Obesity and related metabolic diseases are characterized not only by increased energy intake and fat storage but also by abnormalities in hepatic glucose and lipid metabolism, substrate utilization, and amino acid homeostasis. GCGR is an important Class B1 GPCR that regulates hepatic substrate mobilization during fasting. Its activation can promote hepatic glucose output while also enhancing fatty acid oxidation, ketone body production, and amino acid catabolism.

Keywords: GCGR; glucagon receptor; weight loss; fatty acid oxidation; FGF21; Glucagon-Amino Acid Axis; multi-receptor agonists

1 Metabolic Regulatory Basis of GCGR

1.1 GCGR and Core Signaling

GCGR belongs to the Class B1 G protein-coupled receptor family. After binding of its endogenous ligand Glucagon, it mainly activates Gs-Adenylate Cyclase-cAMP-PKA signaling. The liver is the core organ for the classical metabolic actions of GCGR. After receptor activation, Glycogenolysis and Gluconeogenesis can be rapidly promoted while fatty acid oxidation, Ketogenesis, and amino acid catabolism are also altered. GCGR therefore does not function only to raise blood glucose; its more complete physiological role is to coordinate multi-substrate mobilization and metabolic switching during fasting and states of increased energy demand.

1.2 The Liver as a Multi-Substrate Metabolic Hub

GCGR can simultaneously regulate the three major substrate classes of carbohydrates, lipids, and amino acids. When Glucagon-GCGR signaling is enhanced, hepatic Glycogen is mobilized and utilization of gluconeogenic substrates increases; more fatty acids enter mitochondrial β-oxidation and Ketogenesis; amino acid carbon skeletons can enter the TCA Cycle or Gluconeogenesis, while the generated nitrogen is further cleared through the Urea Cycle. Changes in different substrates are not independent of one another but jointly form a hepatic metabolic state that shifts from nutrient storage toward substrate output and oxidative utilization.

1.3 Tissue Boundaries of the Fat-Reducing Effects of GCGR

A decrease in Fat Mass or hepatic lipid after GCGR activation does not mean that GCGR primarily acts by directly stimulating Lipolysis in white adipocytes. More important changes arise from hepatic lipid utilization, liver-derived endocrine signals, substrate redistribution, and alterations in overall energy balance. GCGR-related fat reduction should first be understood from the perspective of hepatic and systemic energy-substrate utilization rather than inferring direct receptor effects solely from adipose-tissue endpoints.

2 Why GCGR Has Weight-Loss Potential

2.1 Fatty Acid Oxidation and Ketogenesis

GCGR activation can promote entry of hepatic fatty acids into mitochondrial β-oxidation, increase Acetyl-CoA production, and drive part of the Acetyl-CoA into Ketogenesis. As lipid substrates shift from Triglyceride storage toward oxidative utilization, hepatic lipid load can decrease accordingly. Unlike simply reducing food intake, an important pharmacological feature of GCGR is that it changes the fate of hepatic substrates, directing more lipids toward utilization rather than continued storage.

2.2 Coupling of Acetyl-CoA With Glucose and Lipid Metabolism

Acetyl-CoA generated by increased fatty acid β-oxidation can enter the TCA Cycle and Ketogenesis and can also influence Pyruvate Carboxylase-related gluconeogenic flux. Therefore, GCGR-mediated promotion of lipid oxidation and hepatic glucose production are intrinsically linked metabolically. The same receptor activation can simultaneously enhance hepatic lipid utilization and increase hepatic glucose output. GCGR weight-loss pharmacology therefore cannot be judged simply by “decreased hepatic TG = overall metabolic improvement.”

2.3 GCGR-FGF21 Metabolic Axis

GCGR activation can promote hepatic FGF21 expression and release, allowing local hepatic receptor signaling to further connect with systemic nutritional responses and energy homeostasis. FGF21 participates in lipid utilization, nutritional stress, and inter-organ metabolic communication and can therefore serve as an important node in GCGR-mediated liver-derived endocrine regulation. However, FGF21 cannot independently explain all GCGR pharmacology, and the regulation of cAMP-PKA, fatty acid oxidation, Gluconeogenesis, and amino acid metabolism by GCGR still has independent effects.

2.4 Substrate Utilization and Energy Metabolism

Enhanced fatty acid oxidation after GCGR activation can shift overall substrate utilization toward lipids and may be accompanied by changes in Energy Expenditure under some experimental conditions. A decrease in RER mainly reflects a change in the relative oxidation of Carbohydrate and Fatty Acid, whereas energy expenditure is also affected by body weight, Lean Mass, Food Intake, activity, and other factors. The weight-loss effect of GCGR is more appropriately understood as a “change in substrate mobilization and utilization” rather than being simply attributed to a direct increase in thermogenesis.

3 Glucagon-Amino Acid Axis and Nitrogen Metabolism

3.1 Amino Acid Catabolism and Carbon-Skeleton Utilization

Glucagon-GCGR signaling can promote hepatic uptake and catabolism of multiple Amino Acids. Amino acid carbon skeletons can enter the TCA Cycle or Gluconeogenesis. Therefore, changes in Glutamine, Glutamate, and Total Amino Acid levels after sustained GCGR activation can reflect alterations in hepatic amino acid processing and substrate utilization. Amino acid metabolism is an important research dimension that distinguishes GCGR from most weight-loss targets primarily based on food-intake suppression.

3.2 Liver–Pancreatic α-Cell Feedback

Bidirectional feedback exists between hepatic amino acid processing and pancreatic α cells. When GCGR signaling is weakened, hepatic amino acid clearance decreases, and accumulation of circulating Amino Acids can further affect α-cell function and Glucagon secretion, thereby forming the Glucagon-Amino Acid Axis. When GCGR activation enhances hepatic amino acid clearance, the circulating amino acid profile and liver–pancreatic islet feedback state also change accordingly.

3.3 Urea Cycle and Nitrogen Clearance

Nitrogen generated from amino acid catabolism needs to be cleared through the Urea Cycle. Therefore, Ammonia, Urea, Ornithine-related metabolism, Arginase, and related indicators can reflect the effects of GCGR on nitrogen flux. If a decrease in circulating Amino Acids is accompanied by increased Urea production, this more strongly supports increased hepatic amino acid catabolism and nitrogen clearance and cannot be explained solely by changes in tissue uptake.

3.4 Lean Mass and Protein Homeostasis

GCGR-mediated promotion of amino acid catabolism contributes to its characteristic substrate-utilization pattern, but sustained and excessive amino acid catabolism may also affect protein homeostasis. If overall body-weight loss mainly comes from reduced Fat Mass while Lean Mass is relatively preserved, this is more consistent with the desired direction of weight loss. If marked Lean Mass reduction occurs together with decreased Amino Acids and increased Urea production, whether lean-tissue catabolism contributes to body-weight loss needs to be considered.

4 Glucose-Raising Effects of GCGR and the Pharmacological Window

4.1 Glycogenolysis

GCGR activation can rapidly promote hepatic Glycogen breakdown, converting stored Glycogen into Glucose and releasing it into the circulation. This is a basic physiological function through which Glucagon maintains fasting blood glucose and is also one of the direct sources of increased hepatic glucose output after GCGR activation. Under conditions of insulin resistance or already elevated hepatic glucose output, excessive GCGR stimulation can further amplify this effect.

4.2 Gluconeogenesis

GCGR can also promote entry of Lactate, Pyruvate, Glycerol, and some Amino Acids into Gluconeogenesis. At the same time, Acetyl-CoA generated by increased fatty acid β-oxidation can further connect with gluconeogenesis-related metabolism, allowing enhanced lipid oxidation and increased hepatic glucose production to coexist. GCGR activation can therefore produce metabolic dissociation characterized by reduced hepatic lipid and increased lipid utilization while circulating Glucose rises simultaneously.

4.3 Fat-Reducing Benefits and Hyperglycemic Risk

The fat-reducing potential and hyperglycemic risk of GCGR both fundamentally arise from enhanced hepatic substrate mobilization. Increasing receptor activity can promote fatty acid oxidation, Ketogenesis, and amino acid catabolism while also increasing Glycogenolysis and Gluconeogenesis. The key to using GCGR as a weight-loss target is not to achieve maximal receptor activation but to increase the benefits of lipid and energy metabolism while keeping hepatic glucose output within a reasonable range.

5 GLP-1R/GCGR Dual-Receptor Agonists

5.1 Functional Complementarity Between GLP-1R and GCGR

GLP-1R/GCGR dual agonism is not a simple addition of two weight-loss mechanisms. GLP-1R mainly participates in glucose-dependent insulin secretion, glucagon regulation, gastric emptying, and food-intake control, whereas GCGR more prominently increases hepatic fatty acid oxidation, Ketogenesis, amino acid catabolism, and substrate redistribution. When both receptors are activated simultaneously, GLP-1R-related regulation of food intake and glucose can offset part of the hyperglycemic pressure from GCGR, while GCGR adds a hepatic substrate-utilization dimension beyond GLP-1R agonism alone.

5.2 Cotadutide

(1) Dual-Receptor Pharmacological Positioning

Cotadutide is one representative GLP-1R/GCGR dual-receptor agonist. Its pharmacological design covers both GLP-1R-related regulation of food intake and glucose homeostasis and GCGR-related hepatic substrate mobilization, allowing body-weight changes to arise not only from reduced energy intake but also from superimposed changes in hepatic metabolic direction.

(2) Major Pharmacological Characteristics

The GLP-1R component of Cotadutide can reduce Food Intake and participate in Glucose homeostasis control, whereas the GCGR component increases lipid oxidation, amino acid metabolism, and liver-derived metabolic signaling. Its overall weight-loss effect cannot be simply explained as GCGR directly increasing Energy Expenditure, nor can it be fully attributed to GLP-1R-mediated food-intake suppression; both feeding control and substrate utilization participate.

5.3 Survodutide

(1) Basis of Dual-Receptor Action

Survodutide also belongs to the GLP-1R/GCGR dual-receptor agonist system. By simultaneously regulating feeding-related GLP-1R functions and GCGR-mediated hepatic metabolism, it forms a pharmacological profile distinct from GLP-1R agonism alone. The GCGR component extends the research focus further toward hepatic lipids, fatty acid oxidation, and substrate utilization.

(2) Hepatic Metabolic Characteristics

The GCGR-related effects of Survodutide are more appropriately understood together with Liver TG, Ketone Bodies, FGF21, and Glucose homeostasis. If improvement in hepatic lipids is only consistent with overall body-weight or food-intake reduction, this cannot directly demonstrate an independent metabolic contribution from GCGR. The added pharmacological value of GCGR should be reflected in corresponding changes in hepatic substrate-utilization patterns.

5.4 Mazdutide

(1) Dual-Receptor Activity

Mazdutide also belongs to the GLP-1R/GCGR dual-agonist system. Although it acts on the same two receptor classes as Cotadutide and Survodutide, “having dual-receptor activity” does not mean that the three molecules have identical pharmacological profiles. The relative activities of GLP-1R and GCGR and their in vivo exposure both influence the final effects.

(2) Major Pharmacological Characteristics

The overall pharmacology of Mazdutide is jointly composed of GLP-1R-related feeding and glucose regulation and GCGR-related substrate mobilization. Increased GCGR contribution can enhance hepatic lipid and amino acid utilization but can also simultaneously increase the pressure of hepatic glucose output. Therefore, the key to dual-receptor pharmacology is achieving an appropriate balance between the effects of the two receptors.

5.5 Why Do GLP-1R/GCGR Dual Agonists Show Different Pharmacological Profiles?

Although Cotadutide, Survodutide, and Mazdutide share the GLP-1R/GCGR receptor combination, their pharmacological differences do not depend only on whether they activate these two receptors. Relative potency at GLP-1R and GCGR, maximal receptor response, duration of drug exposure, and effective tissue concentrations all alter the relative weight of the two receptors in the overall pharmacological effect. When the GLP-1R contribution is more prominent, pharmacology more readily reflects regulation of food intake and glucose homeostasis; when the GCGR contribution increases, hepatic lipids, Ketogenesis, and amino acid metabolism may be further enhanced, while hyperglycemic pressure also requires greater attention.

6 GIPR/GLP-1R/GCGR Triple-Receptor Agonists

6.1 Retatrutide

(1) Triple-Receptor Pharmacological Positioning

Retatrutide simultaneously activates GIPR, GLP-1R, and GCGR, and its design is not a simple accumulation of three independent weight-loss mechanisms. GLP-1R and GIPR participate in pancreatic islet function, food intake, and energy-homeostasis regulation, whereas GCGR further increases hepatic substrate utilization, lipid oxidation, and amino acid metabolism. The pharmacology therefore spans multiple levels from energy intake to hepatic substrate utilization.

(2) Role of the GCGR Component

Based on established GCGR physiology and pharmacology, the GCGR activity in Retatrutide can contribute to metabolic processes including hepatic lipid oxidation, Ketogenesis, amino acid catabolism, and Ureagenesis; however, the receptor-specific contribution of these processes to the overall pharmacology of Retatrutide requires receptor-dependence evidence. Endpoints such as Food Intake, body weight, Glucose, and hepatic lipids are jointly influenced by GIPR, GLP-1R, and GCGR and therefore cannot be directly attributed to a single receptor.

(3) Characteristics of Triple-Receptor Synergy

Triple-receptor agonism simultaneously alters food intake, pancreatic islet function, hepatic substrate mobilization, and energy balance. Its overall weight-loss pharmacology arises from the combined and mutually balanced actions of different receptors rather than a simple model in which “GLP-1R suppresses food intake and GCGR burns fat.” The relative activity, exposure, and degree of physiological adaptation associated with each receptor jointly determine the final pharmacological profile.

6.2 Differences in GCGR Between Dual- and Triple-Receptor Systems

In GLP-1R/GCGR dual-receptor systems, the metabolic contribution of GCGR is mainly balanced against a GLP-1R regulatory background. After entering a GIPR/GLP-1R/GCGR triple-receptor system, GCGR effects are additionally influenced by pancreatic islet and energy-homeostasis changes introduced by the third receptor. Therefore, the same GCGR activity placed within different receptor combinations does not necessarily produce the same body-weight, hepatic lipid, or Glucose phenotype.

Table 1 Functional Positioning of GCGR in Different Receptor Agonist Systems

7 Why Can GCGR Become a Weight-Loss Target Despite Its Glucose-Raising Effect?

7.1 Weight-Loss Value Comes From Changes in Substrate Utilization

The core function of GCGR is to shift the liver from substrate storage toward substrate mobilization and utilization. Enhanced fatty acid β-oxidation, Ketogenesis, and amino acid catabolism can reduce some lipid storage and increase utilization of energy substrates, while Glycogenolysis and Gluconeogenesis constitute the glucose-raising direction of the same process. GCGR can become a weight-loss target not because its hyperglycemic effect disappears, but because its substrate-mobilization mechanism simultaneously contains pharmacological value that can be used to reduce fat and improve hepatic metabolism.

7.2 Multi-Receptor Synergy Expands Metabolic Benefits

Enhancing GCGR alone readily amplifies both lipid utilization and hepatic glucose output, whereas the addition of GLP-1R or GIPR changes this benefit-risk relationship. GLP-1R-related regulation of food intake and glucose provides a more controllable metabolic background for GCGR, allowing GCGR-mediated hepatic lipid, amino acid, and substrate-utilization effects to become part of multi-receptor weight-loss pharmacology. The key reason GCGR has moved from a traditional glucose-raising-related target into weight-loss drug design is that multi-receptor systems redistribute the relative weight of different metabolic effects.

8 Key Decision Points in GCGR Research

8.1 Decreased Hepatic TG Does Not Equal Enhanced Fatty Acid Oxidation

Reduced hepatic TG can result from GCGR-mediated enhancement of fatty acid utilization but can also occur secondarily to decreased Food Intake and Body Weight. Determining whether lipids truly shift toward oxidation requires evaluation of FFA, Acetyl-CoA, Ketone Bodies, and mitochondrial metabolic indicators rather than assigning mechanism based solely on decreased hepatic TG.

8.2 Body-Weight Reduction Requires Distinguishing Fat Mass From Lean Mass

GCGR simultaneously affects lipid and amino acid metabolism, so overall body-weight reduction does not directly represent ideal fat loss. A reduction in Fat Mass with relative preservation of Lean Mass is more consistent with the desired weight-loss goal. If Lean Mass decreases markedly together with reduced Amino Acids and increased Urea, amino acid catabolism and changes in protein homeostasis should be considered.

8.3 GCGR Metabolic Benefits Must Be Evaluated Together With Glucose Homeostasis

GCGR-mediated promotion of hepatic glucose output is a basic pharmacological effect and cannot be ignored because hepatic lipid or body weight decreases. Ideal GCGR-related pharmacology should increase lipid and substrate utilization while maintaining fasting Glucose, Insulin, and hepatic glucose output within a reasonable range.

8.4 Multi-Receptor Drugs Require Distinguishing the Independent Contribution of GCGR

Changes in body weight, food intake, and Glucose produced by GLP-1R/GCGR and GIPR/GLP-1R/GCGR drugs are jointly generated by multiple receptors. When determining the contribution of GCGR, particular attention should be paid to GCGR-sensitive metabolic dimensions such as hepatic lipids, Ketogenesis, FGF21, Amino Acids, and Urea, together with receptor blockade or other receptor-dependence evidence.

9 GCGR Agonism, Metabolic Mechanisms, and Related Research Products

9.1 GCGR Activation, Blockade, and Signaling Mechanism Research

9.2 Evaluation of Hepatic Glucose Output, Lipid Oxidation, and Energy Metabolism

9.3 Evaluation of the Glucagon-Amino Acid Axis and Nitrogen Metabolism

GCGR coordinates hepatic glucose output, fatty acid oxidation, Ketogenesis, and the amino acid-urea cycle through Gs-cAMP-PKA signaling, and both its fat-reducing potential and glucose-raising limitation arise from enhanced hepatic substrate mobilization. Cotadutide, Survodutide, and Mazdutide use GLP-1R/GCGR dual-receptor synergy to balance food intake, glucose homeostasis, and hepatic substrate utilization, whereas Retatrutide further places the metabolic actions of GCGR within a GIPR/GLP-1R/GCGR triple-receptor regulatory system, transforming GCGR from a traditionally glucose-raising-associated receptor into an important component of multi-receptor weight-loss pharmacology.

For more related articles, please see below:

[1] Exendin-4 and Alzheimer’s Disease

[2] Glucose measurement experiment

[3] A Detailed Guide to the Construction of Animal Models for Metabolic Diseases

[4] Linking Alzheimer’s Disease and Insulin Signaling

[5] Metformin