Abstract
Obesity is associated with systemic low-grade inflammation and is a risk factor for non-alcoholic fatty pancreas disease (NAFPD), but the molecular mechanisms of these associations are not clear. Interleukin (IL)-10, a potent anti-inflammatory cytokine, is released during acute pancreatitis and is known to limit inflammatory responses by downregulating the release of proinflammatory mediators. The origin of IL-10 that suppresses pancreatitis has not been investigated. Since obesity is known to reduce expression of proinflammatory cytokines in the spleen, we examined whether spleen-derived IL-10 regulates NAFPD caused by high-fat (HF) diet-induced obesity. The following investigations were performed: 1) IL-10 induction from spleen was examined in male mice fed a HF diet; 2) triglyceride content, expression of pro- and anti-inflammatory cytokines and infiltration of M1 and M2 macrophages were determined to evaluate ectopic fat accumulation and inflammatory responses in the pancreas of splenectomy (SPX)-treated mice fed HF diet; 3) exogenous IL-10 was systemically administered to SPX-treated obese mice and the resulting pathogenesis caused by SPX was assessed; and 4) IL-10 knockout (IL-10KO) mice were treated with SPX and ectopic fat deposition and inflammatory conditions in the pancreas were investigated. Obesity impaired the ability of the spleen to synthesize cytokines, including IL-10. SPX aggravated fat accumulation and inflammatory responses in the pancreas of HF diet-induced obese mice and these effects were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on fat deposition and inflammatory responses in the pancreas of IL-10KO mice. Our findings indicate that obesity reduces IL-10 production by the spleen and that spleen-derived IL-10 may protect against the development of NAFPD.
Highlights
Obesity leads to the infiltration of fat into multiple organs, including the liver, heart, kidneys, and pancreas
Splenic expression of IL-1b, monocyte chemotactic protein-1 (MCP-1), and IL-10 was significantly lower in mice in the high-fat diet (HF) diet group compared to those in the standard chow group, in serum, only IL-10, but not IL-1b or MCP-1, was significantly lower in the HF diet group compared to the standard chow group (Table 1)
SPX resulted in lower energy intake, body weight, weight of epididymal white adipose tissue (WAT), and interestingly lower serum adiponectin levels compared to shamoperated mice (Table 2)
Summary
Obesity leads to the infiltration of fat into multiple organs, including the liver, heart, kidneys, and pancreas. Metabolic disorders associated with the obese state increase fatty acid flux to the liver and pancreas [1,2]. Non-alcoholic fatty liver disease (NAFLD), a major form of chronic liver disease in adults and children, results from infiltration of fat into the liver [3]. Similar infiltration of the pancreas by fat (non-alcoholic fatty pancreatic disease [NAFPD]), increases the weight of the pancreas due to the accumulation of high levels of triglycerides (TGs) and free fatty acids (FFAs), which can compromise normal pancreatic function. Pancreatic fat accumulation is characterized by increased production of cytokines that are released locally and may result in inflammation, which is associated with organ dysfunction [2]. IL-10 has been reported to have direct antiproliferative and antifibrotic effects [8,9]
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