Comparative Anti-Obesity Potential of Cannabigerol-Dominant Cannabis sativa Inflorescence Extracts

Comparative Anti-Obesity Potential of Cannabigerol-Dominant Cannabis sativa L. Inflorescence Extracts via Differential Regulation of Lipid Metabolism in 3T3-L1 Cells

Source / Quelle: https://www.mdpi.com/1422-0067/27/4/1747

Abstract

Obesity is a chronic metabolic disorder characterized by excessive accumulation of body fat and is a major risk factor for various diseases, including type 2 diabetes, hypertension, and cardiovascular diseases. This study investigated the anti-obesity effects of cannabigerol-dominant C. sativa inflorescence extracts (CEs) obtained using various ethanol concentrations. The extracts were analyzed by UPLC to determine their major components. Additionally, anti-obesity mechanisms of the extracts were further determined through RT-qPCR and Western blot analysis to evaluate gene and protein expression levels. A total of seven cannabinoids, including cannabigerol as a major constituent, were identified within CE. Differentiation of 3T3-L1 cells was dose-dependently inhibited by CE at all ethanol concentrations. Furthermore, the gene and protein expression levels of key adipogenic and lipogenic markers, such as PPARγ, C/EBPα, SREBP-1c, and FAS, were significantly downregulated by CE treatment. In contrast, the expression of factors involved in lipolysis and white adipose tissue browning, such as HSL, ATGL, UCP1, and PGC-1α, was markedly increased by CE treatment. These effects were enhanced in an ethanol concentration-dependent manner. In conclusion, these results demonstrate that cannabigerol-dominant C. sativa effectively mitigates obesity by suppressing adipogenesis and lipogenesis while concurrently stimulating lipolysis and white adipose tissue browning.

Keywords:

Cannabis sativa L.; cannabinoid; cannabigerol; obesity; anti-obesity

1. Introduction

Obesity is a complex, multifactorial chronic disease that has seen a sharp rise in modern society [1]. Beyond being a significant clinical concern on its own, it serves as a primary driver for the onset of metabolic complications, including type 2 diabetes and cardiovascular diseases [2]. Considerable efforts have been made to treat obesity, leading to the development of various pharmacological interventions, including cannabinoid receptor type 1 (CB1) blockers and pancreatic lipase inhibitors [3]. However, these drugs have been reported to cause severe side effects, such as depression and cardiovascular disease [4]. Furthermore, due to limitations including the long-term nature of treatment and weight regain, effective obesity therapy remains a significant challenge.

Obesity is closely linked to several lipid metabolic pathways, including adipogenesis, lipogenesis, lipolysis, and white adipose tissue (WAT) browning. While Peroxisome Proliferator-Activated Receptor gamma (PPARγ) and CCAAT/Enhancer-binding Protein alpha (C/EBPα) act as master transcriptional regulators of adipogenesis, Sterol Regulatory Element Binding Protein 1c (SREBP-1c) and Fatty Acid Synthase (FAS) primarily govern the lipogenic process [5,6]. Suppression of these factors inhibits adipogenesis and reduces subsequent lipid accumulation, effectively mitigating the progression of obesity [7]. Lipolysis is driven by Hormone-Sensitive Lipase (HSL) and Adipose Triglyceride Lipase (ATGL), while thermogenesis and WAT browning are regulated by Uncoupling Protein 1 (UCP1) and Peroxisome Gamma Coactivator 1 alpha (PGC-1α) [8,9]. The coordinated activation of these factors promotes lipolysis and energy expenditure, leading to significant anti-obesity outcomes [10].

Cannabis sativa L. has been utilized for millennia across diverse applications, including medicinal, nutritional, and industrial purposes [11,12]. The plant is reported to possess a broad spectrum of pharmacological properties, including analgesic, anti-inflammatory, anti-cancer, and anti-bacterial effects [13]. Due to these therapeutic benefits, it is currently used as a clinical treatment for diseases such as multiple sclerosis and epilepsy [14,15].

Cannabinoids are considered the primary constituents of C. sativa. Among these, cannabidiol (CBD) exerts anti-obesity effects by inhibiting lipogenesis and promoting lipolysis in adipose tissue [16]. Furthermore, C. sativa comprises various minor cannabinoids, including cannabigerol (CBG) and cannabichromene (CBC), which interact with other cannabinoids or terpenoids to exert synergistic effects [17]. Given that these minor compounds significantly modulate the overall pharmacological profile of the plant, detailed studies on their individual and collective mechanisms are warranted. Such research is crucial for identifying novel therapeutic targets to manage complex metabolic disorders, particularly obesity.

To evaluate the anti-obesity potential of C. sativa, the 3T3-L1 cell line was employed as a widely recognized in vitro model. This cell line mimics the differentiation of preadipocytes into mature adipocytes and is primarily used to investigate the mechanisms of lipid metabolism [18]. Accordingly, the present study investigated the anti-obesity mechanisms of cannabigerol-dominant C. sativa inflorescence extracts (CEs), prepared using various ethanol concentrations, within the 3T3-L1 cell model. Furthermore, the therapeutic potential of CE as both a primary anti-obesity agent and a clinical adjuvant was evaluated.

2. Results

2.1. Quantitative Analysis of Cannabinoids in CE via UPLC

To evaluate the phytochemical characteristics of the extracts, CBG-dominant C. sativa inflorescences were extracted with four different ethanol concentrations: 30%, 50%, 70%, and 99.5%. These extracts were designated as CE30, CE50, CE70, and CE99.5, respectively. The phytochemical profiling of CEs via UPLC revealed the presence of seven distinct cannabinoids (Figure 1). Quantitative analysis identified CBG and cannabigerolic acid (CBGA) as the predominant constituents, followed by CBC. The levels of all detected cannabinoids peaked in CE99.5 (Table 1). Specifically, the total CBG content exhibited an ethanol concentration-dependent increase, with measured values of 115.35 ± 1.42, 184.13 ± 0.43, 272.76 ± 0.57, and 412.55 ± 0.46 μg/mL for CE30, CE50, CE70, and CE99.5, respectively (Table 2).

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