INVESTIGADORES
MARTINEZ CALEJMAN Camila
congresos y reuniones científicas
Título:
Selectivity in mTORC2-AKT signaling to ATP citrate lyase drives brown adipocyte differentiation and de novo lipogenesis
Autor/es:
MARTINEZ CALEJMAN C; ENTWISLE, S.W.; TREFELY, S.; LUCIANO, A.; JUNG, S.M.; HSIAO, WEN-YU; HUNG, C.M.; LI, H.; SNYDER, N.W.; WELLEN, K.E.; VILLÉN, J.; GUERTIN, D.A.
Lugar:
Palm Springs
Reunión:
Congreso; The glucose metabolism meeting; 2019
Institución organizadora:
FASEB
Resumen:
mTORC2 regulates carbohydrate and lipid metabolism in adipocytes. However, the mechanisms have been unclear because mTORC2 loss in either brown or white adipocytes does not appear to impair downstream signaling by its canonical substrate AKT. To begin resolving this mystery, we used immunoblotting, metabolomics, and phospho-proteomics in both precursor and mature brown adipocytes to investigate the mechanisms of mTORC2 action in carbohydrate and lipid metabolism. Consistent with our previous in vivo data, we show that mTORC2 mildly facilitates insulin signaling, but is largely dispensable for many if not most actions of its canonical substrate AKT. In contrast, we identify ATP-citrate lyase (ACLY) as a unique mTORC2-dependent AKT substrate revealing an unappreicated specificity in mTORC2/AKT signaling. ACLY links carbohydrate and lipid metabolism by producing acetyl-coA for glucose-driven de novo lipogenesis (gluco-lipogenesis) and protein acetylation. Time course phospho-proteomics and phopho-mimetic rescue experiments in mature brown adipocytes indicate that insulin acts early to stimulate mTORC2/AKT/ACLY-mediated acetyl-coA synthesis, which both primes gluco-lipogenesis and augments ChREBP activity, histone acetylation, and gluco-lipogenic gene expression. We also find that brown preadipocytes require this selective mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Substrate utilization studies unexpectedly reveal that mTORC2 also promotes acetyl-coA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2), especially when ACLY is impaired. Collectively, these data suggest that mTORC2's principal role in lipid anabolism is to control nuclear-cytoplasmic acetyl-coA synthesis.