Obesity is a chronic, progressive disease, and it is easy to relapse after successful weight loss. The imbalance between energy intake and expenditure is the fundamental cause of obesity [1] . Unhealthy eating habits, such as excessive intake of high-calorie, high-fat, and high-sugar foods, as well as unreasonable dietary structures and reduced levels of physical activity, can all lead to excess energy intake, thereby causing obesity [2] . Genetic factors also play an important role, and individuals with obese family members are more likely to develop obesity [3] . The global obesity prevalence has been rising continuously over the past few decades, and the latest data show that currently, more than 1 billion people worldwide suffer from obesity, including about 880 million adults and 159 million children and adolescents [4] . Since 1990, the number of adults with obesity worldwide has more than doubled, and the number of children and adolescents (aged 5 to 19) with obesity has increased threefold [5] . The total number of children, adolescents, and adults with obesity worldwide has now exceeded 1 billion [6] . According to the WHO definition, a body mass index (BMI, i.e., weight (kilograms) divided by height (meters) squared) greater than or equal to 25 is considered overweight, and greater than or equal to 30 is considered obese (shown in Table 1 ). In 2022, about 43% of adults worldwide were overweight, and 16% had obesity. In China, the obesity rate is also increasing across all age groups. Among 15.8 million adult subjects, 34.8% were overweight and 14.1% were obese, with the overall proportion of overweight individuals at 34.8% and obese individuals at 14.1% [7] .

Obesity is a high-risk factor for type 2 diabetes, dyslipidemia, hypertension, cardiovascular diseases, kidney diseases, non-alcoholic fatty liver disease, osteoarthritis, and other metabolic diseases [8] [9] . Obesity can also lead to male sexual dysfunction, male infertility [10] [11] , female menstrual irregularities, female infertility, hypertensive disorders of pregnancy, gestational diabetes, preterm birth, and stillbirth [12] [13] . At the same time, it is significantly associated with the risk of certain cancers (such as breast cancer, colorectal cancer, endometrial cancer, liver cancer, ovarian cancer, and pancreatic cancer) [14] . It is estimated that high body mass index (BMI) is closely related to the deaths of about 4 million people worldwide, among which cardiovascular diseases account for the majority. Obesity poses a huge threat to public health [15] . This also urgently calls for us to take effective intervention measures to prevent and control the development of overweight, obesity, and their related complications. At present, the main ways to lose weight include exercise [16] , diet [17] , drug [18] and surgery [19] . Exercise and dietary interventions are the preferred methods for controlling body weight [20] . However, lifestyle adjusting usually only leads to a little weight loss, achieving a weight reduction of 3% - 10%. This weight loss effect is often difficult to maintain in the long term, and the body mass is prone to regain [21] . Most people return their weight after 12 months, and only 2% - 20% of long-term weight loss through lifestyle modification is successful [22] . So the use of weight-loss drugs is worth considering. The FDA-approved weight-loss drugs include sympathomimetic inhibitors, pancreatic lipase inhibitors, GABAA receptor activators, serotonin 2C receptor agonists, opioid antagonists, dopamine-norepinephrine reuptake inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists [23] .

Glucagon-like peptide-1 (GLP-1) is an endogenous incretin secreted by the L cells of the small intestine and consists of two bioactive isoforms: GLP-1 (7-37), GLP-1 (7-36). GLP-1 is rapidly degraded by an enzyme called dipe: GLP-1 (9-36), GLP-1 (9-37) [24] . GLP-1 exerts its functions by binding to the glucagon-like peptide-1 receptor (GLP-1R) and is involved in the development and progression of many diseases [25] [26] . The GLP-1R is a transmembrane G protein-coupled receptor family B, discovered in pancreatic B cells, but also distributed in extrapancreatic tissues, including the lung, kidney, central nervous system, enteric nervous system, lymphocytes, blood vessels, and kidneys [27] [28] . The interaction between GLP-1 and GLP-1R exerts multiple physiological functions, including promoting insulin synthesis and secretion, inhibiting the production and release of glucagon by pancreatic islet cells, and reducing hepatic glycogen output, by activating different downstream signaling molecules [29] - [31] . GLP-1R agonists (GLP-1RA) are a group of GLP-1 analogs that are resistant to DPP4 relevant degradation, and exert their effects by activating the GLP-1R and its signaling pathways. They enhance insulin secretion, inhibit glucagon release, slow gastric emptying, reduce appetite and food intake, conduce lower blood glucose and reduce body weight [32] . These make GLP-1RA to be an effective drug for the treatment of type 2 diabetes (T2DM) and other related metabolic diseases. Many studies have shown that the GLP-1/GLP-1R signaling is also involved in the regulation of adipocyte differentiation and lipogenesis [33] . Its influence in adjusting energy balance and body weight has gradually attracted attention [34] .

GLP-1RA weight loss mechanisms are diverse. For example, anorexigenic effects can be produced by activating GLP-1 receptors in the brain [35] , and signaling mediated by GLP-1 receptors at the level of intramuscular neurons, involving nitric oxide and cAMP-dependent mechanisms, inhibiting vagal activity, thereby reducing the phasic contractions of the stomach, delaying gastric emptying, and reducing gastric acid secretion [36] . It is worth mentioning that GLP-1RAs can increase the expression of receptors in neurons related to the ventral tegmental area, nucleus accumbens, and lateral septum, reduce the intake of high-sugar and high-fat foods by regulating brain regions associated with reward and pleasure, thereby controlling body weight [37] [38] . It can also modulate the gut microbiota [39] , delay gastric emptying to increase satiety [40] , and induce browning of white adipose tissue through a soluble guanylate cyclase-dependent pathway, activate the adenylate cyclase pathway to lose weight [41] . In addition, its weight loss effect may be related to the activation of SIRT1 in adipose tissue [42] , SIRT1 is a deacetylase, and its activation can promote mitochondrial biogenesis and respiration, thereby promoting lipolysis and increasing fat breakdown [43] . In terms of promoting lipid mobilization, it can improve lipid metabolism and hepatic lipid accumulation in mice by promoting reverse cholesterol transport via ABCA1 upregulation mediated by ERK1/2 phosphorylation [44] . Our previous studies have found that GLP-1RAs can reduce body weight by inhibiting lipid synthesis and enhancing fatty acid β-oxidation through the HIF-2α/PPARα pathway, while also improving hepatic lipid metabolism [45] . In addition to promoting lipid mobilization, GLP-1RA treatment in mice has been shown to significantly reduce the weight of total body fat, brown fat, subcutaneous fat, and visceral fat. The ceramide content in various types of fat tissue was lower than that in the control group, which may inhibit ceramide synthesis, reduce its content, and thereby promote the browning and thermogenesis of adipose tissue. Moreover, GLP-1RA significantly reduced the adipocyte volume in obese mice while maintaining a nearly constant number of adipocytes, resulting in a significant reduction in body fat weight. Additionally, the expression of genes involved in lipogenesis, such as Acly, Accα1, and Fasn, was decreased, while the expression of genes involved in lipolysis, such as Lipe and Pnpla2, was upregulated [46] . These findings indicate that GLP-1RAs not only suppress appetite and delay gastric emptying but also play a positive role in altering food preferences, regulating energy metabolism, and promoting fat breakdown.

GLP-1RAs can be classified into short-acting and long-acting formulations based on their duration of action (shown in Table 2 ). Short-acting formulations require daily injection, while long-acting formulations have a lower injection frequency,

such as weekly or monthly injections. Currently approved short-acting GLP-1RAs in the domestic market include exenatide, beinaglutide, and liraglutide, while long-acting GLP-1RAs include dulaglutide, semaglutide, polyethylene glycol loxenatide, exenatide microsphere, and dual-target GLP-1R/GIPR drugs such as tirzepatide and masutotide.

GLP-1RAs have shown impressive weight loss efficacy in people with type 2 diabetes. Research indicates that lixisenatide can lower BMI [47] . A meta-analysis has validated that lixisenatide treatment results in significant weight and BMI reductions compared to placebo [48] [49] . In a Phase III study, patients treated with various doses of liraglutide (1.2 mg to 3.0 mg) had an average weight loss of 5% - 10% compared to the placebo group [50] . Clinical trials in children aged 6 to 12 years demonstrated that liraglutide treatment combined with lifestyle intervention was more effective in reducing BMI than placebo plus lifestyle intervention [51] . A Japanese prospective case study indicated that daily treatment with 0.9mg of liraglutide for 24 weeks in obese patients with type 2 diabetes reduced body fat and achieved different levels of reduction in visceral and liver fat [52] . In a clinical study, compared with the control group, participants using semaglutide continuously had a weight loss of up to 18.2%, with an average reduction of 17.8 kg. Combining semaglutide with a low-calorie diet and appropriate exercise resulted in a significant and sustained weight loss of 15.2% [53] . Another randomized, double-blind, placebo-controlled study showed that semaglutide not only reduced cardiovascular event risk but also demonstrated sustained weight loss in overweight or obese adults with cardiovascular disease risk. Over the 208-week study period, patients in the treatment group had an average weight loss of 10.2%, a waist circumference reduction of 7.7 cm, and a 6.9% decrease in waist-to-height ratio, which reflects abdominal fat accumulation [54] . Clinical trials of semaglutide in adolescents with obesity also demonstrated significant weight loss, with an average BMI reduction of 16.1% compared to baseline [55] . Compared with injectable formulations, oral formulations demonstrated similar effects on blood sugar, blood pressure, and lipid regulation. After 68 weeks of treatment with 50 mg of oral semaglutide once daily, the average weight of obese or overweight patients decreased by 15.1% [56] . A Phase III clinical trial in China demonstrated that beinaglutide treatment resulted in an average weight loss of 10.05 kg, with reductions in waist and hip circumference. The weight regain rate 12 weeks after discontinuing beinaglutide treatment was only 0.78% [57] . In a study, dulaglutide treatment for 54 weeks led to significant improvements in glycemic control and weight reduction [58] . The weight loss efficacy of dulaglutide is dose-dependent, with more pronounced effects at the 1.5 mg [59] . Recent research indicates that GLP-1/GCGR dual agonists are more effective for weight loss than GLP-1 agonists alone, with tirzepatide showing superior efficacy in reducing HbA1c and body weight in type 2 diabetes patients [60] . In a 72-week trial, participants receiving 15mg of tirzepatide experienced an average weight loss of 22.5%, or about 24 kg, which confirms that tirzepatide is the most effective weight loss agent reported to date [61] .

In addition, 36 randomized clinical trials have shown that obese individuals without diabetes can achieve significant weight loss through GLP-1RA treatment [62] . Research indicates that exenatide is effective for weight loss in both patients with type 2 diabetes and obese individuals without diabete. In a study, non-diabetic obese women experienced an average weight loss of 2.49kg and a significant decrease in waist circumference [63] - [65] . Thus, GLP-1RA can effectively induce weight loss in adults with obesity or overweight, regardless of diabetes status.

GLP-1RA, as a widely used class of antidiabetic drugs, can induce a series of adverse reactions despite their remarkable therapeutic effects. The most frequent gastrointestinal symptoms of GLP-1RA include nausea, vomiting, and diarrhea, with some patients also reporting constipation, indigestion, and abdominal pain, likely due to the drug’s effects on gastrointestinal motility and individual variability, Symptoms can be mitigated through improved dietary habits, lifestyle modifications, and changes in administration methods. Initiating treatment with a low dose and titrating up based on patient tolerance can help minimize adverse reactions [66] . There is evidence that GLP-1RA use can significantly increase the risk of cholecystitis, gallstones, and biliary diseases, especially with higher doses and longer treatment durations [67] . In non-diabetic obese patients, the use of GLP-1 RA (liraglutide/semaglutide) has been shown to increase the risk of pancreatitis, intestinal obstruction, and gastroparesis, but not the risk of biliary diseases like cholecystitis, gallstones, and common bile duct stones [68] . Thus, the relationship between GLP-1RA and the risk of cholecystitis or gallstones is still uncertain and needs further research to clarify [69] . Reports have shown that after 28 days of treatment with GLP-1RA, heart rate may increase slightly, typically by 2 - 4 beats per minute. This effect may be due to the direct action of GLP-1RA on the sinoatrial node or stimulation of the sympathetic nervous system [70] . Injection site reactions, including pain, redness, and hardening, are common local adverse effects of GLP-1RA. These reactions may be associated with injection techniques, drug concentration, and individual variability [71] . To mitigate these reactions, it is recommended to use different injection sites and improve injection techniques [72] . In extremely rare cases, GLP-1RA can cause allergic reactions, such as rashes, itching, and difficulty breathing, and even anaphylaxis. Therefore, patients with a history of allergies should be particularly cautious when using GLP-1RA. In recent years, there have been reports that GLP-1RA may cause neurological symptoms in a very small number of patients, such as tension, anxiety, and insomnia [73] . The specific mechanisms underlying these symptoms are not yet clear.

Of course, the combination of GLP-1RA with other drugs or treatment modalities has also shown significant advantages in the treatment of obesity and related metabolic diseases. The combination of dulaglutide and dapagliflozin significantly improves metabolic parameters in overweight and obese type 2 diabetes patients, including reduced body weight, BMI, waist-to-hip ratio, visceral fat area, and visceral fat index [74] . One study compared the cardiorenal effects of an SGLT2 inhibitor (SGLT2i) with GLP-1RA in combination with monotherapy. The results showed significant advantages in lowering blood glucose, reducing body weight, and improving cardiovascular and renal outcomes [75] . Compared with metformin monotherapy, the combination of Semaglutide and metformin significantly improved liver inflammation, fibrosis, and β cell function in patients with T2DM and NAFLD [76] .

Studies have found that all GLP-1 drugs are beneficial for weight loss. The combination of GLP-1RA with other drugs has shown significant results in weight loss, further enhancing and improving cardiovascular and liver health through multi-mechanism synergies. GLP-1RA, alone or in combination, is associated with relative and absolute weight loss, and the magnitude of weight loss varies between drugs. However, the combination of drugs can achieve better therapeutic effects at lower doses, thereby reducing the side effects of a single drug [77] . Future studies will continue to explore the long-term efficacy and safety of the combination, as well as the prospects for its use in different patient populations.

Weight loss is now recognized as a multifaceted, scientific, and individualized process that encompasses diet, exercise, medical interventions, and psychological support. Current drug development efforts primarily target reducing energy intake and enhancing fat combustion and energy expenditure to induce weight loss [78] - [82] .

The application of GLP-1 RA drugs in the field of weight loss is of great clinical significance, which not only achieves significant weight loss, but also improves the metabolic health of patients, reduces liver inflammation, and expands the scope of clinical application. These strengths position GLP-1RA as a crucial option for treating obesity. The evolution from single-target GLP-1R to dual-target GLP-1R/GCGR, GLP-1R/GIPR, and back to GLP-1R/GCGR, and then to triple-target GLP-1R/GCGR/GIPR and the latest GLP-1R/GCGR/FGF21R has not only raised the bar for new drug development but also provided patients with more diverse and efficient treatment options [83] .

In addition, a groundbreaking study by the team of Ana I. Domingos at the University of Oxford has shown that neuropeptide Y (NPY) can regulate thermogenic fat tissue through specific neural pathways, promoting the release of energy as heat, thereby effectively combating obesity without reducing food intake [84] . This discovery paves the way for developing weight loss therapies that do not rely on dietary restrictions. A research team at the University of Bonn has explored the functions of brown fat cells and found that adenosine released from apoptotic brown fat cells can not only increase the basal metabolic rate but also promote thermogenesis in healthy brown fat cells and induce the browning of white fat tissue, thereby combating obesity [85] . Meanwhile, a research team at the University of California, San Diego, has revealed the critical role of glycogen metabolism in the energy balance of fat cells. Their research shows that glycogen metabolism is not only an important process for energy storage and mobilization but also directly affects the thermogenic function of fat tissue [86] . The research team led by Professor Yin Zhinan at Jinan University has focused on the immune molecule IL-27, finding that it can directly act on fat cells to promote their browning and enhance thermogenesis [87] . This mechanism helps to reduce body weight by accelerating lipid combustion. With the development of more novel drugs and the advancement of clinical trials, GLP-1RA are expected to provide more effective treatment options for patients with obesity and metabolic diseases. However, there are also some potential challenges to its application, including drug side effects, treatment costs, and long-term safety issues. Future research needs to optimize drug design further and reduce side effects, while exploring more economical treatment options to improve drug access and patient compliance. In addition, there is a need for enhanced regulation and research on the off-label use and long-term safety of GLP-1RA. We look forward to the discovery of more therapeutic targets related to obesity and the development of safer and more efficient weight loss drugs in the future, bringing more innovation and hope for global obesity and related diseases.