Abstract

   Obesity has emerged as a significant health concern, as it is a disease
   linked to metabolic disorders in the body and is characterized by the
   excessive accumulation of lipids. As a plant-derived food, Platycodon
   grandiflorum (PG) was reported by many studies, indicating that the
   saponins from PG can improve obesity effectively. However, the
   anti-obesity saponins from PG and its anti-obesity mechanisms have not
   been fully identified. This study identified the active saponins and
   their molecular targets for treating obesity. The TCMSP database was
   used to obtain information on 18 saponins in PG. The anti-obesity
   target of the PG saponins was 115 targets and 44 core targets. GO and
   KEGG analyses using 44 core anti-obesity genes and targets of PG-active
   saponins screened from GeneCards, OMIM, Drugbank, and DisGeNet showed
   that the PI3K-Akt pathway, the JAK-STAT pathway, and the MAPK pathway
   were the major pathways involved in the anti-obesity effects of PG
   saponins. BIOVIA Discovery Studio Visualizer and AutoDock Vina were
   used to perform molecular docking and process the molecular docking
   results. The molecular docking results showed that the active saponins
   of PG could bind to the major therapeutic obesity targets to play an
   obesity-inhibitory role. The results of this study laid the foundation
   for further research on the anti-obesity saponins in PG and their
   anti-obesity mechanism and provided a new direction for the development
   of functional plant-derived food. This research studied the molecular
   mechanism of PG saponins combating obesity through various signaling
   pathways, and prosapogenin D can be used to develop as a new potential
   anti-obesity drug.

   Keywords: Platycodon grandiflorum, saponins, obesity, network
   pharmacology

1. Introduction

   In today’s society, obesity has dramatically increased to epidemic
   proportions and has become the leading cause of ill health [[28]1].
   Obesity, usually defined as an individual’s body mass index (BMI) ≥ 30
   kg/m^2, is caused by an imbalance between the body’s daily energy
   intake and energy expenditure; obesity has been recognized as a serious
   and rapidly escalating public health problem in the world
   [[29]2,[30]3]. Obesity is a chronic multi-system disease that is
   closely related to metabolic disorders in the body, which also
   increases psychological distress in obese patients and exacerbates the
   occurrence of obesity-related complications [[31]4]. Obesity is
   strongly associated with increased blood pressure, diabetes,
   atherosclerosis, and cardiovascular disease, among other diseases
   caused by abnormal metabolism in the body. These diseases are mainly
   caused by eating excessive fat in the diet [[32]5]. A clearer
   understanding of the impact of obesity and its complications on health
   is necessary to identify high-risk individuals and prioritize treatment
   [[33]6]. Pre-diabetic patients can prevent and even reverse type 2
   diabetes with early weight loss [[34]7]. Obesity can now occur at any
   age and has a negative impact on the quality of life of both men and
   women [[35]8].

   Obesity is a serious health problem that is closely associated with
   metabolic disorders in the body [[36]9]. In the body, an excessive
   accumulation of lipids, particularly in hepatocytes and adipocytes, is
   one of the main causes of this metabolic disorder. Understanding and
   intervening in lipid metabolism, especially controlling the
   proliferation of adipocytes, may be the key to combating obesity and
   its associated diseases [[37]10]. It is crucial to comprehend why
   obesity is closely linked to health issues, as it can aid in the
   creation of successful prevention and treatment methods. Obesity is
   caused by the body’s impaired glucose and lipid metabolism, with
   insulin action primarily targeting hepatocytes and adipocytes [[38]11].
   If lipids accumulate in cells due to disturbed glucose–lipid
   metabolism, it can reduce insulin sensitivity in target cells like
   hepatocytes and adipocytes, leading to chronic metabolic diseases
   associated with insulin resistance [[39]12]. Therefore, inhibiting
   adipocyte differentiation and intracellular fat proliferation to
   ameliorate insulin resistance is an effective way to prevent or treat
   fat production in the body.

   Currently, popular anti-obesity drugs include sympathomimetic drugs
   such as phentermine, diethylpropion, sibutramine, and orlistat, but
   taking them can cause cardiovascular diseases such as heart valve
   damage, pulmonary hypertension, myocardial infarction, diarrhea,
   flatulence, incontinence, and dyspepsia, as well as liver damage
   [[40]13]. In contrast, natural organic compounds have been used in
   plant-derived food for a very long history with consistent safety and
   high efficacy [[41]14]. To date, many plant-derived foods can be used
   in the daily diet and can act as obesity inhibitors [[42]15]. For
   example, the saponin components of PG can be used to treat obesity.
   Several studies have shown that diets rich in saponins from PG can
   reduce systemic cholesterol levels and inhibit obesity [[43]16].
   Saponins in PG can lower the rate of bile acid reuptake and the content
   of serum cholesterol in the blood.

   Platycodon grandiflorum (PG) is a monotypic species of the genus
   Platycodon in the family Campanulaceae, which commonly grows in China,
   North Korea, Republic of Korea, Japan, and eastern Siberia area in
   Russia [[44]17,[45]18]. The fresh or dry root of PG has high
   nutritional value; it is a popular appetizer vegetable in Northeast
   China and the Korean peninsula. The roots of PG are called Platycodi
   Radix. There is a mixture of various compounds containing many types
   and amounts of bioactive compounds in PG, including flavonoids,
   polyphenols, and saponins with some protective effects, such as
   antioxidant, anti-inflammatory, hypolipidaemic, anticancer, and
   hepatoprotective effects. The potential new lead compound in PG is
   saponin [[46]19], and more specifically, PG saponin can inhibit obesity
   in vivo and in vitro and is used to treat obesity in clinics
   [[47]20,[48]21]. The PG saponin showed anti-obesity effects and lowered
   systemic cholesterol in the high-fat-diet-induced obese mice
   [[49]22,[50]23]. There is research about the active compounds in PG to
   improve and regulate the mechanism of action of obesity and
   glucose–lipid metabolism that has received more attention, but the
   mechanism of PG lipid-lowering and anti-obesity action and the
   effective compounds of the anti-obesity is still not completely clear.

   Network pharmacology can be effective in understanding the relationship
   between multiple non-specific compounds and multiple genetic proteins
   [[51]24]. Network pharmacology can also help researchers study the
   molecular mechanism of plant-derived food by analyzing compounds in the
   plant and identifying new mechanisms for treating various diseases
   [[52]25]. There are effective compounds and molecular mechanisms of
   Cnidii Fructus for the treatment of atopic dermatitis that can be
   identified through network pharmacology [[53]26]. Therefore, using
   network pharmacology to screen saponins in PG and the targets of action
   of PG, as well as using target construction, the GO and KEGG pathways
   can be analyzed to construct a network of saponin constituents in PG
   related to anti-obesity proteins and predict feasible manipulations of
   PG to fight obesity.

2. Results

2.1. The Active Saponins of PG

   The screening for active saponins in PG are considered active with an
   OB of at least 30% and DL score of at least 0.18. Eighteen saponin
   constituents were identified in PG and are shown in [54]Table 1,
   including platycodin A, platycodin C, platycodin D, deapioplatycodin D,
   platycodin D2, platycodin D3, deapioplatycodin D3, deapioplatycoside E,
   platyconic acid B lactone, 3″-O-acetylplatyconic acid A, prosapogenin
   D, polygalacin D, polygalacin D3, platycoside E, polygalacin D2,
   dimethyl 2-O-methyl-3-O-a-D-glucopyranosyl platycogenate A, platycodin
   V, and polygalacin XI.

Table 1.

   A total of 18 saponin constituents in PG after the literature and
   database screening.
   PubChem ID Saponins Molecular Formula Structure References