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Targeting Dlat-Trpv3 pathway by hyperforin elicits non-canonical promotion of adipose thermogenesis as an effective anti-obesity strategy

Sijia Lu,Quanxin Jiang,Peihui Zhou,Limin Yin,Ning Wang,Junting Xu,Qiqi Qian,Mijia Tao,Hanrui Yin,Liu Han,Yunqing Gu,Fei Gao,Junli Liu,Suzhen Chen

Introduction Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. Objectives The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. Methods To assess the anti-obesity efficacy of orally administered HPF in vivo , Dlat heterozygous knockout (Dlat +/- ) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro . Results Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca 2+ ) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3-AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat +/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. Conclusion In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.