Loss of cytoplasmic FMR1‐interacting protein 2 (CYFIP2) induces browning in 3T3‐L1 adipocytes via repression of GABA‐BR and activation of mTORC1

Abstract

Obesity and related metabolic disorders are epidemic diseases. Promoting thermogenesis and a functional increase in the browning of white adipocytes may counteract obesity. On the other hand, the molecular mechanism that regulates brown and beige fat-mediated thermogenesis is unclear. This article reports a molecular network led by cytoplasmic FMR1-interacting protein 2 (CYFIP2) that negatively regulates adipocyte browning in white adipocytes. Although the function of CYFIP2 in Fragile X Syndrome (FXS) and autism have been reported, its physiological roles in adipocytes remain elusive. Therefore, this study examined the physiological consequences of its deprivation in cultured 3T3-L1 white adipocytes using loss-of-function studies. Combined real-time quantitative reverse-transcription polymerase chain reaction and immunoblot analysis showed that the loss of CYFIP2 induces fat browning, as evidenced by the gene and protein expression levels of the brown fat-associated markers. A deficiency of CYFIP2 promoted mitochondrial biogenesis and significantly enhanced the expression of the core set beige fat-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmem26) and proteins (PGC-1α, PRDM16, and UCP1). In addition, a CYFIP2 deficiency promoted lipid catabolism and suppressed adipogenesis, lipogenesis, and autophagy. A mechanistic study showed that the loss of CYFIP2 induces browning in white adipocytes, independently via the activation of mTORC1 and suppression of the GABA-BR signaling pathway. The present data revealed a previously unidentified mechanism of CYFIP2 in the browning of white adipocytes and emphasized the potential of CYFIP2 as a pharmacotherapeutic target for treating obesity and other metabolic disorders.

Lactiplantibacillus plantarum N4 ameliorates lipid metabolism and gut microbiota structure in high fat diet-fed rats

“…Furthermore, GABA-rich fermented extracts and oolong tea have been shown to lower plasma triglyceride and low-density lipoprotein levels, down-regulate genes related to adipogenesis (SREBP-1c, FAS, SCD-1, and ACC), and promote lipid metabolism and fatty acid oxidation ( Park et al, 2020 ; Weerawatanakorn et al, 2023 ). Noteworthy is the consistent finding across multiple studies that GABA induces adipocyte browning, facilitates beige fat differentiation, and acts as an inhibitor of obesity and associated metabolic disorders ( Manigandan and Yun, 2022 ). Treatment with GABA has been shown to alter the composition of gut microbiota, elevate beige fat content, and ultimately improve metabolic levels in obese mice ( Ma et al, 2023 ).…”

Novel putative causal mutations associated with fat traits in Nellore cattle uncovered by eQTLs located in open chromatin regions

“…A recent study in cultured cells reported that CYFIP2 is involved in the thermogenesis and regulation of lipid metabolism in white adipocytes, explicitly in uencing the browning of white adipocytes 37 . Other studies reported the possibility of the CYFIP2 locus being associated with diet-induced obesity and metabolic dysfunction in mice 38,39 .…”

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABABreceptor function

“…Through its ability to modulate both the actin cytoskeleton and protein translation, Cyfip2 is well-positioned to be a critical factor for many processes in neurodevelopment [33,34,[37][38][39]45,49]. Further highlighting its importance, Cyfip2 has been implicated in an array of neuropsychiatric and other conditions, including schizophrenia [60], autism [49,[61][62][63], binge eating [64][65][66], obesity [67], amyotrophic lateral sclerosis (ALS) [68,69], Alzheimer's disease [70], epilepsy [63,[71][72][73][74], and cancer [75][76][77][78][79][80]. Here we focused on Cyfip2's role in a common endophenotype of schizophrenia and autism, increased acoustic startle responsiveness [4,24,27,28].…”