Association between intra-pancreatic fat deposition and diseases of the exocrine pancreas: A narrative review

Abstract

Intrapancreatic fat deposition (IPFD) has garnered increasing attention in recent years. The prevalence of IPFD is relatively high and associated with factors such as obesity, age, and sex. However, the pathophysiological mechanisms underlying IPFD remain unclear, with several potential contributing factors, including oxidative stress, alterations in the gut microbiota, and hormonal imbalances. IPFD was found to be highly correlated with the occurrence and prognosis of exocrine pancreatic diseases. Although imaging techniques remain the primary diagnostic approach for IPFD, an expanding array of biomarkers and clinical scoring systems have been identified for screening purposes. Currently, effective treatments for IPFD are not available; however, existing medications, such as glucagon-like peptide-1 receptor agonists, and new therapeutic approaches explored in animal models have shown considerable potential for managing this disease. This paper reviews the pathogenesis of IPFD, its association with exocrine pancreatic diseases, and recent advancements in its diagnosis and treatment, emphasizing the significant clinical relevance of IPFD.

Key Words: Intrapancreatic fat deposition; Pancreatic steatosis; Nonalcoholic fatty pancreas disease; Pancreatitis; Pancreatic cancer

Core Tip: Intrapancreatic fat deposition (IPFD) is a prevalent and clinically significant condition linked to exocrine pancreatic diseases, obesity, age, and sex. Although the mechanisms driving IPFD remain poorly understood, factors like oxidative stress, gut microbiota alterations, and hormonal imbalances are thought to contribute. Imaging is currently the main diagnostic method, but emerging biomarkers and scoring systems offer new diagnostic avenues. While there are no established treatments, glucagon-like peptide-1 receptor agonists and novel experimental therapies show promise. This review highlights recent insights into IPFD’s pathogenesis, diagnosis, and therapeutic potential, underscoring its clinical importance in pancreatic health management.

INTRODUCTION

In recent years, obesity has emerged as a global issue, with the number of overweight and obese individuals increasing steadily across all age groups and socioeconomic strata, particularly in developed and some developing countries[1]. Research on obesity has revealed that the fat distribution pattern within the body plays a critical role in the development of obesity-related abnormalities in glucose and lipid metabolism. This uneven distribution can have multiple adverse effects on health. When triglyceride and free fatty acid (FFA) levels in the bloodstream exceed the metabolic capacity of adipose tissue, the excess lipids cannot be effectively processed or stored, leading to their accumulation in nonadipose tissues. This phenomenon, known as “ectopic fat deposition”, can occur in several vital organs - including the liver, heart, kidneys, and pancreas - potentially compromising their normal functions[2]. Among the various forms of ectopic fat deposition, fat accumulation in the pancreas has attracted increasing attention in recent years. This condition has been described in the literature using various terms, such as “pancreatic steatosis”[3,4], “fatty pancreas”[5,6], “pancreatic lipomatosis”[7,8], “fatty infiltration of the pancreas”[9,10], “nonalcoholic fatty pancreas disease”[11-13], and “intrapancreatic fat deposition”[14,15]. The use of these different terms reflects the diversity and complexity of the current understanding of this condition (Table 1).

Table 1 Nomenclature of the fat in the pancreas.

Name	Definition
Pancreatic steatosis	The description of fat accumulation in the pancreatic gland
Fatty pancreas	Fatty accumulation in the pancreas
Pancreatic lipomatosis	The most frequent benign pathologic condition of the adult pancreas
Fatty infiltration of the pancreas	Deposition of a large amount of fat in the pancreas
Nonalcoholic fatty pancreas disease	The accumulation of fat in pancreatic tissue (located within adipocytes)
Intra-pancreatic fat deposition	Diffuse presence of fat (measured on a continuous scale) within the pancreas; excludes peri-pancreatic (extra-lobular) fat

In this paper, we use the term “intrapancreatic fat deposition (IPFD)” to describe the abnormal accumulation of fat in the pancreas, which is defined as the diffuse presence of fat within the pancreas, excluding peripancreatic (extralobular) fat[16]. IPFD is considered a manifestation of metabolic syndrome (MetS) within the pancreas and encompasses a spectrum of pathological processes, ranging from pancreatic fat deposition to inflammation and subsequent fibrosis. Recent studies have shown that IPFD is associated not only with localized pathological changes in the pancreas but also with broader metabolic dysfunction and systemic inflammation[17,18]. Some researchers have even proposed that IPFD could represent a form of pancreatic aging, with no significant clinical implications in the absence of other risk factors[19]. Therefore, further research into IPFD is crucial to better understand its pathophysiological mechanisms in obesity and MetS, which could provide new directions for prevention and treatment strategies. In this review, existing studies on the mechanism of IFPD and the influence of current treatments on IFPD are discussed in depth, and the correlation between IFPD and exocrine diseases, such as pancreatitis and pancreatic cancer, is emphasized to report new progress in the pathogenesis and treatment of IFPD.

Prevalence

Currently, large-scale epidemiological data to accurately assess the prevalence of IPFD are lacking. However, a cross-sectional study conducted in Indonesia reported that the prevalence of IPFD was approximately 35%[20], whereas a prospective single-center study in the United States reported a prevalence rate of 27.8%[21]. In children, the estimated prevalence of IPFD is approximately 10%[22]. Another retrospective study involving 102 pediatric patients aged 5-18 years indicated that IPFD was relatively common in this group, with a prevalence rate of approximately 26.5%, and it was associated with comorbidities such as diabetes and dyslipidemia[23]. In a study from Japan, the detection rate of IPFD using abdominal ultrasound in a health screening population was reported to be 46.8%[24]. This high detection rate might have been influenced by the older age of the study participants (59.5 ± 13.2 years) and the inclusion of individuals who consumed alcohol. Another study conducted in Chile involving 203 patients without other pancreatic diseases reported that IPFD was detected in approximately 30% of the population[25]. In contrast, a population survey from Yangzhou, China, revealed a lower prevalence of IPFD, 2.7% among the 1228 individuals screened, which was lower than the rates reported in other studies conducted in China and other parts of Asia[26-30]. A meta-analysis of IPFD studies suggested that the overall prevalence was approximately 33% and strongly associated with MetS[31]. The variability in the prevalence of IPFD across different populations could be attributed to regional differences and the methods used for detection, but overall, approximately one-third of the population appears to have IPFD.

Smoking has been identified as a risk factor for IPFD. Research has demonstrated that nicotine exposure during breastfeeding can induce pancreatic steatosis in adult rats[32]. Furthermore, the prevalence of sedentary lifestyles and high-calorie diets has led to an increasing number of obese people. Multiple studies have indicated that body mass index (BMI) and obesity are associated with IPFD[33-35]. Some studies have suggested that the prevalence of IPFD increases with age[28,36] and that IPFD is associated with nonalcoholic fatty liver disease. Moreover, triglyceride, lipoprotein, and adiponectin levels are independent risk factors for non-alcoholic fatty pancreatic disease exacerbation[28]. Other studies have shown that racial and ethnic differences also play a role as risk factors for IPFD, with Hispanic individuals exhibiting a higher risk of developing IPFD than African Americans[37,38]. A retrospective cohort study reported that IPFD was age-related and that the association between pancreatic fat and MetS depends on sex[39]. Age and lifestyle-related diseases may also increase the risk of IPFD[24,40].

Pathogenesis

The pathophysiological mechanisms of IPFD are not yet fully understood. Current research suggests that this disease is primarily associated with excessive fatty deposition and fatty replacement in pancreatic tissue, which involves both intralobular fat and interlobular fat[16,17]. Several processes and components may contribute to the development of IPFD, including the accumulation of excess fat within pancreatic β-cells and acinar cells, the replacement of apoptotic acinar cells with intralobular fat, the transdifferentiation of acinar cells into adipocytes, and the presence of interlobular fat cells rich in triglycerides and pancreatic stellate cells.

Oxidative stress (OS) refers to a state of imbalance between oxidation and antioxidants in the body, which can disrupt normal oxidative protein folding. Endoplasmic reticulum (ER) stress is a cellular stress response caused by abnormal protein folding and modification in the ER. Under stress conditions, OS is also the cause of ER stress, which leads to the development of pathogenic states[41]. OS has been associated with MetS and diabetes. Both IPFD and nonalcoholic fatty liver disease are considered manifestations of MetS in different organs. In the “two-hit” hypothesis of nonalcoholic steatohepatitis, OS is viewed as the “second hit” (the “two-hit” theory suggests that peripheral insulin resistance (IR) leads to the accumulation of FFAs in the liver, causing liver steatosis, which constitutes the first hit; lipid accumulation sensitizes the liver to OS, triggering a series of liver toxicity events that cause inflammation, forming the second hit); therefore, OS may also play a crucial role in the development of IPFD[42,43]. OS can lead to the accumulation of misfolded proteins, inducing ER stress. The interaction between OS and ER stress plays a significant role in cellular homeostasis dysfunction and may be associated with accelerated lipid droplet (LD) formation in the pancreas[17,41]. ER stress is closely linked to fat metabolism and influences lipid synthesis, storage, and utilization by altering lipid metabolism and LD dynamics, which can lead to lipotoxicity and metabolic disturbances[44]. In mice with glucose metabolism disorders, many lipid compounds have been observed inside and outside pancreatic cells in the form of LDs, along with abnormal ER structural abnormalities and mitochondrial structural transformation. These findings suggest a potential correlation between IPFD and OS[45]. A 2021 study using a high-fat diet model in mice also suggested that ER stress might be involved in IPFD[46].

Gut microbiota have a significant impact on human health and disease. In recent years, many metabolic diseases, including obesity, type 2 diabetes, nonalcoholic liver disease, metabolic heart disease, and malnutrition, have been linked to gut microbiota. Anatomically, the pancreas is connected to the gastrointestinal tract via the pancreatic duct, where a vast array of microbiota resides, which may influence pancreatic homeostasis and the development of various pancreatic diseases[47]. A 2024 study of the gut-pancreas axis revealed that the IPFD was highly correlated with the metabolic products of gut microbiota, such as trimethylamine N-oxide and butyrate levels, suggesting a possible link between IPFD and gut microbiota[48].

IPFD also seems to be associated with hormonal imbalances. Adipose tissue is an important endocrine organ that secretes various adipokines to regulate metabolic homeostasis. In response to external stimuli, adipose tissue can undergo functional impairments, structural changes, and phenotypic alterations[49,50]. Studies have shown that the gut hormone guanylin peptide can prevent β-cell steatosis under lipotoxic conditions and reduce fat accumulation in the pancreas[51]. Guanylin peptide also has a complete expression system in the pancreas and is involved in regulating electrolyte homeostasis. In palmitate-treated RIN-m5F β-cells, guanylin peptide downregulated the expression of lipogenic factors, such as Srebf1, Mogat2, and Dgat1, reducing both basal and palmitate-induced steatosis. Additionally, ghrelin appears to be related to IPFD[52]. Ghrelin, which is produced primarily by ε-cells in the fetal pancreas, may contribute to ectopic fat deposition by increasing the release of FFAs from adipocytes[53,54]. In the four models used in this study, ghrelin in the fasted state was significantly associated with IPFD, whereas postprandial pancreatic fat accumulation was not related to any of the gut hormones involved in the study. These findings suggest that gut-brain axis signaling might play a role in hormone regulation during this process.

Furthermore, previous studies have shown that the regulatory factor serine/threonine protein kinase 25, which is associated with ectopic fat storage, metabolic inflammation, and fibrosis, can exacerbate the severity of IPFD in mouse models, although the underlying mechanisms remain unclear[55]. Low levels of uric acid may also inhibit pancreatic steatosis via the glycerophospholipid metabolic pathway in mice[56].

DISEASE

Pancreatitis

Excessive IPFD may disrupt normal pancreatic function and affect the secretion function of the pancreas. Now IPFD, as an increasingly common pancreatic disease, plays an important role in pancreatitis, the most common exocrine disease of the pancreas. In patients with pancreatitis, pancreatic fat deposition levels are elevated[52,57]. A 2021 study evaluated the association between IPFD and acute pancreatitis (AP), suggesting that IPFD might be a risk factor for AP and hypothesizing that IPFD may mediate the onset of AP by inducing endogenous tissue stress or low-grade inflammation[58]. Recently, a prospective cohort study involving 42599 patients demonstrated a significant association between increases in IPFD and AP[59]. Another 2023 study explored the relationship between IPFD and the severity of AP, indicating that IPFD might be an important indicator of the severity of AP[60]. In this study, patients with IPFD had higher systemic inflammatory response syndrome scores than those without IPFD[60]. IPFD is associated with substantial damage in AP. The increased volume of pancreatic fat cells in obese individuals might have caused more extensive pancreatic necrosis during AP. Moreover, the increased systemic inflammatory response in AP might be related to adipokines released from peripancreatic adipose tissue[61,62]. Additionally, IPFD was associated not only with the occurrence of AP but also with pancreatic size and exocrine function following an AP episode[63] (Figure 1). Currently, research on the association between IPFD and chronic pancreatitis is limited. A six-year prospective cohort study revealed that IPFD may be a risk factor for subclinical chronic pancreatitis[5]. Another retrospective study involving 118 patients indicated that chronic pancreatitis was associated with higher pancreatic fat scores[64]. A 2022 quantitative magnetic resonance imaging (MRI) study assessing chronic pancreatitis reached a similar conclusion[65].

Figure 1 Mechanism of intrapancreatic fat deposition-induced pancreatitis. In intrapancreatic fat deposition, chronic endogenous tissue stress and dysfunction initiate a persistent inflammatory response. Over time, this inflammation escalates, eventually manifesting as clinically significant acute pancreatitis. Additionally, adipokines secreted from adipose tissue surrounding the pancreas further exacerbate systemic inflammation. IPFD: Intrapancreatic fat deposition; AP: Acute pancreatitis.

Pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancy, accounting for approximately 90% of malignant pancreatic tumors. By 2030, PDAC is projected to become the second leading cause of cancer-related death[66]. IPFD is currently considered significantly associated with PDAC, and IPFD is believed to promote the spread of PDAC and worsen the prognosis of tumor patients[59,67-71]. A recent prospective cohort and Mendelian randomization study suggested that IPFD was a high-risk factor for PDAC and may not be related to overall body fat[14]. This association may involve inflammatory and cancer-promoting signals from local adipocytes. This study also revealed that the characteristics of pancreatic steatosis potentially differ from those of fat deposition in other organs[14]. Another study involving overweight patients revealed that pancreatic steatosis indicated by computed tomography (CT) before the diagnosis of PDAC was an independent risk factor for PDAC[72].

Fatty infiltration in the pancreas falls into one of two categories: Intralobular fatty infiltration and extralobular fatty infiltration. The lipid compositions of these types differ and play distinct roles in oncogenesis development and progression, especially in obese patients. In patients with malignant tumors, pancreatic intraepithelial tumors affect specific lipids found in extralobular fatty infiltration, whereas obesity affects the composition of both intralobular and extralobular fatty infiltration[9]. This study also suggested that intralobular fatty infiltration plays a major role in acinar modifications and the development of precancerous lesions in obese patients. In contrast, extralobular fatty infiltration was more likely to contribute to the progression of PDAC.

LDs are organelles that regulate intracellular lipid homeostasis. In healthy tissues, intrapancreatic adipocytes and LDs store lipids for metabolic needs. In cases of obesity or visceral fat accumulation, LDs increase the intracellular levels of cytotoxic FFAs, inducing mitochondrial damage and the unfolded protein response[73]. Additionally, IPFD may drive the development of early pancreatic cancer, with inflammatory processes in the fat-rich pancreas being a crucial trigger for PDAC development[74,75]. High levels of proinflammatory adipokines and cytotoxic FFAs released by pancreatic fat cells contribute to the recruitment of tumor-promoting immune cells and create a microenvironment conducive to cancer formation. Furthermore, the size of LD pools in cancer cells is an important determinant of tumor metastatic potential. In addition, tumor lipid reprogrammed metabolism is potentially regulated by intrapancreatic adipocytes and abundant LDs[75,76] (Figure 2).

Figure 2 Mechanism of intrapancreatic fat deposition-induced pancreatic cancer. During intrapancreatic fat deposition, the accumulation of intracellular lipid droplets leads to an elevation in toxic free fatty acids, which induces mitochondrial dysfunction and triggers the unfolded protein response. These events contribute to the development of pancreatic cancer. Moreover, pro-inflammatory cytokines and cytotoxic fatty acids released by pancreatic adipocytes in the intrapancreatic fat deposition environment foster an inflammatory microenvironment. This microenvironment facilitates the proliferation of transformed cells with carcinogenic potential by promoting the recruitment of tumor-supportive immune cells. IPFD: Intrapancreatic fat deposition; PDAC: Pancreatic ductal adenocarcinoma; FFA: Free fatty acid.

Exocrine dysfunction

IPFD is also associated with impaired pancreatic exocrine function. Fecal elastase-1, a highly stable enzyme, is commonly used to assess pancreatic exocrine function. Individuals with impaired pancreatic exocrine function harbor significantly more pancreatic fat, which negatively correlated with fecal elastase levels in the tested population[77,78]. Lipids may affect acinar cells or replace lost acinar cells and necrotic apoptotic endocrine tissue, leading to pancreatic exocrine dysfunction[77].

Others

Pancreatic fistula is a common and serious complication following pancreatic surgery. The development of postoperative pancreatic fistula is associated with the softness of the pancreatic parenchyma, and IPFD can increase pancreatic gland softness[79-81]. Additionally, MetS and type 2 diabetes have been linked to IPFD, as obesity - a condition closely associated with MetS - leads to fat accumulation in various organs, including the pancreas. IPFD is increasingly regarded as a manifestation of MetS within the pancreas[82]. Several studies have reported elevated pancreatic fat content in patients with type 2 diabetes, and this increase may also occur in individuals with pre-diabetes[18,83,84]. Furthermore, a 2014 study indicated that IPFD is associated with carotid atherosclerosis and may serve as a risk marker for cardiovascular disease[85] (Table 2).

Table 2 Disease.

Disease	Mechanism	Ref.
Pancreatitis	Inflammation induced by fat deposition and adipokine secreted by adipose tissue promote the occurrence and development of pancreatitis	Sbeit and Khoury[58], 2021; Tirkes et al[64], 2019
Pancreatic cancer	The inflammatory process of the pancreas in the context of fatty pancreas is an important inducible factor, and the different types of fatty infiltration of the pancreas also play a role in the different processes of tumor development	Frendi et al[9], 2024; Lilly et al[75],2023
Exocrine dysfunction	Lipids have affected acinar cells or replaced lost acinar cells and necrotic apoptotic endocrine tissue	Tahtacı et al[77], 2018
POPF	IPFD increases the softness of the pancreatic glands and raises the risk of POPF	Gaujoux et al[79], 2010; Dei et al[81], 2022
Type 2 diabetes mellitus	IPFD leads to dysfunction of islet beta cells, affecting insulin secretion and exacerbating insulin resistance	Lu et al[83], 2019; Chin et al[84], 2021
Metabolic syndrome	IPFD is associated with components of metabolic syndrome such as obesity, hyperglycemia, dyslipidemia, etc	Smits and van Geenen[82], 2011
Cardiovascular disease	IPFD is associated with abnormal fat distribution and metabolic disorders throughout the body, which may affect the development of atherosclerosis	Kim et al[85], 2014

IPFD: Intrapancreatic fat deposition; POPF: Postoperative pancreatic fistula.

Diagnosis

At present, no universally accepted standard exists for diagnosing pancreatic fat content, and imaging remains the primary method for assessing and diagnosing IPFD. Histological examination of pancreatic samples has revealed fat cell infiltration and LDs localized within acinar cells[42,86,87]. However, due to the retroperitoneal location of the pancreas[31], pancreatic biopsy is challenging. Due to the uneven distribution of fat in the pancreas among IPFD patients, histological examinations might not have accurately reflected fat deposition throughout the entire pancreas. Furthermore, pancreatic tissue samples can be obtained only during pancreatic surgery, which is limited to specific indications. Most individuals at risk for IPFD have never undergone pancreatic surgery, making the specific evaluation of pancreatic fat content via histological methods difficult.

Imaging techniques, including abdominal ultrasound, endoscopic ultrasound, CT, proton magnetic resonance spectroscopy, and MRI, are commonly used to detect pancreatic fat content. An abdominal ultrasound diagnosis of IFPD is usually compared with the echoes of the liver, kidney cortex, and spleen; the main manifestation of IFPD is diffuse enhancement of the pancreatic parenchymal echo[27,30,88,89]. Ultrasound evaluation of the echogenicity of the pancreas may have predictive value for prediabetes/diabetes[89,90]. Ultrasound shear wave dispersion measurements are considered useful for objectively assessing changes in fat content in the pancreas because of their good reproducibility[91]. Additionally, endoscopic ultrasound may provide more detailed pancreatic images and simultaneously image other organs, making it more reliable for assessing the degree of pancreatic fat infiltration[21,92,93]. Compared with the other two impact tests, ultrasound is widely available and inexpensive, and endoscopic ultrasound can simultaneously image neighboring organs, such as the liver and spleen, in real time. These advantages make ultrasound widely used in the determination of pancreatic fat content. However, transendoscopic ultrasonography is invasive and difficult to evaluate as a whole. Therefore, both abdominal ultrasound and endoscopic ultrasound are associated with difficulties in attempts to accurately assess the overall pancreatic fat content, which limits their application in the diagnosis of IFPD.

CT can provide a (semi)quantitative analysis of pancreatic fat via attenuation of the pancreas, depending on the contrast with the spleen[94,95], with unenhanced CT often providing more accurate results than enhanced CT[96]. The combination of quantitative CT parameters, specifically pancreas attenuation and pancreas surface lobularity, enhances the accuracy of detecting pancreatic fat infiltration. In the validation cohort, this method yielded negative and positive predictive values of 91% and 70%, respectively[94]. A visceral fat tissue area threshold of ≥ 107.2 cm² may predict pancreatic fat degeneration[97]. CT attenuation indices and visual assessments of CT images have aided in studying the clinical relevance of IPFD with impaired glucose metabolism and type 2 diabetes[98,99]. Additionally, the CT fat volume fraction can automatically measure the severity of IPFD[100]. Moreover, quantitative CT assessments of pancreatic fat infiltration location and content are accurate[101], which could help in preoperative planning and postoperative complications[102-105]. Compared with other imaging methods, CT is more accurate and convenient for measuring pancreatic volume and abdominal fat content. However, CT involves potential radiation exposure and is relatively expensive, and it does not show a significant advantage over ultrasound in the quantitative assessment of pancreatic fat[18,97].

MRI is based on signal differences between water and fat. It offers better soft tissue contrast and higher sensitivity, playing an important role in the assessment and clinical application of IPFD. Chemical shift-encoded MRI is based on the difference in resonant frequencies caused by the different distributions of the surrounding electron clouds of hydrogen protons in water and adipose tissue, and its measured fat fraction is highly correlated with the actual fat fraction[16,36,106]. It maps the region of interest in the caput, corpus, and cauda of the pancreas to minimize the influence of other visceral fat. Compared with nuclear magnetic resonance spectroscopy, it needs less time and is more convenient. The proton density fat fraction is an objective measure of the intrinsic properties of tissues. The use of MRI to quantify the proton density fat fraction can standardize and objectively measure fat content, with good repeatability, and can reflect the overall fat content[107-109]. Moreover, multiparametric MRI of the pancreas provides more reliable and accurate fat quantification than conventional MRI[110]. 1H-magnetic resonance spectroscopy is considered the gold standard to noninvasively measure pancreatic fat content, with accuracy comparable to that of histological and biochemical markers[111]. Another new technique, 3D-IDEAL (iterative decomposition with echo asymmetry and least squares estimation), provides faster imaging, less signal contamination from surrounding fat, and reduced susceptibility to respiratory motion effects, potentially offering superior performance in evaluating fat content in small organs such as the pancreas[112,113]. However, MRI-related imaging technology is also associated with several problems, such as high costs and long scanning intervals, which affect its application.

With the increasing influence of artificial intelligence (AI) on diagnostic technologies, recent studies have proposed that AI-assisted MRI and CT models could be utilized as objective, automated, and reproducible tools for assessing pancreatic fat infiltration[114]. Additionally, several emerging biomarkers have been identified as potential screening tools for patients with IPFD. The level of serum fibroblast growth factor-21 (FGF-21), a cytokine intimately involved in glucose and lipid metabolism, has been shown to be closely associated with metabolic diseases. A previous study indicated that serum FGF-21 was strongly linked to IPFD and could serve as a reliable screening marker for the disease[115]. However, the transabdominal ultrasound used in the diagnosis of IPFD in this study can only be used to identify is the presence fat infiltration in the pancreas, not its quantity. Therefore, the correlation between the serum FGF-21 level and the degree of fat infiltration in the pancreas was difficult to explore in this study, and whether the serum FGF-21 level is a prognostic indicator for patients with an IPFD also needs to be further explored. In the lipidomic analysis of serum, triglycerides were identified as significant markers for the development of IPFD following AP, which can be used to assess and identify individuals at high risk of IPFD[116]. IPFD in healthy nonobese individuals in this study was not significantly associated with any markers of lipid metabolism, and new prospective longitudinal studies are needed to validate this finding and to focus on changes in IPFD over time and its association with markers of lipid metabolism. Furthermore, an Egyptian study revealed statistically significant differences in fatty acid-binding protein-1 (FABP-1) levels based on the presence of fatty deposits among fatty pancreas patients[117]. Thus, FABP-1 may be a direct and noninvasive predictor of IPFD[117]. Although the diagnosis of IPFD was graded in this study, verifying whether the level of FABP-1 was correlated with the severity of IPFD was difficult because the diagnosis was based on transabdominal ultrasound, and the correlation between the FABP level and the IPFD grade was not discussed. The hypertriglyceridemic waist phenotype, a clinical indicator of visceral fat accumulation that reflects visceral obesity and metabolic disorders, was found to be significantly associated with IPFD and could be a useful screening reference, particularly for Asians who are underweight but prone to developing visceral obesity[118]. A new diagnostic score that includes obesity, hyperlipidemia and fatty liver has also been developed to initially identify IPFD[119]. Common anthropometric parameters and biochemical markers also demonstrated good predictive value, including weight-related parameters such as BMI and triglyceride-related measures, with a combination of multiple parameters offering potentially greater predictive accuracy[120].

TREATMENT

Nonpharmacological treatment

Currently, the clinical significance and related mechanisms of IPFD are not fully understood, and routine, effective management strategies are lacking. Lifestyle modification appears to be the most effective treatment approach available. Exercise is considered beneficial in reducing ectopic fat accumulation in the pancreas[121]. However, this finding was based on a small study focusing only on individuals with prediabetes and type 2 diabetes. The effects of exercise on pancreatic fat accumulation in other normal populations, as well as the optimal exercise duration and intensity, remain unstudied. Additionally, low-calorie diets have been found to help reduce pancreatic fat accumulation in type 2 diabetes patients[122]. Altering the intake of other nutrients also seemed to influence the incidence of IPFD. Lactoferrin, an iron-binding protein with numerous biological functions and significant immunomodulatory effects, was found to improve pancreatic fat levels and function and to mitigate weight gain when administered as a supplement[123]. Probiotics have shown great potential in inhibiting the development of IPFD and alleviating related metabolic and pathological abnormalities[124]. Moreover, reducing branched-chain amino acid intake might improve IPFD by activating the liver kinase B1/AMP-activated protein kinase pathway or inhibiting the mechanistic target of rapamycin complex 1 pathway[125]. However, these dietary changes have only been validated in animal models and lack supporting clinical data.

Lifestyle modifications appear to be a promising approach for the prevention and treatment of IPFD. However, existing studies examining the effects of lifestyle changes on pancreatic fat content have primarily focused on diabetic patients and animal models, leaving a gap in data across broader population samples. Additionally, risk factors for IPFD, such as smoking, high BMI, and obesity, are strongly linked to lifestyle habits, suggesting that future studies targeting lifestyle interventions could potentially enable early intervention and achieve preventive effects for IPFD.

Pharmacotherapy

Evidence-based medicine for the pharmacological treatment of IPFD is lacking. Glucose-lowering drugs, lipid-regulating medications, angiotensin II receptor blockers, somatostatin receptor agonists, and antioxidants are promising candidates for improving IPFD[126]. In preclinical studies, glucose-lowering drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, lipid-regulating statins, pancreatic lipase inhibitors, somatostatin receptor agonists such as octreotide, and antioxidants such as ascorbic acid have shown favorable results[127]. Metformin reduced IPFD severity in animal models, but imaging studies before and after metformin administration did not reveal significant changes in the clinical setting[128]. Newer therapies [such as GLP-1 receptor agonists, DPP-4 inhibitors, and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors] and classical therapies (such as statins, metformin, and angiotensin II receptor blockers) at least partially reduce pancreatic ER stress[129]. The administration of the GLP-1 receptor agonist liraglutide in high-fat diet-fed mouse models suggested that it might reduce IPFD by modulating ER stress pathways and downstream apoptosis signals[46,130,131]. A retrospective study in Japan suggested that SGLT-2 inhibitors might reduce pancreatic fat accumulation in type 2 diabetes patients, but this study had a small sample size and could not exclude the effects of other antidiabetic drugs on fat accumulation, indicating that the results were only suggestive[132,133]. A 2021 study of the SGLT-2 inhibitor empagliflozin revealed that it effectively reduced liver fat in mice and humans, but the changes in pancreatic fat were not statistically significant[134].

Additionally, some new drug therapies have appeared to offer new possibilities based on animal model studies. Oral glucosamine may provide some protection against fat accumulation and pancreatic tissue damage in rats fed a high-fat diet[135]. Sodium butyrate improved metabolic disorders as well as pancreatic lipid accumulation and uric acid metabolism abnormalities in rats[136]. Simvastatin was found to improve pancreatic fat accumulation[137,138]. Specifically, the simvastatin-A indica extract combination resulted in a lower pancreatic fat percentage than the single treatment, although the difference was not statistically significant. The active compound 6-gingerol from ginger appeared to reduce pancreatic lipid accumulation by lowering body weight, which in turn reduced OS and inflammation in the pancreas to improve the incidence of IPFD[139]. Additionally, benzyl propylene glycoside, a cGAS-STING pathway modulator, was found to inhibit pancreatic inflammation and fibrosis in high-fat high-sucrose diet-fed rat models, improving IPFD and reducing metabolic disorders in nonalcoholic fatty pancreatic inflammation animal models[140].

Currently, there is no evidence-based medical guideline recommending specific, effective drugs for the treatment of IPFD. Among the potential therapeutic options, GLP-1 receptor agonists and DPP-4 inhibitors show the most promise, but further large-scale clinical studies are necessary to evaluate their effectiveness in treating IPFD. Such studies could facilitate the development of reliable therapies aimed at reducing pancreatic fat accumulation and mitigating the pathological damage caused by excessive fat deposition (Figure 3). Although new treatment approaches for IPFD have been tested in animal models, these studies have primarily relied on high-fat diet models and focused on the impact of these factors on blood lipids. The mechanisms of lipid deposition in the pancreas have been explored only briefly, and there is a lack of genetic models tailored to IPFD, limiting the depth of mechanistic investigation. Consequently, further research is needed to assess the efficacy of these potential therapies and to build a foundation for targeted treatment options (Table 3).

Figure 3 Therapeutic mechanism of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in intrapancreatic fat deposition. Glucagon-like peptide-1 receptor agonists potentially mitigate intrapancreatic fat deposition and its complications by modulating the endoplasmic reticulum stress pathway and downstream apoptosis signaling. In contrast, dipeptidyl peptidase-4 inhibitors exert therapeutic effects by regulating adipokines - such as reducing tumor necrosis factor-α levels and enhancing adiponectin production - and by modulating intracellular lipid droplet content. IPFD: Intrapancreatic fat deposition; GLP-1: Glucagon-like peptide-1; DPP-4: Dipeptidyl peptidase-4; TNF: Tumor necrosis factor.

Table 3 Summary of intrapancreatic fat deposition treatment methods.

Treatment method	Category	Mechanism of action	Research evidence	Ref.
Low-calorie diets	Non-pharmacological	Reduces insulin secretion and decreases adipose tissue accumulation in the pancreas and body	Evidence indicates that low-carbohydrate diets effectively diminish pancreatic and visceral fat deposition in individuals with obesity and type 2 diabetes	Taylor et al[122], 2018
Exercise	Non-pharmacological	Enhances overall insulin sensitivity and reduces pancreatic fat content	Numerous small clinical trials have demonstrated that physical activity can lower pancreatic fat deposition, regardless of the baseline glucose tolerance of participants	Heiskanen et al[121], 2018
Lactoferrin	Non-pharmacological	Improves lipid profiles, pancreatic function, and histological integrity	Supplementation with lactoferrin has been shown to mitigate weight gain, improve lipid levels, and enhance pancreatic function in models fed a high-fat diet	Hassan et al[123], 2022
Metformin	Pharmacological	Improves insulin resistance and reduces pancreatic and overall adipose tissue	In studies involving high-fat diet-fed mouse models, metformin significantly decreased pancreatic fat deposition and ameliorated insulin resistance	Souza-Mello et al[128], 2010
GLP-1 receptor agonists	Pharmacological	Stimulates insulin secretion, inhibits glucagon release, promotes weight loss, and decreases pancreatic fat	A growing body of clinical and preclinical evidence supports the efficacy of GLP-1 receptor agonists in reducing fat accumulation in both the pancreas and liver while enhancing pancreatic function	Kuriyama et al[131], 2024; Vanderheiden et al[130], 2016; Fang et al[46], 2021
SGLT-2 inhibitors	Pharmacological	Increases glucose excretion through urine, reduces lipogenesis, and improves pancreatic fat deposition	Research has demonstrated that SGLT-2 inhibitors, such as dapagliflozin, effectively improve body fat distribution and reduce pancreatic fat accumulation in patients with type 2 diabetes	Ghosh et al[133], 2022; Shi et al[132], 2023
DPP-4 inhibitors	Pharmacological	Enhances insulin secretion from pancreatic beta cells, suppresses glucagon secretion from alpha cells, and improves fat accumulation	Clinical trials and animal studies indicate that the DPP-4 inhibitor sitagliptin can effectively manage pancreatic steatosis and prevent the progression of pancreatic diseases	Souza-Mello et al[128], 2010; Nag et al[127], 2024
Statins	Pharmacological	Lowers blood lipid levels, inhibits pancreatic cell proliferation, and alleviates endoplasmic reticulum stress	Animal studies have demonstrated that statins significantly reduce pancreatic fat accumulation in models subjected to high-fat diets	Chen et al[138], 2014; Krisnamurti et al[137], 2022
Angiotensin II receptor blockers	Pharmacological	Mitigates intracellular calcium overload and lipid accumulation, improving insulin sensitivity and preventing fat degeneration	Various animal studies suggest that angiotensin II receptor blockers can alleviate pancreatic steatosis by enhancing metabolic conditions in diabetic patients	Souza-Mello et al[128], 2010; Lee et al[129], 2023

GLP-1: Glucagon-like peptide-1; DDP-4: Dipeptidyl peptidase-4; SGLT-2: Sodium-glucose co-transporter type 2.

CONCLUSION

The understanding of IPFD has remained insufficient. Although it is a very common condition, it has not been adequately addressed clinically. More multicenter, large-scale population surveys are needed to clarify the prevalence and related risk factors for IPFD in different regions and populations. Given the rise in obesity, the systemic metabolic disturbances caused by excessive fat accumulation warrant significant attention, especially because the pancreas is an important organ related to metabolism. The pathogenesis of IPFD is not fully understood, and further clinical and basic research is needed to explore its detailed mechanisms and validate its clinical significance. IPFD is highly related to exocrine pancreatic diseases, with excessive lipid accumulation in the pancreas creating an inflammatory microenvironment that promotes pancreatitis and pancreatic cancer, which further impairs pancreatic function and leads to more severe clinical outcomes. Furthermore, existing animal models of IPFD have primarily used high-fat diet models, and genetic models that specifically investigate the regulation of pancreatic fat cell accumulation are lacking. Future research might involve the development of relevant genetic animal models to further explore the mechanisms of IPFD.

Given the numerous and serious clinical consequences of IPFD, there is a pressing need for more accessible and efficient screening methods. These methods could complement traditional examinations to assess pancreatic fat content, facilitate timely identification of IPFD, and help prevent its worsening effects on the endocrine environment, thereby reducing the risk of progression to malignant disease. Furthermore, robust studies are needed to clarify specific pancreatic fat thresholds for IPFD diagnosis and classification using standard imaging techniques, ultimately working toward a diagnostic gold standard for IPFD. Although specific drugs for treating pancreatic fat changes have not yet been approved, repurposing antidiabetic drugs, statins, and other medications has shown promise in reducing the burden of IPFD. However, research on the effects of these drugs on IPFD has been limited to small-scale preclinical and prospective clinical studies. More reliable clinical research is needed to explore and validate the effectiveness of these drugs in preventing and treating IPFD. Interdisciplinary collaboration is essential to fully understand IPFD and to provide reliable diagnostic and therapeutic strategies for clinical practice.

ACKNOWLEDGEMENTS

We thank each of the authors for their contributions to this article.