Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs

Abstract

Obesity, a global public health crisis driven by dysregulated systemic energy homeostasis, is increasingly recognized as a disorder of interorgan communication, with the pancreas and liver serving as central interconnected metabolic hubs. Their bidirectional crosstalk, mediated through neural and humoral pathways, is a key driver of disease progression. Recent breakthroughs have uncovered novel molecular mechanisms amplifying this pathogenic axis: Adipocyte-derived exosomes carrying miR-138-5p directly target pancreatic β-cell SOX4, suppressing insulin secretion and promoting apoptosis, while hepatic RNA demethylase ALKBH5 stabilizes glucagon receptor mRNA and activates lipogenic pathways, exacerbating hyperglycemia and steatosis. Further, colonic inflammation activates hepatic ERK signaling, which is converted into neural signals by the liver and precisely delivered to the pancreas through the liver-pancreas vagus nerve circuit, driving adaptive β-cell proliferation in early obesity by releasing neurotransmitters such as acetylcholine. Traditional pathogenic loops persist: Pancreatic exocrine insufficiency disrupts gut-liver homeostasis, inducing systemic inflammation, and hepatic free fatty acid flux exerts direct and immune-mediated lipotoxicity on pancreatic β-cells, forming a self-perpetuating vicious cycle. Emerging interventions target this axis: GLP-1/GIP dual agonists (e.g., tirzepatide) demonstrate remarkable efficacy in weight loss and non-alcoholic steatohepatitis remission, while time-restricted feeding (e.g., 16:8 regimen) reduces liver fat through circadian and metabolic pathway activation, independent of caloric restriction. This review synthesizes novel interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.

Key Words: Obesity; Pancreatic-liver axis; MiR-138-5p; ALKBH5; GLP-1/GIP dual agonists

Core Tip: This minireview synthesizes the key role of the pancreas-liver axis in the pathogenesis of obesity, highlighting novel molecular mediators (e.g. adipocyte-derived exosomal miR-138-5p and hepatic ALKBH5) and neuroimmune pathways that drive pancreatic-liver crosstalk. It further discusses emerging therapeutic breakthroughs, including GLP-1/GIP dual agonists and intermittent fasting, which aim to improve metabolic outcomes and provide comprehensive strategies for obesity management and prevention of related metabolic diseases.

INTRODUCTION

Research shows that by 2050, more than half of the world's adults will be affected by overweight or obesity. Specifically, it is estimated that the total number of overweight and obese adults (≥ 25 years old) in the world will reach nearly 3.8 billion[1]. The main factors leading to obesity are that the widespread adoption of Western-style diets (e.g., processed foods high in fat and sugar) and physical inactivity. Approximately one billion individuals currently exhibit body fat levels that pose a potential threat to health and life span. Obesity has developed into a global public health crisis, and the long-term imbalance of energy homeostasis is the core cause of obesity[2,3]. This imbalance is not a simple “intake is greater than consumption”, but a systemic pathological state involving the precise regulatory network of the brain, functional disorders of peripheral metabolic organs (such as pancreas and liver), and complex interactions between environmental and behavioral factors[3,4]. This minireview integrates the research progress and the latest therapeutic breakthroughs of the signaling mechanism between tissues in recent years, deeply explores the mechanism of the bidirectional crosstalk of the pancreas-liver axis driving the process of obesity, and provides therapeutic strategies for obesity management based on the new mechanism.

Obesity is not only the accumulation of fat, but also a systemic metabolic disorder. This state involves the dysregulation of signal dialogue between multiple organs. Among them, the pancreas and liver are the key metabolic regulation centers, and the bidirectional “crosstalk” between them is very important for maintaining blood glucose and lipid balance, and the disorder of this link is the core cause of obesity-related metabolic diseases such as type 2 diabetes (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD)[5,6]. The pancreas-liver axis communicates through two main pathways: Neural and humoral. In obesity, both pathways become dysfunctional. Their interaction worsens the disease process.

Within the neural pathway, the pancreas and liver engage in rapid, two-way communication with the brain. This occurs via a precise autonomic network, often called the “neuro-metabolic axis”, which provides immediate regulation of whole-body energy balance. Both organs receive dual innervation from the sympathetic and parasympathetic (mainly vagus) nervous systems. These systems often work antagonistically to maintain equilibrium[7,8]. The sympathetic nerves primarily inhibit and stress-regulate the pancreatic-liver axis. In obesity, the body enters a chronic stress state. Sympathetic nervous system activity becomes excessively enhanced. This sustained excitation inhibits compensatory insulin secretion from beta cells. It also exacerbates hepatic insulin resistance, forming a “neuro-metabolic” vicious cycle[8,9]. The vagus nerve regulates this axis bidirectionally via its afferent and efferent fibers. Research shows hepatic vagal afferent signaling is crucial for glucose homeostasis. Obesity weakens this signal, impairing its normal promotion of insulin secretion. This weakening becomes a key factor in insulin resistance and postprandial hyperglycemia[8,10]. The dysfunction of “neuro-metabolic axis” drives the development of metabolic diseases (Figure 1).

Figure 1 The mechanism diagram delineates the core pathways by which pathological crosstalk between the pancreas and liver drives metabolic dysfunction in the context of obesity. Adipose tissue-derived exosomes carrying miR-138-5p inhibit insulin secretion and promote apoptosis in pancreatic β-cells. Concurrently, mediators such as lipopolysaccharide from intestinal inflammation reach the liver via the portal vein, polarizing Kupffer cells toward a pro-inflammatory M1 phenotype and triggering hepatic inflammation. Functioning as a metabolic hub, the liver exhibits upregulated expression of the RNA demethylase ALKBH5. This enzyme exacerbates hyperglycemia by stabilizing glucagon receptor mRNA and promotes de novo lipogenesis by activating the EGFR-mTORC1 pathway. These processes are reinforced by a vicious cycle mediated by “free fatty acid (FFA) flux”: Insulin resistance leads to increased lipolysis and FFA influx into the liver, aggravating hepatic lipid deposition and inflammation. The stressed liver, in turn, releases inflammatory signaling molecules including small extracellular vesicles and fetuin-A, which further impair pancreatic β-cell function, resulting in insufficient insulin secretion, thereby creating a closed loop that amplifies metabolic dysregulation. Emerging therapies directly target this axis: GLP-1/GIP dual receptor agonists (e.g., Tirzepatide) coordinately act on the pancreas, liver, and central nervous system to promote insulin secretion and alleviate hepatic steatosis and inflammation. Complementarily, the 16:8 time-restricted feeding regimen exerts therapeutic effects by activating key hepatic metabolic pathways (e.g., AMPK/PGC-1α/PPARα) to enhance lipid oxidation and by remodeling the gut microbiota to improve circadian metabolic rhythm. FFA: Free fatty acid; GCGR: Glucagon receptor; EGFR: Epidermal growth factor receptor.

NOVEL MOLECULAR MEDIATING MECHANISMS OF THE PANCREATIC-LIVER AXIS IN OBESITY

In obesity, dysfunction of the pancreatic-liver axis involves not only neural regulation but also relies on a complex humoral communication network composed of numerous molecules and metabolites shuttling between the pancreas and liver. Adipose tissue secretes various bioactive factors, particularly exosomes, while simultaneously transmitting dysregulated signals to both the pancreas and liver, driving and amplifying systemic metabolic abnormalities.

On one hand, adipose tissue directly impairs pancreatic β-cell function through exosomes, constituting the initial hormonal dysregulation signal transmitted to the liver. On the pancreatic side, obesity leads to upregulation of the adipocyte-derived exosome miR-138-5p expression, which directly impairs pancreatic β-cell function by targeting SOX4 to inhibit the Wnt/β-catenin pathway[11]. Concurrently, the β-cell-specific long non-coding RNA (lncRNA) βFaar is downregulated in obese environments due to hypermethylation, thereby reducing its ability to act as a competitive endogenous RNA (ceRNA) and bind to miR-138-5p. This further exacerbates the suppression of key insulin synthesis target genes such as Ins2, NeuroD1, and Creb1 by miR-138-5p, ultimately hindering insulin secretion[12]. This process is environment-dependent and may exert protective effects after metabolic stress alleviation[13,14]. Therefore, under obesity, adipocyte-derived miR-138-5p serves as a critical mediator impairing β-cell function, leading to insufficient insulin secretion and relative glucagon dominance, thereby transmitting the primary abnormal metabolic signal to the liver.

On the other hand, adipocyte-derived exosomes can directly act on the liver, constituting a parallel adipose-liver direct pathway within the pancreas-liver axis. In obesity-related pathological states, specific molecular cargos carried by adipocyte-derived exosomes, such as the lncRNA TCONS_00039830, competitively bind to miR-455-3p as a ceRNA in hepatocytes, thereby upregulating the expression of the fibrotic promoter Smad2 and directly driving hepatic steatosis and disease progression[15].

Upon receiving direct attacks from adipose tissue (exosomal signals) and indirect hormonal dysregulation signals from the pancreas (decreased insulin/relative increase in glucagon), the liver acts as a powerful signal integrator and amplifier. Specifically, obesity upregulates ALKBH5, which is phosphorylated via the glucagon-PKA pathway and translocates to the cytoplasm. There, its m⁶A demethylase activity stabilizes glucagon receptor (GCGR) mRNA, hyperactivating hepatic glucagon response and leading to excessive glucose output and hyperglycemia. This amplified GCGR signal stimulates secretion of fibroblast growth factor 21 (FGF21), which circulates to the pancreas and directly inhibits glucagon secretion from α-cells. Thus, altered GCGR stability enhances hepatic FGF21 production, establishing a remote negative feedback loop that regulates α-cell secretion[16]. In lipid metabolism, ALKBH5 promotes lipogenesis not only by directly binding to-and activating-the intronic enhancer of the epidermal growth factor receptor (EGFR) gene via two specific structural loops (Gln¹⁴⁵-Gly¹⁵² and Cys²³¹-Glu²⁴²), independently of its demethylase activity, which in turn triggers the EGFR-PI3K-AKT-mTORC1 pathway, but also, under non-alcoholic fatty liver disease (NAFLD) conditions, by impairing VPS11dependent autophagy flux as a result of its downregulated expression, thereby further exacerbating lipid deposition[17].

ALKBH5 activity itself is subject to precise epigenetic regulation; for instance, methyl donor folic acid and betaine can reduce hepatic lipid deposition by inhibiting its expression, either by enhancing autophagy or reprogramming lipid metabolism gene networks, respectively, providing potential therapeutic targets for functional intervention[18,19].

More critically, this “adipose-liver” communication is bidirectional and modulable. Hepatic steatosis may feedback-influently alter the secretory phenotype of adipose tissue. Conversely, intervention of adipocyte secretory profiles can directly improve hepatic metabolism. For instance, Nobiletin-derived exosome-like vesicles obtained from adipocyte treatment with nobiletin undergo reprogramming of their miRNA composition. Upon uptake by hepatocytes, these exosomes upregulate proteins promoting lipid oxidation such as SIRT1 and FGF21, while inhibiting key enzymes of lipid synthesis like ACC and FASN, thereby directly alleviating hepatic steatosis[20].

In summary, the disruption of the pancreatic-liver axis in obesity originates from abnormal adipose-pancreatic dialogue (mediated by miR-138-5p), which subsequently leads to hepatic metabolic dysregulation (centered on ALKBH5). Therefore, targeted intervention of the pivotal hepatic molecule ALKBH5 (e.g., via GalNAc-siRNA delivery technology or specific nutritional interventions) holds promise as an integrated therapeutic strategy to simultaneously improve glycemic homeostasis and hepatic lipid metabolism, offering a novel therapeutic perspective for T2DM and its associated fatty liver disease (MAFLD/NAFLD)[16,18]. Precise “regulation” of key nodes in this axis signaling to restore pancreatic-liver dialogue balance represents a promising new pathway for metabolic disease intervention (Figure 1).

In addition to the chronic regulatory network constructed by the aforementioned humoral pathways, the pancreatic-liver axis also harbors a neuro-immunometabolic integration pathway, with both forming a complementary architecture of “humoral slow remodeling-neural rapid response”. The core mechanism of this pathway is the colonic inflammation-hepatic ERK signaling-pancreatic β-cell proliferation axis, which converts intestinal inflammatory signals into direct commands for pancreatic β-cell function through liver-mediated neural signal conversion and relay, achieving conduction speeds on the millisecond scale and playing a critical role in the early compensatory stage of obesity[21]. This pathway originates from gut microecological dysbiosis and barrier dysfunction. High-fat diets induce reduction in beneficial bacteria such as Akkermansia muciniphila, and pathogenic bacteria overcolonize and disrupt the intestinal mucus layer, leading to massive entry of lipopolysaccharide (LPS) and pro-inflammatory factors (TNF-α, IL-6) into the bloodstream[22,23]. These inflammatory signals, on one hand, activate hepatic innate immunity through the portal vein, and on the other hand, more directly stimulate vagal afferent fibers in the intestinal wall, initiating neuro-immune co-transmission. The liver plays a unique role as a “neural signal amplification and conversion hub”: Inflammatory factors entering the liver activate the hepatocellular MEK-ERK1/2 cascade, after which the liver releases neurotensin and glucagon-like peptide-1 through the intrahepatic glial cell-neuronal network and significantly enhances the afferent discharge frequency of the hepatic vagal branch[24], converting chemical signals into electrochemical signals. This metabolism-neural coupling mechanism renders the liver a genuine “signal conversion station” rather than merely a passive inflammatory receptor organ. Signals are precisely relayed to the pancreas via the hepatic-pancreatic vagal loop. Activated hepatic vagal afferent fibers project to the nucleus tractus solitarius in the medulla oblongata, integrate through the arcuate nucleus, and directly innervate pancreatic islets via parasympathetic preganglionic fibers. The neurotransmitters acetylcholine and vasoactive intestinal peptide released from nerve terminals bind to M3 muscarinic receptors and VPAC1 receptors on the β-cell membrane, activating the PI3K-AKT-mTOR pathway, upregulating Cyclin D1-CDK4/6 expression and inhibiting p21/p27 checkpoint factors, thereby driving β-cell proliferation[25,26]. This process exhibits marked inflammatory intensity dependence and time-window specificity: It is significantly activated only in early-stage obesity (8-12 weeks of high-fat diet) when the colonic inflammation score ≥ 3, during which the β-cell proliferation index can increase by 2.3-fold; whereas in chronic obesity, persistent LPS stimulation leads to desensitization of vagal afferents, and excessive ERK phosphorylation instead activates transcriptional suppressors such as ATF3, terminating the proliferation program and initiating apoptosis[21]. Experimental evidence demonstrates that hepatic vagotomy can block 80% of ERK-dependent β-cell proliferation effects but only partially improves insulin resistance, confirming that this neural pathway primarily regulates β-cell mass, whereas humoral pathways more dominantly govern functional quality[21,27]. This neural pathway demonstrates clear functional division of labor and synergy with the miR-138-5p/ALKBH5 axis. The neural pathway rapidly responds to blood glucose fluctuations within 30 minutes postprandially and enhances the first-phase insulin secretion via acetylcholine; whereas the humoral pathway mediates chronic metabolic memory, acting on the SOX4/Wnt pathway to maintain β-cell identity[11]. Together they establish a “mass-quality” dual regulation of β-cell function, jointly constructing the pathological integrity of the pancreatic-liver axis. From a clinical translational perspective, this pathway reveals the existence of an entero-hepato-pancreatic subtype of obese patients, providing targets for precision intervention. Vagal nerve stimulation combined with GLP-1 receptor agonists can synergistically restore early β-cell compensatory capacity and protect nascent cells from lipotoxic apoptosis[26,28], while targeted intestinal barrier repair (e.g., Akkermansia supplementation) can suppress pathological activation of the pathway at its source, forming an “upstream-downstream” whole-axis blockade strategy with interventions targeting hepatic ALKBH5[18,22].

TRADITIONAL PATHOGENIC LOOPS ASSOCIATED WITH THE PANCREATIC-LIVER AXIS

Pancreatic exocrine insufficiency not only leads to disorder of digestion and absorption[29], but also triggers a systemic, persistent inflammatory cascade by disrupting the immunometabolic homeostasis of the gut-liver-pancreas axis. This response originates from insufficient pancreatic exocrine function, resulting in impaired digestion of fats, proteins, and other nutrients within the intestines[30]. Undigested fats and protein breakdown products accumulate in the intestinal lumen, disrupting the ecological balance of the gut environment and altering the metabolic activity and microenvironment of the gut microbiota. This aberrant metabolic milieu rapidly initiates a dual pathological response. On one hand, undigested nutrients and abnormal metabolites produced by the microbiota directly damage intestinal epithelial cells, compromising the physical barrier[31] and leading to a state commonly referred to as “leaky gut”. On the other hand, the altered gut metabolic environment causes a disruption in the microbial ecosystem[32]. In the dysregulated microbiota, an overgrowth of pro-inflammatory microorganisms[33] coincides with a reduction in commensal microbes. LPS produced by pro-inflammatory microorganisms translocates through the compromised intestinal barrier into the bloodstream and intestinal tissue, where it is recognized by innate immune cells such as macrophages, thereby activating the gut’s innate immune system. Immune cells launch an inflammatory response program, releasing large quantities of cytokines and chemokines[34].

Inflammatory mediators released by activated intestinal immunity, bacterial components that breach the barrier, and undigested metabolic waste products are all transported in substantial amounts via the portal vein to the liver[35]. Consequently, the liver endures a combined assault from both gut-derived immune activation and metabolic toxicity. Hepatic immune cells, particularly Kupffer cells, are polarized into an inflammatory M1 phenotype by the massive influx of LPS[36] and transition to a highly inflammatory state, producing and releasing large amounts of inflammatory factors, thereby exacerbating systemic inflammation. Simultaneously, as hepatocytes attempt to process the excess of abnormal lipids and metabolic intermediates, they undergo endoplasmic reticulum stress and mitochondrial dysfunction, leading to oxidative stress[37]. This, in turn, acts as a damage-associated molecular pattern, further activating immune cells within the liver[38] and continuously stimulating and amplifying the release of additional inflammatory factors by these cells. Acute-phase response proteins (such as C-reactive protein) and additional inflammatory factors produced by the liver enter the systemic circulation[39], resulting in a generalized state of low-grade inflammation throughout the body. Inflammatory mediators and activated immune cells disseminate via the bloodstream and return to pancreatic tissue. These inflammatory factors deliver a “second hit” to the already compromised pancreas, not only directly suppressing the secretory function of the remaining acinar cells but also recruiting additional immune cells from the circulation to migrate and infiltrate the pancreatic tissue, exacerbating local inflammation and damage within the pancreas. This process can also induce the immune system to attack its own tissues, leading to autoimmune injury[40], which further disrupts the secretory function of the pancreas.

Under conditions of obesity and insulin resistance, lipolytic activity in white adipose tissue is significantly enhanced. A large amount of free fatty acids (FFAs) flood into the liver via the portal vein, constituting the core starting point of a vicious cycle within the pancreas-liver axis[41]. Studies confirm that in obese individuals, over half of the FFAs accumulating in the liver originate from adipose tissue lipolysis, while insulin resistance further elevates plasma FFA levels, exacerbating ectopic lipid deposition in the liver[42]. This persistent FFA overload itself represents a form of metabolic stress that can directly activate hepatic innate immunity: FFAs bind to receptors such as TLR4 on Kupffer cell surfaces, promoting the release of pro-inflammatory factors like TNF-α and IL-1β, thereby creating a chronic, low-grade inflammatory microenvironment[42,43]. This process aligns closely with the core mechanism of lipid-induced inflammation in the "multiple-hit" hypothesis of fatty liver disease[43]. This "metabolic-immune" interaction amplifies both metabolic dysregulation and inflammatory responses, forming a vicious cycle that ultimately disrupts systemic metabolic homeostasis by impairing insulin signaling and gluconeogenesis regulation (Figure 1)[41,44].

The excessive production and release of FFAs from the liver into the bloodstream exert synergistic “direct-indirect” dual damage on pancreatic β-cells. On one hand, excessive FFAs (such as palmitic acid) taken up by β-cells disrupt intracellular calcium ion homeostasis, leading to intracellular lipid accumulation, endoplasmic reticulum stress, and mitochondrial dysfunction[44]. This disturbance in calcium signaling not only impairs the calcium oscillations essential for insulin secretion but can also activate stress pathways like JNK/p38 MAPK, driving β-cell apoptosis, constituting direct lipotoxic damage[42,45].

On the other hand, hepatic FFA flux indirectly assaults β-cells through immunometabolic cascades. Under lipotoxic stress, small extracellular vesicles (sEVs) released by hepatocytes can migrate directionally to the pancreas and are specifically taken up by intra-islet macrophages[46]. These sEVs drive macrophage polarization towards a pro-inflammatory M1 phenotype by activating surface TLR4 receptors[46,47].

Furthermore, the liver under fatty liver conditions transforms into an active endocrine organ, over-secreting a series of “hepatokines”. Among these, fetuin-A serves as a crucial mediator linking hepatic lipid accumulation to distal islet inflammation. Research confirms that hepatocyte-derived fetuin-A levels are significantly elevated in NAFLD. It not only acts as an endogenous TLR4 ligand to directly activate macrophages in peripheral tissues like the pancreas, promoting the release of pro-inflammatory cytokines such as IL-1β and TNF-α[48], but also directly exacerbates systemic insulin resistance by inhibiting insulin receptor signaling pathways in adipose tissue and skeletal muscle (Table 1)[49]. This action establishes a critical positive feedback loop: Insulin resistance worsens adipose tissue lipolysis and hepatic lipid accumulation, which in turn stimulates the liver to produce more fetuin-A, continuously amplifying systemic inflammation and metabolic dysregulation.

Table 1 Mechanisms of the pancreas-liver axis vicious cycle.

Stage	Core driving factors	Key mechanisms	Pathological effects	Therapeutic entry points	Ref.
Cycle initiation	Enhanced adipose tissue lipolysis, increased FFA influx into the liver	Under obesity and insulin resistance, adipose tissue lipolysis is activated; FFA enter the liver via the portal vein	Hepatic ectopic lipid deposition	Inhibit excessive adipose tissue lipolysis	[41,42]
Hepatic activation	FFA accumulate in the liver and trigger metabolic stress	FFA bind to TLR4 on Kupffer cells, activating innate immunity and releasing pro-inflammatory cytokines	Chronic hepatic inflammation, impaired insulin signaling	Target hepatic inflammatory pathways	[42,43]
Direct attack (pancreas)	Excess circulating FFA taken up by β-cells	FFA induce calcium imbalance, ER stress, mitochondrial damage; activate JNK/p38 MAPK pathways	β-cell dysfunction, apoptosis	Protect β-cells from lipotoxic injury	[42,45]
Indirect attack (pancreas)	Liver releases pathogenic mediators, remotely inducing islet inflammation	sEVs and Fetuin-A activate islet macrophages via TLR4, promoting M1 polarization and cytokine release	Impaired β-cell function, local islet inflammation	Block liver-pancreas communication; target hepatokines	[46-49]
Cycle closure	β-cell dysfunction exacerbates lipid metabolism disorders via feedback	Decreased insulin secretion → reduced inhibition of adipose tissue lipolysis → persistently elevated circulating FFA	Self-reinforcing pathological cycle	Exogenous insulin; enhance β-cell function	[42-46]

FFA: Free fatty acid; ER: Endoplasmic reticulum.

Therefore, hepatic FFA flux not only creates direct lipotoxic pressure but also, by inducing the release of sEVs and fetuin-A, transforms metabolic disorder into signals for cross-organ immune and endocrine attack.

The insulin secretion deficiency resulting from β-cell dysfunction completes the self-amplifying closed loop of this vicious cycle. Declining insulin levels weaken the inhibition of adipose tissue lipolysis, further increasing circulating FFA levels. This directly aggravates hepatic lipid accumulation and metabolic pressure, and persistently activates hepatic immune-inflammatory responses[42,43]. As hepatic lipid accumulation and inflammatory responses continually compound, the liver is prompted to release large quantities of inflammatory signals and specific mediators such as sEVs. These signaling molecules act directionally on pancreatic tissue, further exacerbating local islet inflammation infiltration and β-cell functional damage[46,47]. This pathological signal transmission between the liver and islets establishes a mutually reinforcing pathological link between liver-derived lipotoxicity and islet dysfunction, ultimately constituting a self-perpetuating, positive-feedback vicious cycle.

2025 THERAPEUTIC BREAKTHROUGHS FOR OBESITY TARGETING THE PANCREATIC-LIVER AXIS

Obesity and its associated comorbidities such as T2DM and non-alcoholic steatohepatitis (NASH) have evolved into a global health burden. In 2025, two groundbreaking therapeutic approaches have brought new prospects for obesity treatment, namely the clinical application of dual incretin receptor agonists and the elucidation of the calorie-restriction-independent fat-lowering mechanism of time-restricted feeding (TRF).

GLP-1/GIP dual receptor agonists have been approved for the treatment of T2DM and obesity, demonstrating remarkable efficacy, with superior weight loss effects compared to GLP-1 single agonists[50]. For instance, overweight or obese adults without T2DM who received 15 mg tirzepatide for 72 weeks achieved an average weight reduction of 20.9%[28]. Notably, treatment with 12 mg retatrutide (a triple agonist with GLP-1/GIP activity) for 48 weeks resulted in an even greater weight loss of 24.2%. Both agents significantly reduce visceral fat and hepatic fat content[28]. In the treatment of NASH, tirzepatide improves hepatic steatosis in a dose-dependent manner: The NASH resolution rates in the 5 mg, 10 mg, and 15 mg dose groups were 44%, 56%, and 62%, respectively. Additionally, 55% of patients achieved at least one-stage improvement in liver fibrosis without NASH progression[51], which can correct the metabolic disorders of the pancreatic-liver axis. Mechanistically, this class of drugs acts on both the central nervous system (CNS) and peripheral tissues/organs. In the CNS, activation of receptors in regions such as the hypothalamus suppresses appetite[28], enhances satiety, and in combination with effects on the gastrointestinal tract, delays gastric emptying to reduce caloric intake. In the pancreas, they promote glucose-dependent insulin secretion, reduce β-cell apoptosis, increase β-cell mass[51], and decrease glucagon concentrations, optimizing glucose metabolism. Meanwhile, GIP administration upregulates adiponectin expression in adipose tissue, improving insulin sensitivity[51]. In the liver, these agents reduce de novo lipogenesis, promote fatty acid oxidation to decrease hepatic lipid accumulation, alleviate hepatic inflammation and fibrosis[51], and downregulate the expression of α-smooth muscle actin and type I collagen in liver tissue[52]. In adipose tissue, they regulate metabolism to promote lipolysis, further reducing the metabolic burden on the pancreatic-liver axis[52].

TRF, a core model of intermittent fasting (IF), exerts therapeutic effects such as promoting tissue repair, regeneration, and fat metabolism[53]. Multiple studies have shown that TRF’s mechanism of action aligns with the body’s intrinsic circadian rhythm. A key distinction between TRF and other IF models lies in TRF’s emphasis on matching the eating window with circadian rhythm, hormonal profiles, and metabolic characteristics, whereas other IF models disregard chronobiology. Alignment of the eating period with the active phase of humans (daytime) and rodents (nighttime) facilitates the conversion of glucose in adipose tissue to glycolysis and the tricarboxylic acid cycle. Conversely, eating during the inactive phase disrupts adipocyte circadian rhythm and may induce metabolic disorders[54]. TRF plays a crucial role in resetting the disrupted circadian rhythms of the liver and pancreas. By restoring the rhythmic expression of hepatic clock genes and downregulating aldehyde oxidase 1 (AOX1) activity, TRF inhibits hepatic steatosis[55]. For the pancreas, TRF resynchronizes the pancreatic circadian clock, enhances the rhythmicity of insulin secretion, improves glucose uptake and utilization in peripheral tissues, and enhances insulin sensitivity and glucose homeostasis without significant caloric restriction[56]. TRF also significantly increases the richness and diversity of the gut microbiota and restores its normal circadian fluctuations[55]. In animal experiments, six weeks of TRF reduced mouse liver weight, liver index, and hepatic lipid deposition area by approximately 50%. Compared to calorie restriction groups, TRF exhibited more pronounced effects in regulating plasma and hepatic lipid homeostasis[55]. At the cellular level, TRF regulates adipocyte thermogenesis through rhythmic creatine metabolism, enhances the expression amplitude of core clock genes (e.g., BMAL1) in adipose tissue, activates the futile creatine cycle, promotes uncoupled respiration, and thereby increases energy expenditure-an effect independent of reduced caloric intake[57]. Furthermore, TRF upregulates the expression of genes related to glycolysis and the tricarboxylic acid cycle in adipocytes during the active phase, improving glucose utilization and lipid catabolism, which further validates its fat-burning effect independent of calorie restriction[57].

In conclusion, these two groundbreaking strategies-dual incretin receptor agonists and TRF-have opened up novel avenues for obesity treatment. They form a complementary framework of pharmacological and non-pharmacological interventions, and exhibit substantial application potential in the field of obesity management (Figure 1).

CONCLUSION

The root of obesity and metabolic complications lies in energy homeostasis imbalance across multiple organs. The pancreas-liver axis serves as the central hub within this regulatory network. This review synthesizes recent evidence from neuroanatomy, molecular mediators, and traditional pathogenic loops. The evidence confirms a key conclusion: Dysregulated function and signaling between the pancreas and liver drive the onset and progression of insulin resistance and T2DM, etc. The clinical success of GLP-1/GIP dual agonists stems from their coordinated regulation of the pancreas-liver axis. This success provides strong clinical support for therapeutic strategies that target this axis.

Metabolic disorders in different patients may be dominated by different links in the pancreatic-liver axis. In the future, it is necessary to identify the subgroups of patients with “hepato-genic”, “pancreato-genic” or “entero-genic” diseases through multiple groups of classification, and formulate individualized treatment plans. In addition, exploring the combination treatment strategy of pharmacological intervention (such as GLP-1RA) and lifestyle intervention (such as time-restricted feeding) or targeting intestinal flora (such as supplementing specific probiotics such as Akkermansia) may achieve synergistic effects greater than the sum of their parts.

In conclusion, the in-depth exploration of the mechanism of pancreatic-liver crosstalk has continuously promoted the innovation of treatment strategies for obesity and related metabolic diseases. In the future, there will be more multidimensional and individualized therapies that integrate multi-target drugs, precise lifestyle guidance, neural regulation and micro-ecological intervention.