Research ArticleObesity and Pancreatitis

Lipotoxicity Causes Multisystem Organ Failure and Exacerbates Acute Pancreatitis in Obesity

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Science Translational Medicine  02 Nov 2011:
Vol. 3, Issue 107, pp. 107ra110
DOI: 10.1126/scitranslmed.3002573

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The Burden of Adiposity

As if diabetes and heart disease were not burden enough, obese people who suffer trauma, burns, or other critical conditions have an increased likelihood of death. During these exacerbated illnesses, multiple organs can fail, a situation that is particularly hard to reverse. How the presence of excess adipose tissue contributes to the severity of these diseases is not clear, but understanding the mechanisms could provide clues for possible treatments. Pancreatitis is a relatively well-defined disease that tends to be worse in the obese and, in its most severe form, is accompanied by multi-organ failure. By using a combination of patient investigation, in vitro cell studies, and an animal model, Navina et al. have assembled evidence that pinpoints the culprits in the obesity-related complications of this disease: unsaturated fatty acids liberated by lipolysis from adipose tissue.

The authors carefully examine the pancreases of 24 patients who had died of pancreatitis. The staining patterns indicated that nonesterified fatty acids, derived by lipolysis of excess intrapancreatic fat, contributed to the pancreatic necrosis in these patients. To test this idea, the authors used a cell culture system and showed that it is unsaturated fatty acids that do the damage, impairing acinar cell activities, inhibiting mitochondrial function, releasing calcium, and causing cell death. But what about the failure of other organs? To answer this question, the authors used obese mice with pancreatitis and, by inhibiting lipolysis with the drug orlistat, were able to prevent the pancreatic-associated rise in serum unsaturated fatty acids and, of most importance, to reduce damage to the lung and kidney, as well as mortality.

It is not yet clear which lipase is the critical one for multiorgan failure or where it is located. But once revealed, this potential therapeutic target may specify a treatment that enhances the survival of critically ill obese patients.

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