l-Theanine Activates the Browning of White Adipose Tissue Through the AMPK/α-Ketoglutarate/Prdm16 Axis and Ameliorates Diet-Induced Obesity in Mice

Abstract

l-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with l-theanine (100 mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1, and other thermogenic genes. Meanwhile, administration of the mice with l-theanine increased energy expenditure. In vitro studies indicated that l-theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of l-theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. l-theanine treatment enhanced AMPKα phosphorylation both in adipocytes and iWAT. Knockdown of AMPKα abolished l-theanine–induced upregulation of Prdm16 and adipocyte browning. l-Theanine increased the α-ketoglutarate (α-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for l-theanine–induced increase of α-KG and DNA demethylation on the Prdm16 promoter. Moreover, intraperitoneal administration with l-theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol, and free fatty acids in the high-fat diet–fed mice. Our results suggest a potential role of l-theanine in combating diet-induced obesity in mice, which may involve l-theanine–induced browning of WAT.

Whey protein and soy protein prevent obesity by upregulating uncoupling protein 1 to activate brown adipose tissue and promote white adipose tissue browning in high-fat diet-fed mice

“…It has been reported that sirtuin 1 (SIRT1) and PR domain-containing 16 (PRDM16) pathways were also involved in beige fat activation. 47,48 Therefore, further studies are needed to explore whether the anti-obesity effect of WPI is involved in the SIRT1 or PRDM16 pathways. It is well known that FGF21 and irisin are activators of BAT function and WAT browning.…”

L-Theanine Alleviates IMQ-Induced Psoriasis Like Skin Inflammation by Downregulating the Production of IL-23 and Chemokines

“…The neuroprotective mechanisms of L-THE include the reduction of oxidative protein and lipid damage as well as the elevation of GSH levels to prevent neurotoxicity and environmental toxin‐induced neuronal cell death in the brain ( Matsuu-Matsuyama et al, 2020 ; Saeed et al, 2020 ). It has been reported that L-THE regulates glucose, lipid, and protein metabolism by promoting the activation of insulin and AMP-activated kinase signaling pathways ( Peng et al, 2021 ). L-THE can decrease the expression of IL-1β, IL-6 and TGF-β though inhibiting the activation of NF‐κB signaling pathway to prevents liver fibrosis ( Pérez-Vargas et al, 2016 ).…”

The Potential to Fight Obesity with Adipogenesis Modulating Compounds

“…As AMPK lies on the energy sensing hub, increasing the AMP-ATP ratio would activate AMPK indirectly. There are many natural products that are also AMPK indirect activators, including resveratrol [34], cyptotanshinone [35,36], medicarpin [37], L-theanine [38], crocin [39], sulforaphane [40,41] and platycodin D [42,43] (Table 1). These have all been confirmed to promote brown and beige adipogenesis and/or inhibit white adipogenesis dependent on AMPK activation.…”

“…C3H10T1/2 is another well-established MSC cell line for adipogenic differentiation studies [44]. L-Theanine, a nonprotein amino acid enriched in green tea, was recently found not only to significantly induce the beiging of subcutaneous WAT in mice, but also ameliorate obesity and improve glucose tolerance and insulin sensitivity in HFD-fed mice [38]. Methyl cinnamate, an active component of Zanthoxylum armatum, inhibited differentiation of 3T3-L1 preadipocytes partially through activation of the CaMKK2-AMPK signaling pathway [45].…”