The incidence of obesity and a cluster of disorders associated with obesity such as type 2 diabetes, dyslipidemia and cardiovascular disease have risen to alarming proportions and there is great need for effective therapeutic and preventive measures against these health threats. Metabolic disorders often affect an intertwined network of signaling and metabolic pathways, and it is crucial to understand the interactions of these pathways in a patient-specific setting for drug target discovery and therapy development. We have obtained diabetes patient skin fibroblasts with insulin receptor mutations and Dunning-type familial partial lipodystrophy samples with lamin A/C mutation, and have converted them into iPS cells. We are differentiating insulin receptor mutant iPS cells into hepatocytes and lamin A/C mutants into adipocytes. We will screen for altered metabolic pathways and adipokine productions in these functional metabolic cells carrying known disease-causing mutations and confirm their pathological role in immunodeficient NSG mice that are engrafted with the control and mutant cells.
