Project description:Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion resulted in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Preadipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered new regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.
Project description:Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion resulted in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Preadipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered new regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.
Project description:We used microarrays to detail the gene expression profile during WAT -beige transition by treatment of beta adrenergic receptor agonist . Stromal vascular fractions (SVF) from mice (n = 3/group) that received vehicle or beta3 adrenergic receptor agonist, CL, treatment were served for RNA extraction and hybridization on Affymetrix microarrays. We are trying to find out angiogenic factors genes dynamics during white adipose tissues (WAT) - beige transition.
Project description:We used microarrays to detail the gene expression profile during WAT -beige transition by treatment of beta adrenergic receptor agonist .
Project description:Protein kinase A phosphorylates proteins including histone H3 lysine 9 (H3K9) demethylase JMJD1A to facilitate beige adipogenesis upon β-adrenergic receptor (β-AR) activation, however, phosphatase(s) that antagonizes phosphorylation to inhibit beige adipogenesis is incompletely understood. Here we show that MYPT1-PP1β is a phosphatase that negatively regulates beige adipogenesis via dephosphorylation of pS265-JMJD1A and myosin regulatory light chain. Upon β-AR activation, MYPT1-PP1β is inhibited via T694 phosphorylation of MYPT1, facilitating phosphorylation of JMJD1A and beige adipogenesis under cold stress. Depletion of MYPT1-PP1β induces Ucp1 by orchestrating JMJD1A-mediated H3K9 demethylation and actomyosin-tension mediated YAP/TAZ activation. This induction of Ucp1 is abrogated in adipocytes expressing catalytically dead JMJD1A mutant, indicating that the coordinated epigenetic and transcriptional mechanisms are essential for beige adipogenesis. We also show that preadipocytes specific Mypt1 deficient mice exhibit higher cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice confirming its role at animal levels.
