contribute to NF1 pathobiology.