Causes and Consequences of Pathological Adipose Remodelling (360G-Wellcome-210752_Z_18_Z)

This proposal addresses two factors important in obesity-related disease, namely determinants of healthy adipose remodelling in chronic positive energy balance, and mechanisms linking insulin resistance to disease. Two rare, informative human disorders will first be dissected, one featuring subcutaneous lipodystrophy due to heterozygous loss of DNA polymerase delta activity and the second a mixture of lower body fat loss and dramatic upper body adipose hyperplasia due to a missense mutation in mitofusin 2, involved in mitochondrial fusion and other processes. Physiological, tissue and cellular studies of humans and mouse models will address the role of DNA replication/repair and mitochondrial dynamics in depot-specific human adipose remodelling, and will test both mitigating strategies and relevance for common disease. The second part of the project will exploit emerging techniques for saturation mutagenesis coupled to downstream functional assays to develop "look up" tools for stratification of genetic variants by functional consequence. Saturating mutation libraries and such derived tools have myriad applications, including genetic diagnosis of rare disease, patient stratification for experimental medicine studies, and linking of functional perturbations to lifecourse human phenotypes in genotyped cohorts. The approach will be applied first to the insulin receptor, and thence other genes involved in insulin signal transduction.