關(guān)注

編者按：肥胖已成為全球亟需應(yīng)對的公共健康問題?！?025年世界肥胖報告》指出，到2030年，全球?qū)⒂谐^29億成年人的體重超重（BMI≥25 kg/m2），其中11億人將達到肥胖標準（BMI≥30 kg/m2）。肥胖與2型糖尿病、高血壓、冠心病、中風(fēng)及多種癌癥等慢性疾病密切相關(guān)，因此探索安全有效的減重手段已刻不容緩?？上驳氖?，司美格魯肽和替爾泊肽等創(chuàng)新多肽藥物的上市為肥胖治療帶來了重大突破。新一代減重療法通過靶向多條關(guān)鍵信號通路，不但有望實現(xiàn)更顯著的減重效果，還可能幫助維持肌肉質(zhì)量、降低停藥后的體重反彈，為肥胖患者提供更高質(zhì)量的減重方案。為推動這類療法的研發(fā)，藥明康德旗下WuXi Biology已建立了多種模擬人體肥胖的動物模型，幫助合作伙伴在臨床前階段高效、精準地評估候選藥物。本文將介紹新一代減重療法的開發(fā)方向，以及藥明康德的一體化CRDMO平臺在這一領(lǐng)域的賦能能力。

靶向多重信號通路，提高減重效果

靶向多重信號通路是多款目前處于后期臨床階段的減重療法的重要研發(fā)趨勢。這些療法靶向的信號通路包括胰高血糖素樣肽-1（GLP-1），葡萄糖依賴性促胰島素多肽（GIP）、胰高血糖素（GCG）、胰淀素等腸促胰島素。例如，安進公司的MariTide、諾和諾德的CagriSema、以及禮來公司的retatrutide，通過同時作用于多條關(guān)鍵信號通路，有望更有效地調(diào)節(jié)食欲、能量攝入和能量消耗，從而實現(xiàn)更顯著的減重效果。

不過，臨床前研究面臨的關(guān)鍵挑戰(zhàn)之一，是標準嚙齒類動物模型能否準確反映多靶點藥物的綜合療效。例如，GLP-1受體激動劑司美格魯肽在人體和高脂飲食誘導(dǎo)肥胖（DIO）小鼠模型中均表現(xiàn)出顯著減重效果，原因在于兩者GLP-1受體的高度同源性。相比之下，激活GIP和GLP-1受體的雙靶點藥物替爾泊肽情況則更為復(fù)雜：在人類中，其療效依賴于兩種受體的協(xié)同作用，但在常規(guī)DIO小鼠中，阻斷GLP-1受體會完全消除替爾泊肽的療效，而阻斷GIP受體則對胰島素分泌或血糖調(diào)節(jié)作用影響不大。這種差異表明，該藥在小鼠中的效果主要來自GLP-1受體激活。這種差異很可能源于人和小鼠GIP受體的氨基酸序列同源性較低，使得小鼠模型無法完全復(fù)制人體藥理反應(yīng)。

為解決這一問題，WuXi Biology的代謝疾病團隊開發(fā)了表達人類GIP受體的DIO小鼠模型。實驗結(jié)果顯示，與常規(guī)DIO小鼠相比，該模型在評估同時靶向GLP-1受體和GIP受體的減重藥物時，能更好地體現(xiàn)雙靶點藥物的協(xié)同減重效果，并更準確反映藥物對白色與棕色脂肪組織的作用。這些結(jié)果表明，表達人類GIP受體的小鼠模型能夠更準確地反映人體藥理反應(yīng)，為評估多靶點減重藥物的療效提供更具轉(zhuǎn)化價值的數(shù)據(jù)信息。

▲表達人類GIP受體的DIO小鼠模型評估多種減肥藥物的實驗結(jié)果（圖片來源：參考資料[1]）

減脂不減肌，長期健康減重的下一步

雖然GLP-1類藥物能顯著降低體重，但研究發(fā)現(xiàn)，減掉的體重中部分來自肌肉流失，這可能導(dǎo)致肌力下降、活動能力減弱及整體健康受損，在老年人中尤為值得關(guān)注。因此，保持肌肉質(zhì)量是實現(xiàn)長期健康減重的重要方向之一。

目前，靶向雄激素受體、激活素受體以及肌肉生長抑制素等信號通路的多種候選藥物已進入臨床開發(fā)階段，與GLP-1類藥物聯(lián)合使用時，可在減少脂肪的同時維持甚至增加瘦體重。WuXi Biology的研究團隊也在實驗中驗證其開發(fā)的小鼠肥胖模型，能夠在臨床前研究中準確反映創(chuàng)新藥物保存肌肉質(zhì)量的效果。同時，團隊具備進行多種肌肉功能檢測的能力，包括對嚙齒類動物肌肉力量和耐力的檢測。

▲在小鼠模型中開展的肌肉功能檢測結(jié)果（圖片來源：參考資料[1]）

傳統(tǒng)行為學(xué)測試容易受到個體差異和操作者因素影響，導(dǎo)致數(shù)據(jù)一致性不足。此外，由于肥胖個體活動水平普遍下降，評估抗肥胖藥物對肌肉功能的影響也面臨挑戰(zhàn)。為克服這些限制，WuXi Biology開發(fā)了更精細、客觀的電生理檢測平臺，通過監(jiān)測肌纖維特征變化并量化肌肉應(yīng)力，更全面、準確地評估肌肉功能與藥效。

防止體重反彈，延長療效持久性

減重藥物研發(fā)的另一大目標，是確保療效的持久性。部分藥物在停用后會引起體重快速反彈，不僅削弱療效，還可能帶來額外健康風(fēng)險。因此，需要能夠模擬停藥后體重回升過程的臨床前模型。

WuXi Biology團隊已在DIO小鼠模型中開展了體重回升研究：在既定治療期結(jié)束后停藥，并持續(xù)觀察3-4周。結(jié)果顯示，停藥后藥物的抑制食欲作用迅速減弱，一些動物的進食量甚至超過對照組，導(dǎo)致體重明顯回升。值得注意的是，回升的體重主要來自脂肪質(zhì)量，而在減重階段減少的則包括肌肉和脂肪。這種以脂肪為主的反彈不僅降低了治療凈收益，還可能惡化代謝狀況。

▲在DIO小鼠模型中開展的體重回升研究結(jié)果（圖片來源：參考資料[1]）

這些發(fā)現(xiàn)強調(diào)了研發(fā)能夠?qū)崿F(xiàn)持久減重并在停藥后最大限度減少反彈的藥物的重要性。目前，靶向黑皮質(zhì)素4受體（MC4R）、?；o酶A合成酶5（ACSL5）、以及激活素受體等信號通路的創(chuàng)新藥物已經(jīng)表現(xiàn)出減少GLP-1藥物停用后體重反彈的效果。

今年，《自然》雜志上發(fā)表的一篇評論文章指出，減重療法領(lǐng)域正迎來一個飛速發(fā)展的時期，創(chuàng)新療法不斷涌現(xiàn)。在藥明康德，我們提供一體化研發(fā)服務(wù)，加速肥胖及相關(guān)代謝性疾病創(chuàng)新療法的開發(fā)。藥明康德的CRDMO平臺可支持合作伙伴從早期發(fā)現(xiàn)到臨床開發(fā)的全流程，涵蓋藥物化學(xué)、生物學(xué)以及臨床前測試等多個領(lǐng)域的專業(yè)能力。展望未來，藥明康德將持續(xù)賦能合作伙伴的減重藥物開發(fā)，早日將科學(xué)創(chuàng)新轉(zhuǎn)化為造?；颊叩男滤幒盟?。

The Next-Generation Weight Loss Therapies Are Coming

Obesity has become a pressing public health challenge worldwide. According to the 2025 World Obesity Atlas, by 2030, more than 2.9 billion adults globally will be overweight (BMI ≥ 25 kg/m2), of which 1.1 billion will meet the criteria for obesity (BMI ≥ 30 kg/m2). Obesity is closely linked to chronic diseases such as type 2 diabetes, hypertension, coronary heart disease, stroke, and various cancers, which makes the development of safe, effective weight-loss interventions an urgent priority.

In recent years, the launch of innovative peptide drugs such as semaglutide and tirzepatide has marked a major breakthrough in obesity treatment. The next generation of weight-loss therapies aims to go further—targeting multiple key signaling pathways to deliver greater weight reduction, while also preserving muscle mass and reducing post-treatment weight regain. These approaches promise higher-quality, longer-lasting solutions for patients with obesity. To advance such therapies, WuXi Biology, a key part of WuXi AppTec, has developed a range of animal models that closely simulate human obesity, enabling partners to evaluate drug candidates efficiently and with high translational relevance at the preclinical stage.

Targeting Multiple Pathways to Boost Weight-Loss Efficacy

One prominent trend in late-stage clinical development is the design of therapies that act on multiple signaling pathways, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), and amylin. By acting on more than one pathway to regulate appetite, energy intake, and expenditure more effectively, they can potentially achieve more pronounced weight loss.

However, preclinical evaluation of such drugs presents unique challenges. While GLP-1 receptor agonists like semaglutide demonstrate strong, consistent weight-loss effects in both humans and high-fat diet-induced obese (DIO) mouse models—thanks to high GLP-1 receptor homology between species—the picture is more complex for dual-target agents like tirzepatide. In humans, tirzepatide’s efficacy depends on the combined activation of GIP and GLP-1 receptors. Yet, in conventional DIO mice, blocking GLP-1 receptors eliminates efficacy, while blocking GIP receptors has minimal impact. This discrepancy stems from the lower amino acid sequence homology of GIP receptors between mice and humans, limiting the mouse model’s ability to replicate human pharmacological responses.

To address this gap, WuXi Biology’s metabolic disease team developed a DIO mouse model expressing the human GIP receptor. Studies showed that, compared to conventional DIO mice, this model more accurately reproduced the synergistic weight-loss effects of dual GLP-1/GIP receptor activation, as well as effects on white and brown adipose tissues. These results provide a more reliable foundation for evaluating multi-target obesity therapies in preclinical research.

Fat Loss Without Muscle Loss: Supporting Long-Term Health

While GLP-1 drugs can significantly reduce body weight, research shows that part of this loss comes from lean body mass. In older adults especially, muscle loss can reduce strength, mobility, and overall health. Preserving muscle mass has therefore become a key goal in next-generation weight-loss drug development.

Several candidates now in clinical development target pathways such as the androgen receptor, activin receptor, and myostatin signaling. In combination with GLP-1 drugs, they aim to reduce fat while maintaining or even increasing lean body mass. WuXi Biology has validated the ability of its obesity models to capture these effects in preclinical studies, with capabilities for detailed muscle function testing, including strength and endurance assays in rodents.

Traditional behavioral muscle function tests, however, can be influenced by individual variability and operator technique, leading to inconsistent results—particularly in obese subjects with naturally lower activity levels. To overcome these limitations, WuXi Biology employed a more refined and objective approach using electrophysiological platforms to monitor changes in muscle fiber characteristics and quantify muscle stress. This method provides a more comprehensive and accurate assessment of muscle function and drug efficacy.

Preventing Weight Regain: Extending the Benefits of Therapy

Another major challenge is sustaining weight loss over time. Many drugs lead to rapid weight regain after discontinuation, negating the benefits and potentially worsening health risks. This makes preclinical models that simulate post-treatment weight regain essential for drug development.

In DIO mouse models, WuXi Biology researchers studied the post-discontinuation period by observing animals for 3–4 weeks after treatment stopped. Appetite-suppressing effects diminished quickly, with some animals eating even more than controls. Most of the regained weight came from fat, while weight lost during treatment had included both fat and muscle. This fat-dominant rebound reduces overall health benefits and may further impair metabolic function.

Encouragingly, emerging drug candidates targeting melanocortin-4 receptor (MC4R), acyl-CoA synthetase long-chain family member 5 (ACSL5), and activin receptors have shown the ability to limit weight regain after stopping GLP-1 therapy.

A recent Nature commentary highlighted that weight-loss therapy is entering a period of rapid expansion, with a growing pipeline of innovative treatments. At WuXi AppTec, we offer integrated R&D services to accelerate the development of innovative therapies for obesity and related metabolic disorders. Our platform supports partners from early discovery through clinical development, providing expertise in areas such as medicinal chemistry, biology, and preclinical testing. Looking ahead, WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO platform to support partners in advancing novel weight-loss drugs, ultimately helping to transform scientific breakthroughs into life-changing therapies for patients worldwide.

參考資料：

[1] Innovative R&D Strategies for Peptide Drugs in Obesity Treatment. Retrieved August 11, 2025, from https://wuxibiology.com/resource/innovative-rd-strategies-for-peptide-drugs-in-obesity-treatment/

[2] 2025年世界肥胖報告. Retrieved August 13, 2025, from https://data.worldobesity.org/publications/atlas-2025-cn.pdf

[3] 32nd European Congress on Obesity. Retrieved August 13, 2025, from https://wuxibiology.com/32nd-european-congress-on-obesity/

免責聲明：本內(nèi)容來自騰訊平臺創(chuàng)作者，不代表騰訊新聞或騰訊網(wǎng)的觀點和立場。

舉報

相關(guān)知識

行穩(wěn)致遠 重在協(xié)同
送教交流促均衡，篤行致遠共成長
貓科團隊主任獸醫(yī)馬云峰：知行合一，篤行致遠
篤行致遠 砥礪前行Volunteer service Forge ahead .
【地評線】太陽鳥時評：促進直播帶貨規(guī)范 推動行業(yè)行穩(wěn)致遠
“行而不輟 履踐致遠”大學(xué)生原創(chuàng)心理健康公益廣告大賽結(jié)果揭曉
[健康之路]與奧運同行 一起動起來 3 學(xué)會騎行技巧 遠離運動疼痛
在“熱辣”中努力堅持 在“滾燙”中實現(xiàn)夢想—行遠育才開學(xué)致辭
青島市稅務(wù)局稅惠添翼 護航電商新業(yè)態(tài)行穩(wěn)致遠
咖啡致癌？遠不如炸雞“危險”

網(wǎng)址: 同行致遠 http://m.u1s5d6.cn/newsview1810372.html