Long Fen, Challa Tenagne Delessa, Ding Lianggong, Sharma Anand Kumar, Wu Chunyan, Ghosh Adhideb, Noé Falko, Horvath Carla, Liebisch Gerhard, Höring Marcus, Wang Tongtong, Klug Manuel, Zimmermann Tina, Azevedo Pereira Mafalda Maria, Rist Wolfgang, Strobel Benjamin, Pekcec Anton, Neubauer Heike, Wolfrum Christian
Laboratory of Translational Nutrition Biology, Institute of Food Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland.
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, 93053 Regensburg, Germany.
J Hepatol. 2025 Jun 21. doi: 10.1016/j.jhep.2025.06.011.
BACKGROUND & AIMS: Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, particularly the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remains poorly defined.
We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical, and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits.
We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, glucagon receptor (GCGR) signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis.
These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
This study provides fundamental mechanistic insights into GCG pharmacology with direct clinical implications. The obesity-specific enhancement of energy expenditure by GCGR agonist substantiates the superior efficacy of GCGR/glucagon-like peptide-1 receptor (GLP-1R) dual agonists in individuals with obesity compared to GLP-1R mono-agonists. Importantly, differential PDE4 expression patterns may provide a molecular basis for the variable weight-loss responses to GCG-based agonists, identifying PDE4 inhibition as a potential strategy to restore efficacy in GCG-non-responders. Furthermore, the PDE4-overexpression model preserved the lipid-clearing capacity of GCGR agonist while attenuating hyperglycemic risk, demonstrating a translatable strategy to optimize the safety-efficacy profile of GCG-based therapies for cardio-renal-metabolic diseases such as obesity and MASH.
胰高血糖素（GCG）类似物作为基于肠促胰岛素的肥胖症和代谢功能障碍相关脂肪性肝炎治疗药物中有前景的成分正受到关注。然而，慢性胰高血糖素治疗的生物学机制，尤其是GCG诱导能量消耗和脂质代谢的分子基础，仍不清楚。
我们将长效GCG类似物（LA-GCG）与肝脏和脂肪组织胰高血糖素受体敲除小鼠模型联合使用。通过结合代谢、生化和组学技术的综合方法，我们研究了GCG诱导能量消耗和代谢益处的分子机制。
我们证明LA-GCG可增强饮食诱导的肥胖小鼠的能量消耗，其中肝脏而非脂肪组织的胰高血糖素受体（GCGR）信号起关键作用。有趣的是，仅在肥胖小鼠而非瘦小鼠中观察到能量消耗增加。这种优先疗效可能是由于LA-GCG通过下调PDE4B/4D使cAMP/PKA信号通路持续激活所致。相反，瘦小鼠中PDE4B/4D活性可迅速减弱cAMP/PKA信号。有趣的是，与能量消耗表型不同，LA-GCG的脂质清除能力与PDE4/cAMP/PKA轴无关。
这些发现为GCG诱导的能量消耗和代谢益处提供了分子基础，并提示了cAMP/PKA依赖性和非依赖性效应的表型分离。
本研究为GCG药理学提供了基本的机制见解，具有直接的临床意义。GCGR激动剂对肥胖症患者能量消耗的特异性增强证实了与GLP-1R单激动剂相比，GCGR/胰高血糖素样肽-1受体（GLP-1R）双激动剂在肥胖个体中的卓越疗效。重要的是，不同的PDE4表达模式可能为基于GCG的激动剂的体重减轻反应差异提供分子基础，确定PDE4抑制作为恢复GCG无反应者疗效的潜在策略。此外，PDE4过表达模型保留了GCGR激动剂的脂质清除能力，同时降低了高血糖风险，证明了一种可转化的策略，可优化基于GCG的肥胖症和代谢功能障碍相关脂肪性肝炎等心肾代谢疾病治疗的安全性-疗效概况。
