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Obesity, defined as a chronic complex disease characterized by excessive abnormal fat accumulation, has emerged as a critical global public health issue. According to data from the World Health Organization (WHO) in 2024, the global prevalence of obesity reached 1/8 of the world's total population in 2022 [1]. Moreover, obesity is a core risk factor for non-communicable diseases (NCDs), including cardiovascular diseases, diabetes, and certain cancers. Among these, Type 2 diabetes mellitus (T2DM) is a metabolic disorder triggered by insulin resistance and β-cell damage, which are pathologies induced by excess nutrition and physical inactivity. T2DM accounts for 90%–95% of all diabetes cases, and obesity is directly linked to 55% of premature mortalities in T2DM patients [2].
Figure 1. Distribution of the proportion of adults worldwide with
BMI ≥ 25 kg/m2 in 2022 (%)
(a: Females; b: Males)
In addition to long-term diet and exercise management, current immediate intervention methods for obesity mainly include surgical treatment and drug therapy. Among them, laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy are the mainstream surgical procedures for obesity: the former acts by altering the digestive tract path of food, while the latter achieves weight loss by reducing gastric volume. However, both carry certain surgical risks, resulting in low subjective acceptance among patients [3].
In contrast, anti-obesity drugs have higher patient compliance and can produce significant short-term effects. The five drugs approved by the National Medical Products Administration (NMPA) for weight loss in adult patients with primary obesity are orlistat, liraglutide, beinaglutide, semaglutide, and tirzepatide. Of these, all except orlistat belong to the class of GLP-1R agonists. Currently, GLP-1R agonists represented by semaglutide have become the primary choice for obesity treatment [4].
Figure 2. Mainstream surgical treatment regimens for obesity
GLP-1, whose full name is glucagon-like peptide-1, is an incretin hormone secreted by L cells in the small intestine. It exhibits effects such as lowering blood glucose and reducing body weight, and serves as a key substance in the treatment of obesity and T2DM. With a few exceptions, the majority of its physiological functions are achieved through binding to GLP-1 receptors distributed in multiple parts of our body, with target sites including pancreatic β cells, the gastrointestinal tract, the hypothalamic neural center, kidneys, and the cardiovascular system.
GLP-1 regulates glucose metabolism and improves obesity by promoting insulin gene transcription and expression, stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, enhancing pancreatic β-cell proliferation and differentiation, suppressing pancreatic β-cell apoptosis, delaying gastric emptying, and inhibiting appetite.
Furthermore, GLP-1's regulatory effect on blood glucose is concentration-dependent: when blood glucose levels fall below a certain threshold, GLP-1 no longer exerts its effect, which ensures that a slight excess of GLP-1 does not cause hypoglycemia [5]. Based on these properties, GLP-1R agonists are promising agents for the treatment of obese individuals and T2DM.
Figure 3. Relevant mechanisms of GLP-1 in its blood glucose-lowering and weight-loss effects
After food intake, intestinal L cells distributed in the mucosa of the duodenum, distal colon, terminal ileum, and rectum secrete GLP-1 into the circulatory system upon stimulation by nutrients. Subsequently, GLP-1 is transported via the bloodstream to the entire body to exert its effects, making subcutaneous injection the primary administration method for GLP-1-based drugs. Additionally, the plasma half-life of native GLP-1 is only 1–2 minutes, as it is primarily degraded by dipeptidyl peptidase-4 (DPP-IV), neutral endopeptidase NEP-24.11, and trypsin, and simultaneously cleared by the kidneys [6]. Thus, it requires stability modification before clinical application.
Through molecular modification strategies, GLP-1 has been successfully modified to obtain long-acting formulations such as liraglutide, semaglutide, and loxenatide. However, these drugs still require administration via injection (with low patient adherence), and sequences modified based on heterologous exendin-4 are often associated with immunogenicity [4]. Teams such as iGEM squirrel-chn 2024 have designed protease inhibitors targeting the primary degrading enzyme DPP-IV to extend the circulatory half-life of GLP-1, but such inhibitors carry the risk of disrupting normal protein degradation in the human body. Therefore, our team is committed to developing an oral long-acting formulation for blood glucose lowering and weight loss based on human-derived GLP-1, aiming to significantly reduce administration frequency and minimize adverse reactions.
Figure 4. Common types of GLP-1 receptor agonists
To address the issues above, the iGEM HiZJU-China 2025 team designed an oral bacterial agent using the human natural intestinal strain Escherichia coli Nissle 1917 (EcN) as the chassis organism, integrating sensing modules such as green tea metabolite-responsive circuits. This agent leads to long-term synthesis of GLP-1 in the intestine and improves the half-life and stability of GLP-1 in blood circulation after administration through modification of restriction enzyme cleavage site sequences. On the one hand, it increases GLP-1 supply by inducing and amplifying pre-synthesis; on the other hand, it enhances its in vivo circulation and functional activity through molecular stability modification. The combination of these two strategies is expected to produce truly "ultra-long-acting" GLP-1R agonist drugs for blood glucose regulation and weight loss.
For more information, please refer to our Design section.
Figure 5. GlucoXpert: Schematic diagram of the process for long-acting production of modified GLP-1 based on intestinal probiotics
[1] World Health Organization. (2024). Accelerating action to stop obesity. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
[2] GBD 2019 Mental Disorders Collaborators (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. The lancet. Psychiatry, 9(2), 137–150.
[3] Shi, H., Yang, M., & Dong, J. (2022). Current status of bariatric surgery for the treatment of obesity-related comorbidities. Chinese Journal of Modern Medicine, 24(6), 105-108.
[4] Wang, J. Y., Wang, Q. W., Yang, X. Y., Yang, W., Li, D. R., Jin, J. Y., Zhang, H. C., & Zhang, X. F. (2023). GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach. Frontiers in endocrinology, 14, 1085799.
[5] Drucker D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell metabolism, 27(4), 740–756.
[6] Yang, N., Zhang, Y., & Wang, W. (2024). Structural Modification Strategies and Drug Research Progress of GLP-1. Chinese Journal of Modern Applied Pharmacy, 41(18), 2547-2555.