Review Article
Fat, epigenome and pancreatic diseases. Interplay and common pathways from a toxic and obesogenic environment

https://doi.org/10.1016/j.ejim.2014.10.012Get rights and content

Highlights

  • Obesity epidemic is paralleled by a rise in fatty pancreas, pancreatitis and cancer.

  • These conditions may have common pathways involving gene–environment interaction.

  • The toxic effects of fat may interact with toxics of environmental origin.

  • Adult obesity may have a very early origin (pediatric age or fetal life).

  • Primary prevention may act on lifestyle, environmental exposure and the epigenome.

Abstract

The worldwide obesity epidemic is paralleled by a rise in the incidence of pancreatic disorders ranging from “fatty” pancreas to pancreatitis and cancer. Body fat accumulation and pancreatic dysfunctions have common pathways, mainly acting through insulin resistance and low-grade inflammation, frequently mediated by the epigenome. These mechanisms are affected by lifestyle and by the toxic effects of fat and pollutants. An early origin is common, starting in pediatric age or during the fetal life in response to nutritional factors, endocrine disruptor chemicals (EDCs) or parental exposure to toxics. A “fatty pancreas” is frequent in obese and is able to induce pancreatic damage. The fat is a target of EDCs and of the cytotoxic/mutagenic effects of heavy metals, and is the site of bioaccumulation of lipophilic and persistent pollutants related with insulin resistance and able to promote pancreatic cancer. Increased Body Mass Index (BMI) can act as independent risk factor for a more severe course of acute pancreatitis and obesity is also a well-known risk factor for pancreatic cancer, that is related with BMI, insulin resistance, and duration of exposure to the toxic effects of fat and/or of environmental pollutants. All these mechanisms involve gene–environment interactions through epigenetic factors, and might be manipulated by primary prevention measures. Further studies are needed, pointing to better assess the interplays of modifiable factors on both obesity and pancreatic diseases, and to verify the efficacy of primary prevention strategies involving lifestyle and environmental exposure to toxics.

Introduction

Obesity is recognized as the global epidemic of the 21st century [1], [2] and the increase has accelerated since the year 2000 [3]. Excessive fat storage and endocrine/exocrine pancreatic dysfunctions are simultaneously involved in several metabolic diseases and may be secondary to fat deposition in the pancreas [4], [5]. This condition is mediated by a direct toxic effect of obesity on pancreatic islets [6], and acts as a well documented increase of risk of pancreatic diseases in obese subjects [7], [8]. A chronic low-grade inflammation and the activation of the immune system have been indicated as main pathogenic factors governing the onset of insulin resistance and type 2 diabetes mellitus (T2DM) [9], and the pancreas acts as one of the target-organs of inflammation in obesity [10]. Obesity is a strong predictor of T2DM [11], another disease characterized by insulin resistance and chronic low-grade inflammation [10], and T2DM is also undergoing a dramatic epidemiological rise [12]. Of note, the spread of obesity among children and adolescents also puts these populations at increased risk of obesity, metabolic syndrome and T2DM [13]. A role for obesity and/or environmental factors has also been suggested for pancreatic disorders including fatty pancreas [14], [15], [16], acute [17], [18] and chronic [19], [20], [21] pancreatitis, β-cell dysfunction and type 1 diabetes [22], as well as pancreatic cancer [23], [24] (Table 1). Growing evidences emerging from both animal and human studies also suggest that early (i.e. in utero) exposure to environmental factors (including pollutants) leads to visceral fat disorders [25], obesity [26], [27], [28], [29], and insulin resistance [30], [31], [32].

The chronic exposure to environmental pollutants can activate pathways similar to those involved in the toxic effects of fat, i.e. chronic inflammation and immune system dysfunction [33], [34] with injuries starting at the cellular level [35], [36], [37], [38], [39], and including oxidative stress [40]. Despite the fact that current tobacco use has been indicated as the single most important risk factor for pancreatic diseases (followed by obesity) [8], the role of other environmental pollutants on exocrine and endocrine pancreatic diseases has not been homogenously investigated, so far. It might be hypothesized that a complex interplay exists between pathogenic factors involved in obesity and alterations of both exocrine and endocrine pancreatic functions. A role should exist, therefore, for both environmental toxics and gene–environment interaction characterizing, at least in part, common pathogenic pathways.

This article will provide a timely overview of the role of obesity and environmental changes/pollutants, as conditions capable of influencing pancreatic function, risk of pancreatitis, and pancreatic cancer. The possibility that clues exist for primary prevention strategies by acting on modifiable factors will be discussed.

Section snippets

The fat, the pancreas and the environment

Obesity is increasing worldwide [1], [2], [3] and, since 1980, a progressive shift toward obesity has been showed at any age, with a greater surge of obesity prevalence in lower- and middle-income developing countries rather than in higher-income countries [41], [42]. In the USA, over 60% of adults are overweight and 30% are obese, while 4.7% are extremely obese (i.e. with a BMI greater than 40 kg/m2) [43], [44].

Genetic variations certainly contribute to the susceptibility to obesity, but the

Obesity and acute pancreatitis

The rise in the cumulative incidence of acute pancreatitis (AP) parallels the increasing prevalence of obesity [95], [96], [97].

Well established risk factors for AP include gallstones, alcohol, cancer, anatomic abnormalities, hypertriglyceridemia, hypercalcemia, drugs, and infections.

Metabolic syndrome is a complex condition linking central obesity, hypertension, hyperglycemia, dyslipidemia, insulin resistance and diabetes [98]. Many patients with metabolic syndrome experience acute

Obesity, environmental toxics and pancreatic cancer

The incidence of pancreatic cancer is slowly increasing, and it has been calculated a worldwide occurrence of at least 250,000 new cases per year [111].

Epidemiological studies show that besides cigarette smoking, dietary factors, chronic pancreatitis, diabetes, some inherited familial disorders, infectious disease and advancing age, obesity is a further risk factor for pancreatic cancer [111], [112], [113], [114]. Metabolic syndrome may also have a role in the development of pancreatic cancer,

Conclusions

Common pathways involving genetic, epigenetic and “obesogenic” environmental factors and acting through fatty pancreatic infiltration, low-grade inflammation, pancreatic stem cell involvement, oxidative stress, autophagy and insulin resistance, link the global epidemics of obesity and several pancreatic disorders ranging from metabolic diseases to pancreatitis and cancer.

Genetic changes cannot fully explain the rapid increment observed in the rate of obesity worldwide and, on the other hand,

Learning points

  • Obesity is recognized as the global epidemic of the 21st century, and its increase is paralleled by a rise in the incidence of pancreatic disorders ranging from “fatty” pancreas to pancreatitis and cancer.

  • Body fat accumulation and several pancreatic diseases have common pathways, mainly acting through insulin resistance and low-grade inflammation, frequently mediated by the epigenome and involving lifestyle, environmental toxics and gene–environment interaction.

  • An early origin of obesity is

Conflict of interests

No conflict of interest has been declared by the authors.

Acknowledgments

This work was supported in part by a research grant MRAR08P011-2012 (to P.P.) from Italian Agency of Drug (AIFA).

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