In-depth Analysis of the GCGR Target: From the Hub of Glucose Metabolism to the Key Coreceptor for Multi-Target Metabolic Therapy

The glucagon receptor (GCGR) is a key member of the Class B G protein-coupled receptor (GPCR) family, forming a core receptor network with GLP-1R and GIPR to regulate glucose homeostasis and energy metabolism. The endogenous ligand of GCGR is glucagon, primarily secreted by pancreatic α-cells, which plays a critical role in maintaining fasting blood glucose, promoting lipid oxidation, and increasing energy expenditure.

Historically, GCGR has been viewed as a "glucose-raising receptor"—its activation promotes hepatic glucose output, making it primarily a target for antagonism in diabetes treatment. However, recent studies have revealed that in multi-target agonist strategies, GCGR activation provides thermogenic and fat-burning effects that GLP-1R lacks, transforming it from an "obstacle to glucose lowering" to an "engine for weight loss." With the clinical breakthroughs of multi-target agonists like mazdutide, survodutide, and retatrutide, GCGR has evolved from a classic glucose-raising receptor to a core synergistic target in the development of multi-target drugs for metabolic diseases. This article systematically analyzes the biological basis and clinical translation prospects of GCGR from the perspectives of molecular structure, signal transduction, tissue distribution, physiological functions, and drug development.

GCGR belongs to the B1 class of secretin/glucagon subfamily GPCRs, consisting of a seven-transmembrane helical domain (7TM) and an extracellular ligand-binding domain (ECD), with a molecular weight of approximately 62 kDa. Similar to GLP-1R and GIPR, GCGR contains a long extracellular loop 1 (ECL1) with 11-26 residues, compared to only 4-6 residues in other Class B and most Class A GPCRs. Studies suggest that GCGR's ECL1 may participate in binding its endogenous ligand, glucagon, and regulate receptor activity.

GCGR's ligand recognition follows the classic "two-step model" of Class B GPCRs: the C-terminus of glucagon first binds to the receptor's ECD, followed by the insertion of its N-terminus into the transmembrane domain core, inducing conformational rearrangement of the receptor. This sequential binding mechanism ensures ligand specificity and precise signal activation.

Recent breakthroughs in cryo-electron microscopy and single-molecule fluorescence technology have enabled the structural resolution of GCGR in complex with ligands and G proteins, providing essential tools for understanding its signal transduction mechanisms. Research has found that the interaction interface between GCGR's ECD and 7TM plays a critical role in signal transduction, with synergy between different domains being a key determinant of receptor function.

GCGR primarily couples with the Gαs protein. When glucagon binds to GCGR, the receptor undergoes conformational changes, activating the receptor and enabling it to bind to the G protein Gαs, leading to the activation of adenylate cyclase (AC) and an increase in intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which regulates multiple downstream targets through phosphorylation cascades.

In hepatocytes, the activation of the GCGR/cAMP/PKA pathway has multiple metabolic effects:

Glycogenolysis: PKA phosphorylates and activates phosphorylase kinase, which in turn activates glycogen phosphorylase, promoting the breakdown of liver glycogen into glucose-1-phosphate.

Gluconeogenesis: PKA phosphorylates the CREB transcription factor, upregulating the expression of key gluconeogenesis genes such as PGC-1α. Studies show that GCGR endocytosis enhances cytoplasmic cAMP elevation induced by GCGR activation and promotes the expression of PCK1 (the enzyme catalyzing the rate-limiting step of gluconeogenesis).

Lipid metabolism: Activation of the cAMP/PKA pathway promotes lipolysis, releasing free fatty acids into the bloodstream. GCGR signaling also enhances triglyceride breakdown and fatty acid oxidation.

Additionally, GCGR can regulate receptor desensitization and internalization through β-arrestin-dependent pathways, forming a complex signal regulatory network.

GCGR gene expression is highest in the liver, with moderate or low levels of mRNA expression in the kidneys, heart, and pancreatic islets. It is also distributed in small amounts in adipose tissue, the central nervous system, adrenal glands, gastrointestinal tract, intestinal smooth muscle, and pancreatic α- and β-cells. This broad tissue distribution determines GCGR's multi-system physiological functions.

Liver: The core site of GCGR's regulation of glucose metabolism, including glycogenolysis, gluconeogenesis, and glycolysis. Under fasting conditions, GCGR signaling increases fuel availability, promotes the breakdown of glycogen and triglycerides, and drives gluconeogenesis.

Central nervous system: GCGR is distributed in the limbic system (olfactory tubercle, olfactory bulb, hippocampus, amygdala, septum) of the rat brain, as well as in the hypothalamus, thalamus, and medulla oblongata. Intracerebroventricular injection of glucagon dose-dependently reduces short-term food intake in male mice, suggesting GCGR may regulate feeding behavior by modulating hypothalamic agouti-related protein levels.

Adipose tissue: GCGR activation promotes lipolysis and fatty acid oxidation, increasing energy expenditure. GCGR signaling can also increase energy expenditure by activating futile cycles in the liver and promoting thermogenesis in other tissues.

Heart: GCGR is also expressed in the heart. A 2025 study found that the triple agonist retatrutide specifically enhances right atrial automaticity in mice through the GCGR/cAMP/PKA signaling pathway but has no effect on left atrial contractility. This "functional selectivity" mode of action provides new insights into the cardiac safety assessment of multi-target metabolic drugs.

Kidneys: GCGR is also expressed in the kidneys, where it may participate in processes such as electrolyte transport.

GCGR exhibits a seemingly paradoxical dual role in metabolic regulation, profoundly influencing its drug development strategies.

Under physiological conditions, GCGR maintains fasting blood glucose levels by activating hepatic gluconeogenesis, preventing hypoglycemia. In pathological conditions (e.g., type 2 diabetes), excessive glucagon secretion or hyperactive GCGR signaling can increase hepatic glucose output, exacerbating hyperglycemia. Thus, GCGR antagonists improve glycemic control by reducing excessive hepatic glucose production.

However, GCGR activation also promotes lipolysis and energy expenditure. In multi-target agonist strategies, GCGR activation provides thermogenic and fat-burning effects that GLP-1R lacks. GCGR agonism increases energy expenditure through two mechanisms: (a) activating hepatic metabolic pathways, triggering futile cycles that waste energy; and (b) targeting other tissues to promote thermogenesis. Preclinical studies show that the glucagon-GCGR system enhances whole-body thermogenic capacity and prevents obesity by influencing key metabolic organs such as the liver, white adipose tissue, and brown adipose tissue.

Both GCGR agonism and antagonism strategies can yield metabolic benefits. This "two sides of the same coin" characteristic makes GCGR a highly valuable synergistic receptor in the design of multi-target metabolic drugs.

According to incomplete statistics, there are currently 103 GCGR-targeted drugs globally, but most are in preclinical stages or have no progress. Among clinically staged drugs, there are 8 synthetic peptide drugs, 2 small-molecule chemical drugs, and 7 other drug types (including fusion proteins, monoclonal antibodies, and hormones), with indications primarily focused on diabetes and obesity.

5.1 GCGR Antagonists

Small-molecule GCGR antagonists offer advantages in glycemic control, oral bioavailability, and cost-effectiveness, but their clinical development has been hindered by safety concerns. GCGR antagonists have not yet been approved for clinical treatment, with key limitations including potential adverse effects such as α-cell hyperplasia, hyperglucagonemia, abnormal amino acid metabolism, and lipid metabolism disorders.

In the monoclonal antibody field, Regeneron's crotedumab (REGN1193) is a fully human IgG4 monoclonal antibody targeting GCGR, binding and inhibiting GCGR with an affinity of 0.1 nM. Long-term studies show that GCGR monoclonal antibodies maintain sustained improvements in glycemic control in diet-induced obese mice.

5.2 GLP-1R/GCGR Dual-Target Agonists

GLP-1R/GCGR dual-target agonists combine GLP-1's insulinotropic and gastric emptying-delaying effects with GCG's thermogenic and lipolytic effects, achieving superior weight loss while effectively controlling blood glucose.

Mazdutide, developed by Innovent Biologics and Eli Lilly, is a GLP-1R/GCGR dual agonist that has completed Phase III clinical trials and is awaiting approval. Its uniqueness lies in activating hepatic GCGR to promote fatty acid oxidation and lipolysis, improving hepatic fat metabolism.

Survodutide (BI 456906) is another GLP-1R/GCGR dual-target agonist currently being evaluated in multiple clinical trials. Studies show that hepatic GCGR is essential for survodutide analogs to achieve superior weight loss and metabolic effects.

Qingmu Lutiide demonstrates significant glucose-lowering and weight-loss effects in DIO mouse models, with weight loss superior to liraglutide.

P052 injection, a GLP-1R/GCGR dual-target agonist independently developed by Huisheng Biotech, received NMPA clinical trial approval in September 2025. Preclinical data show its glucose-lowering effects are comparable to semaglutide, with significantly superior weight loss.

5.3 GLP-1R/GIPR/GCGR Triple-Target Agonists

Triple-target agonists simultaneously target three complementary metabolic pathways, representing the cutting edge of the field.

Retatrutide is the first triple agonist to publish Phase II clinical data, achieving an average weight loss of 24.2% over 48 weeks in obese populations. Studies show that retatrutide can restore normal weight in GLP-1R knockout obese mice, indicating that synergistic activation of GIPR and GCGR is sufficient to reverse obesity without relying on GLP-1R.

ASC37, a next-generation triple-target agonist peptide developed by Ascletis Pharma, shows superior agonistic activity for GLP-1R, GIPR, and GCGR compared to retatrutide in vitro. Ascletis plans to submit an IND application to the FDA in Q2 2026.

HRS-4729 and MWN-109, among other triple-target agonists, have also entered preclinical or early clinical development stages.

A 2025 study published in Nature revealed unique functions of GCGR in birds. The research team found that avian GCGR's high expression in the liver and its constitutive activation of the Gs signaling pathway depend on synergistic interactions between different receptor domains. This constitutive activity gives birds fasting blood glucose levels nearly twice those of mammals, supporting the rapid energy demands of flight. In vivo experiments confirmed that constitutively active GCGR in fish, reptiles, birds, and mammals leads to corresponding hyperglycemia, rapid utilization of hepatic fat, and high metabolic rates.

This discovery has important translational implications. The study also found that a point mutation near the chicken GCGR gene region reduces GCGR mRNA expression and increases body weight. In humans, high expression of a naturally occurring GCGR variant (HsGCGR(H339R)) with moderate constitutive activity similarly increases blood glucose concentration and reduces body weight. These results provide new perspectives on the relationship between GCGR signal regulation intensity and species-specific metabolic demands, as well as an evolutionary biology foundation for developing GCGR-targeted metabolic modulators.

GCGR, as a Class B GPCR target with both classic glucose-raising and energy expenditure-regulating functions, has been deeply characterized in terms of molecular structure, signal transduction mechanisms, and tissue distribution. In the liver, GCGR drives glycogenolysis and gluconeogenesis to maintain fasting blood glucose, while in adipose tissue and the central nervous system, it participates in energy expenditure and feeding regulation. This dual "glucose-raising" and "fat-burning" property allows GCGR to serve as either an antagonistic target (reducing hepatic glucose output for glycemic control) or an agonistic target (increasing energy expenditure for weight loss)—in multi-target agonist strategies, GCGR activation provides the thermogenic and lipolytic effects that GLP-1R lacks. With the clinical advancement of dual- and triple-target agonists like mazdutide, survodutide, and retatrutide, GCGR is evolving from a classic "glucose-raising receptor" to an indispensable synergistic engine in multi-target metabolic therapy, driving the paradigm shift from single-target inhibition to multi-target synergy in drug development.