Review ArticleFat, epigenome and pancreatic diseases. Interplay and common pathways from a toxic and obesogenic environment
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
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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.
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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.
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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).
References (211)
- et al.
Obesity and the risk and prognosis of gallstone disease and pancreatitis
Best Pract Res Clin Gastroenterol
(2014) - et al.
Global estimates of the prevalence of diabetes for 2010 and 2030
Diabetes Res Clin Pract
(2010) - et al.
Chronic pancreatitis
Lancet
(2011) - et al.
Zurich Pancreatitis Study G. Is obesity an additional risk factor for alcoholic chronic pancreatitis?
Pancreatology: official journal of the International Association of Pancreatology
(2010) - et al.
Risk of dying of cancer in the vicinity of multiple pollutant sources associated with the metal industry
Environ Int
(2012) - et al.
In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective
Toxicol Lett
(2013) - et al.
Prenatal and postnatal tobacco smoke exposure and development of insulin resistance in 10 year old children
Int J Hyg Environ Health
(2011) - et al.
Lifestyle and environmental factors associated with inflammation, oxidative stress and insulin resistance in children
Atherosclerosis
(2009) - et al.
Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context
J Nutr Biochem
(2013) - et al.
Redox and electrophilic properties of vapor- and particle-phase components of ambient aerosols
Environ Res
(2010)
AGA technical review on obesity
Gastroenterology
The global obesity pandemic: shaped by global drivers and local environments
Lancet
Obesity at the age of 50 y in men and women exposed to famine prenatally
Am J Clin Nutr
Lifestyle determinants of the drive to eat: a meta-analysis
Am J Clin Nutr
Persistent organic pollutant levels in human visceral and subcutaneous adipose tissue in obese individuals—depot differences and dysmetabolism implications
Environ Res
Simultaneous exposure of non-diabetics to high levels of dioxins and mercury increases their risk of insulin resistance
J Hazard Mater
Interrelationship between exposure to PCDD/Fs and hypertension in metabolic syndrome in Taiwanese living near a highly contaminated area
Chemosphere
Adipocytes under assault: environmental disruption of adipose physiology
Biochim Biophys Acta
Bisphenol A: an endocrine and metabolic disruptor
Ann Endocrinol
Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans
Chemosphere
Age and sex differences in childhood and adulthood obesity association with phthalates: analyses of NHANES 2007–2010
Int J Hyg Environ Health
PPAR-mediated activity of phthalates: a link to the obesity epidemic?
Mol Cell Endocrinol
Cholesterol gallstone disease
Lancet
The obesity pandemic: where have we been and where are we going?
Obes Res
The epidemic of obesity
J Clin Endocrinol Metab
National, regional, and global trends in adult overweight and obesity prevalences
Popul Health Metrics
Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery induced weight loss
Int J Obes
Pancreatic fat accumulation, fibrosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet
Pancreas
12-Lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets
Mol Cell Biol
Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies
Clin Gastroenterol Hepatol
The role of adipose tissue immune cells in obesity and low-grade inflammation
J Endocrinol
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes
Diabetes Res Clin Pract
Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study
PLoS Med
Obesity and type 2 diabetes in children: epidemiology and treatment
Curr Diab Rep
Fatty pancreas, insulin resistance, and beta-cell function: a population study using fat-water magnetic resonance imaging
Am J Gastroenterol
Ectopic fat in youth: the contribution of hepatic and pancreatic fat to metabolic disturbances
Obesity
Increased pancreatic fat fraction is present in obese adolescents with metabolic syndrome
J Pediatr Gastroenterol Nutr
Body mass index influences the outcome of acute pancreatitis: an analysis based on the Japanese administrative database
Pancreas
Pancreatitis induced by environmental toxins
Pancreas
Occupational exposure to hydrocarbons and chronic pancreatitis: a case-referent study
Occup Environ Med
Association between air pollutant emissions and type 1 diabetes incidence in European countries
Adv Res
Metabolic syndrome, insulin resistance, circadian disruption, antioxidants and pancreatic carcinoma: an overview
J Gastrointestin Liver Dis
Traffic-related air pollution and obesity formation in children: a longitudinal, multilevel analysis
Environ Health
Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner
FASEB J
Association of childhood obesity with maternal exposure to ambient air polycyclic aromatic hydrocarbons during pregnancy
Am J Epidemiol
Exposure to hexachlorobenzene during pregnancy increases the risk of overweight in children aged 6 years
Acta Paediatr
Long-term exposure to traffic-related air pollution and insulin resistance in children: results from the GINIplus and LISAplus birth cohorts
Diabetologia
Non-nutrient causes of low-grade, systemic inflammation: support for a ‘canary in the mineshaft’ view of obesity in chronic disease
Obes Rev
The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types
Inhal Toxicol
Free radical activity of PM10: iron-mediated generation of hydroxyl radicals
Environ Health Perspect
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