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

  • J Adv Res. 2024 Dec 2:S2090-1232(24)00555-1. doi: 10.1016/j.jare.2024.11.035.
Sijia Lu  1 ,  Quanxin Jiang  1 ,  Peihui Zhou  1 ,  Limin Yin  1 ,  Ning Wang  1 ,  Junting Xu  1 ,  Qiqi Qian  1 ,  Mijia Tao  1 ,  Hanrui Yin  1 ,  Liu Han  1 ,  Yunqing Gu  1 ,  Fei Gao  1 ,  Junli Liu  2 ,  Suzhen Chen  3
Affiliations
  • 1. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 2. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: [email protected].
  • 3. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: [email protected].
PMID: 39631519 DOI: 10.1016/j.jare.2024.11.035
Abstract

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 (CA2+) 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.

Keywords
Dlat; Hyperforin; Obesity; Pharmacokinetics; Thermogenesis.
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