Fuziline Ameliorates Glucose and Lipid Metabolism by Activating Beta Adrenergic Receptors to Stimulate Thermogenesis

Abstract

Radix aconiti carmichaeli is a widely used traditional Chinese medicine that has been found to be effective in treating cardiovascular diseases and metabolic disorders. Patients with these diseases often experience a heat generation disorder, which is characterized by chilliness and can worsen the progression of the disease. This study established an in vitro screening model combining the examination of cellular mitochondrial membrane potential and mitochondrial temperature to screen drugs with thermogenic activity. After differentiation and determination of the content of characteristic metabolites of the drug-containing serum blood components, it was found that Fuziline (FZL) is the key thermogenic property in Radix aconiti carmichaeli, responsible for its thermogenic effects with a high relative importance of 33%. Experiments were conducted to evaluate the thermogenic activity of Radix aconiti carmichaeli and FZL in vivo by assessing temperature changes in various organs, including the rectum, liver, and brown adipose tissue. Moreover, the effects of intracellular β3-adrenergic receptor (β3-AR) agonistic effects were evaluated using transient β3-AR transfection and dual-luciferase assay systems. The molecular mechanism by which FZL promotes thermogenesis and improves mitochondrial function was investigated by verifying the β-adrenergic receptors (β-AR) downstream signaling pathway. The results suggest that FZL activates β-AR nonselectively, which in turn activates the downstream cAMP-PKA signaling pathway and leads to an increase in liver glycogenolysis and triglyceride hydrolysis, accompanied by enhancing mitochondrial energy metabolism. Consequently, the liver and brown adipose tissue receive energy to generate heat. In summary, these findings provide insight into the therapeutic application of Radix aconiti carmichaeli for metabolic disorders associated with heat generation disorders.

Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial

“…FZ and Cinnamon in FQGBG are TCM that generate heat in the interior body and eliminates cold. Alkaloids in FZ, including fuziline, neoline, and BMA, are identified as β-adrenergic receptor (β-AR) agonists, for regulating the thermogenic function and regulate glucose and lipid metabolism by activating the β3-AR receptor of adipocytes ( Gao et al, 2023 ). Cinnamaldehyde, the main metabolite of Cinnamon, activated PKA signaling, increased thermogenic gene expression levels, and induced phosphorylation of hormone-sensitive lipase (HSL) and Perilipin 1 in primary murine primary adipocytes ( Jiang et al, 2017 ).…”

Cardiovascular protection of YiyiFuzi powder and the potential mechanisms through modulating mitochondria-endoplasmic reticulum interactions

“…The diterpene alkaloid in Fuzi, FZL ( Xiong et al, 2012 ; Fan et al, 2020 ), activates β-adrenergic receptors (β-AR), which then activate the downstream cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. This enhances mitochondrial energy metabolism and stimulates liver lipolysis to improve lipid profiles ( Gao et al, 2023 ). Overall, YYFZ helps maintain mitochondrial function, biogenesis, energy metabolism, and ER stress through its upregulation of the cAMP/PKA signaling pathways, and downregulation of the PERK/SREBP-1c/FAS signaling pathways, thereby modulating lipid metabolism and protecting the cardiovascular system.…”

“…FZL increases mitochondrial function in muscle, enhancing glucose transport and lowering blood glucose ( Gao et al, 2023 ). Interestingly, this process is associated with the rise in mitochondrial temperatures and MMP.…”

“…Interestingly, this process is associated with the rise in mitochondrial temperatures and MMP. Additionally, by enhancing mitochondrial energy metabolism, FZL also increases liver glycogenolysis via the cAMP/PKA signaling pathway ( Gao et al, 2023 ). AC, another alkaloid found in Fuzi, improves energy metabolism disorders, resulting in the remodeling of mitochondrial function and mediating mitochondrial function via upregulating the AMPK/optic atrophy 1 (OPA1)/adenosine triphosphate synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1) signaling pathway ( Qiu et al, 2021 ).…”