Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR signaling
Schuermans, N.; El Chehadeh, S.; Hemelsoet, D.; Bogaert, E.; Debackere, E.; Hilbert, P.; Van Doninck, N.; Taquet, M.-C.; Rosseel, T.; De Clercq, G.; Van Haverbeke, C.; Chanson, J.-B.; Funalot, B.; Authier, F.-J.; Kaya, S.; Terryn, W.; Callens, S.; Depypere, B.; Van Dorpe, J.; Program for Undiagnosed Diseases (UD-PrOZA), ; Poppe, B.; Depienne, C.; Dermaut, B.
Show abstract
PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.
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