On obesity in acute pancreatitis

Over-nutrition is one of today s most visible public health problems. Currently over 40% of the Swedish population is either overweight or obese. Acute pancreatitis (AP) is an acute inflammatory process of the pancreas with variable involvement of regional tissues and/or remote organ systems. The morbidity and mortality associated with acute pancreatitis is largely determined by the involvement of distant organs such as the liver and lung and by the development of organ failure. The systemic manifestation of pancreatic disease is mediated by pro- and anti-inflammatory cytokines. Several studies have shown that obesity is a negative prognostic factor in acute pancreatitis. The mechanisms underlying the involvement of obesity have not been fully elucidated.

The aim of this thesis was to investigate the involvement of obesity in acute experimental pancreatitis (AEP). The five studies examined AEP in obese rats or mice. AEP was induced by taurocholate in rats and by cerulein in mice. Lean AEP animals and lean or obese untreated animals were used as controls. In the different studies, the animals obesity varied in etiology (genetic/dietary), severity, and duration. We studied the role of a mitochondrial protein, uncoupling protein 2 (UCP2), in AEP. Further, we investigated the gene expression of inflammatory cytokines, in the pancreas, liver, and lungs using real-time polymerase chain reactions. In addition, the integrity and function of these organs were assessed by histological and biochemical analyses. Finally, the gene expression data were related to the histological and biochemical parameters. UCP2 gene expression was analyzed likewise.

The mortality rate in severe AEP was higher in animals with genetic obesity than in lean animals or those with diet-induced obesity. However, this difference was not seen when the severity of AEP was reduced. Furthermore, the pathological morphology of AEP seen in obese animals was not significantly different from that seen in lean AEP controls. The amount of fat did not influence the severity of AEP, but there was a trend toward decreased survival rate after long-term obesity. UCP2 was increased in the pancreas, and this increase was correlated with the severity of AEP. Pro-inflammatory cytokine expression increased and anti-inflammatory cytokine expression decreased in AEP animals with genetic obesity. These animals also showed hepatic dysfunction and injury. Obese AEP mice displayed an augmented pulmonary inflammatory response.

In conclusion, genetically-induced obesity, but not diet-induced obesity, in rodents is associated with an increased mortality rate in AEP. However, the negative impact of obesity is dependent on the severity of the primary insult. The duration rather than the degree of diet-induced obesity influences the outcome of AEP, suggesting that physiological changes associated with obesity underlie the negative impact of obesity on AEP. The degree of systemic response, rather than the local pancreatic injury, determines the impact of obesity in AEP. Genetic obesity is associated with an altered inflammatory response in AEP, suggesting an immune cell dysfunction. Obese animals also show increased hepatic dysfunction and injury, as well as augmented pancreatitis-associated lung injury in AEP. UCP2 may be an important modifier of the local severity of AEP.

List of scientific papers

I. Segersvard R, Sylvan M, Herrington M, Larsson J, Permert J (2001). Obesity increases the severity of acute experimental pancreatitis in the rat. Scand J Gastroenterol. 36(6): 658-63.
https://pubmed.ncbi.nlm.nih.gov/11424327

II. Segersvard R, Sylvan M, Lempinen M, Larsson J, Permert J (2004). Impact of chronic and acute high-fat feeding on acute experimental pancreatitis complicated by endotoxinaemia. Scand J Gastroenterol. 39(1): 74-80.
https://pubmed.ncbi.nlm.nih.gov/14992565

III. Segersvard R, Rippe C, Duplantier M, Herrington MK, Isaksson B, Adrian TE, Erlanson-Albertsson C, Permert J (2005). mRNA for pancreatic uncoupling protein 2 increases in two models of acute experimental pancreatitis in rats and mice. Cell Tissue Res. Mar 22: Epub ahead of print.
https://pubmed.ncbi.nlm.nih.gov/15782323

IV. Segersvard R, Tsai J, Herrington MK, Permert J (2005). Obese rats with acute necrotizing pancreatitis exhibit increased hepatic injury and an altered cytokine response. [Submitted]

V. Segersvard R, Tsai J, Herrington MK, Permert J (2005). An altered inflammatory response is seen in cerulein-induced pancreatitis in obese mice. [Manuscript]