Jens Jordan and Michael Boschmann

Summary

Type 2 familial partial lipodystrophy (FPLD, OMIM #151660) is an autosomal-dominant condition commonly referred to as Dunnigan-type familial partial lipodystrophy. FPLD patients are born with normal fat distribution. After puberty, the patients lose subcutaneous fat from their extremities, trunk, and gluteal regions. Excess fat may be deposited within the face, neck, back, and abdominal cavity. Fat is also redistributed to other organs as evidenced by the high prevalence of hepatic steatosis. Fat distribution alterations in FPLD are associated with insulin resistance, predisposing to type 2 diabetes mellitus and dyslipidemia. Many FPLD patients suffer from muscular pain and tolerate endurance exercise poorly. Yet, skeletal muscles are hypertrophied in FPLD. Mutations in the LMNA gene that encodes the nuclear proteins lamin A and C, cause FPLD. We hypothesize that oxidative metabolism and mitochondriogenesis are impaired in FPLD patients. We speculate that the transcription factor E2F-1 may be involved. We will assess skeletal muscle metabolism and contractile function in FPLD families that we have already recruited. We will rely on microdialysis under controlled conditions in muscle and fat, as well as biopsies of these tissues. Furthermore, we will determine the metabolic and clinical response to PPAR gamma manipulation with glitazones. A careful pathophysiological characterization will help to narrow down the molecular pathways that are amenable to direct study. In addition, we will identify candidate pathways using gene expression profiling and ex vivo – metabolic studies in FPLD myoblast cultures.