Lactobacillus amylovorus KU4 induces adipose browning in obese mice by regulating PP4C

We previously reported that Lactobacillus amylovorus KU4 (LKU4) promotes adipocyte browning in mice fed a high-fat diet (HFD mice) in part by remodeling the PPARγ transcription complex. However, the mechanism through which LKU4 enables PPARγ to drive adipocyte browning remains elusive. Here, we report that LKU4 inhibits the expression of PP4C in inguinal white adipose tissue of HFD mice and in insulin-resistant 3T3-L1 adipocytes, which promotes SIRT1-dependent PPARγ deacetylation by activating AMPK, leading to the browning of adipocytes. Consistently, the silencing of PP4C further enhances this pathway. Furthermore, we observed that lactate, a key LKU4 metabolite, reduces insulin-induced PP4C expression and suppresses PP4C inhibition of PPARγ deacetylation and transcriptional activity via AMPK-SIRT1, thereby facilitating the browning of adipocytes. Together, these data demonstrate that LKU4 promotes the AMPK-SIRT1-PPARγ pathway by inhibiting PP4C, thereby facilitating adipocyte browning in HFD mice.