Project Grant R01DK137904

AUTOIMMUNE BASIS OF ACQUIRED LIPODYSTROPHIES - OBESITY REMAINS A MAJOR HEALTH PROBLEM IN US AND CAUSES METABOLIC COMPLICATIONS SUCH AS DIABETES, DYSLIPIDEMIA AND INSULIN RESISTANCE. SIMILAR COMPLICATIONS ALSO OCCUR IN PATIENTS WITH AUTOIMMUNE LIPODYSTROPHIES CHARACTERIZED BY ALMOST COMPLETE (ACQUIRED GENERALIZED LIPODYSTROPHY OR AGL) OR PARTIAL (ACQUIRED PARTIAL LIPODYSTROPHY, APL) LOSS OF BODY FAT. RECENTLY, CIRCULATING AUTOANTIBODY AGAINST PERILIPIN-1 (PLIN1) HAS BEEN IMPLICATED IN THE PATHOGENESIS OF AGL. HOWEVER, NEARLY TWO-THIRDS OF AGL PATIENTS DO NOT HAVE PLIN1 AUTOANTIBODIES SUGGESTING OTHER ADIPOCYTE ANTIGENS MAY BE INVOLVED IN THE AUTOIMMUNE RESPONSE. FURTHERMORE, THE PATHOGENESIS OF APL REMAINS UNKNOWN. THUS, THE FIRST TWO AIMS OF THIS PROPOSAL ARE TO IDENTIFY ADDITIONAL AUTOANTIBODIES AGAINST ADIPOCYTE EXPRESSED PROTEINS THAT CAUSE AGL OR APL AND TO DETERMINE THEIR FUNCTION IN ADIPOCYTE BIOLOGY. WE WILL USE TWO STATE-OF-THE-ART COMPLEMENTARY TECHNIQUES, A. PHAGE IMMUNOPRECIPITATION SEQUENCING (PHIP-SEQ) ASSAY AND B. HUMAN PROTEOME MICROARRAY (HUPROTTM VERSION 4 CHIP) TO IDENTIFY THE SERUM AUTOANTIBODIES IN AGL AND APL PATIENTS. OUR RECENT DATA FROM A MOUSE MODEL OF HUMAN AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1)(AIRE-/- MICE) REVEAL CIRCULATING PLIN1 AUTOANTIBODIES AND LOSS OF BOTH SUBCUTANEOUS AND VISCERAL FAT DUE TO INFLAMMATORY LESIONS IN ADIPOSE TISSUE. THEREFORE, THE THIRD AIM OF OUR PROPOSAL IS TO DETERMINE UNDERLYING AUTOIMMUNE MECHANISMS INVOLVED IN LOSS OF TOLERANCE TO PERILIPIN-1 IN AIRE-/- MICE. LASTLY, WE WILL DETERMINE PATHOGENICITY OF NOVEL AUTOANTIBODIES DISCOVERED IN PATIENTS WITH AGL AND APL AGAINST ADIPOCYTE EXPRESSED PROTEINS BY INFUSING THEM INTO MICE AND EVALUATING LOSS OF BODY FAT, DEVELOPMENT OF INSULIN RESISTANCE AND METABOLIC DERANGEMENTS. THESE STUDIES WILL UNRAVEL AUTOIMMUNE MECHANISMS INVOLVED IN CAUSATION OF LIPODYSTROPHY, AND INSULIN RESISTANCE AND ITS ASSOCIATED MORBIDITIES. THIS NEW KNOWLEDGE MAY PROVIDE TARGETS FOR DEVELOPING NOVEL DRUGS FOR TREATING DIABETES, DYSLIPIDEMIAS AND HEPATIC STEATOSIS.