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INFLAMMATION/IMMUNITY/MEDIATORS

A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis

Department of Surgery, Indiana University School of Medicine

Submitted 3 April 2008 ; accepted in final form 19 June 2008

	ABSTRACT

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Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (Lep^Ob), and obese hyperleptinemic (Lep^Db) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 µg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1β and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: Lep^Ob mice were heaviest; however, Lep^Db mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

adiponectin; leptin

Acute pancreatitis (AP) represents a substantial clinical problem, accounting for over 240,000 hospital admissions yearly in the United States, at a cost of over 2.3 billion dollars (9). The spectrum of severity in AP is broad. The majority of patients with AP experience a relatively mild, self-limited episode; 15–20% of patients with AP, however, develop a severe form of the disease, with necrosis of the pancreatic parenchyma and surrounding soft tissue resulting in a massive systemic inflammatory response (12). Patients with severe AP require extended intensive care and hospital stays and often require surgical intervention to debride necrotic pancreatic and peripancreatic tissue. Despite advances in supportive care, the mortality accompanying severe AP is still substantial (10–30%) (3, 4, 7, 14). The reason(s) why only a small percentage of patients develop severe AP are unknown; however, numerous clinical studies have demonstrated obesity to be an independent risk factor for developing severe AP (8, 23, 31, 37). Remarkably little basic research has been directed toward understanding the impact of obesity on the development of AP, and the mechanisms underlying this association remain poorly understood.

Two strains of congenitally obese mice provide an ideal platform on which to elucidate the impact of obesity and the adipokine milieu on the pathogenesis of AP. Lep^Ob mice have a spontaneous mutation of the ob gene and consequently produce virtually no leptin. Lep^Db mice manifest the phenotype of a defective leptin receptor (similar to the human obese situation), and stimulation of the feedback loop leads to markedly elevated circulating leptin levels. We have previously shown that pancreata of congenitally obese Lep^Ob mice contain an increased volume of fat, a different composition of fat, and increased basal levels of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) relative to wild-type lean mice (26). The present experiments were therefore designed to test the hypothesis that alteration of the adipokine milieu contributes to development of severe pancreatitis associated with obesity. The aims of these experiments were twofold. We sought, first, to establish a model of AP in the context of obesity and, second, to further characterize the role of the adipokines leptin and adiponectin in the development of AP.

	MATERIALS AND METHODS

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All experiments were approved by the Institutional Animal Care and Use Committee of Indiana University and performed in accordance with protocols outlined in the American Physiological Society's Guiding Principles in the Care and Use of Animals.

Animals and diet. Female obese Lep^Ob (leptin deficient) and Lep^Db (hyperleptinemic) and wild-type lean mice (C57BL/6J) were obtained from the Jackson Laboratory (Bar Harbor, ME). Adult 7-wk-old animals were allowed to acclimate for 1 wk in a climate-controlled room with a 12:12-h light-dark cycle. At 8 wk of age, mice were fed a diet consisting of (% calories) 25% fat (soybean oil and corn oil), 55% carbohydrate, and 20% protein (Dyets, Bethlehem, PA). All experiments were performed in animals at 12 wk of age; typical experiments included 10–16 animals in experimental groups.

Induction of AP and tissue preparation. AP was induced by pancreatic hyperstimulation with the cholecystokinin agonist cerulein (Sigma-Aldrich, St. Louis, MO). Sixteen mice of each strain (lean C57BL/6J, Lep^Ob, and Lep^Db) were administered 50 µg/kg cerulein intraperitoneally hourly for 6 h. Ten mice of each strain served as control, receiving intraperitoneal injection of vehicle (0.5% NH₄/saline) on the same time schedule. Nine hours after the first injection, mice were anesthetized with ketamine (50 mg/kg) and xylazine (15 mg/kg) and underwent pancreatectomy. Blood was collected at this time by ventricular puncture. A portion of pancreas was preserved in 10% formalin for histological analysis, and the remainder was immediately frozen in liquid nitrogen and preserved at –80°C for further analysis. A portion of lung was similarly frozen in liquid nitrogen and preserved at –80°C. Blood was centrifuged at 15,000 rpm, and serum was stored for subsequent analysis. Chemicals were obtained from Sigma-Aldrich unless otherwise noted.

Microscopy and histological analysis. Formalin-preserved pancreas was embedded in paraffin blocks, sectioned into 5-µm segments, and stained with hematoxylin and eosin. Sections of pancreas were taken from a standard location, the mid body of the gland. One section from each animal was evaluated. Histological severity of pancreatitis was determined by three separate observers who were unaware of the animal strain or treatment. A total pancreatitis score was determined by a validated method based on the degree of inflammation, vacuolization, and edema (32).

Chemical assays. Pancreatic tissue was homogenized in buffer containing 50 mM Tris, 250 mM NaCl, 5 mM EDTA, 1 mM NaF, 20 mM Na₄P₂O₇, 0.02% NaN₃, proprietary detergent, and protease inhibitor (Sigma) at a volume of 50 µl per gram tissue. Homogenates were centrifuged at 10,000 rpm at 4°C for 15 min, and protein concentration of the supernatant was assayed (Bio-Rad, Hercules, CA). Pancreatic tissue levels of the cytokines IL-1β and IL-6 and the chemokine monocyte chemoattractant protein-1 (MCP-1) were determined with commercially available ELISA kits (R & D Systems, Minneapolis, MN). Pancreatic and lung tissue concentration of myeloperoxidase (MPO) was determined by ELISA (Cell Sciences, Canton, MA). Serum levels of leptin and adiponectin were determined by using ELISA kits from Linco Research (St. Charles, MO). Serum insulin concentration was determined by ELISA (Crystal Chem, Downers Grove, IL). Serum glucose and amylase concentration were determined by colorimetric assay according to the manufacturer's instructions (Stanbio Laboratory, Boerne, TX).

Statistical analysis. Statistical analyses were performed by use of SigmaStat software (Jandel, San Rafael, CA). Data are expressed as means ± SE. ANOVA and Tukey's tests were applied as appropriate. A P value of <0.05 was accepted as statistically significant.

	RESULTS

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Animal weight. Twelve-week-old mice were weighed just prior to injection of cerulein or vehicle. Lean mice were significantly lighter than both congenitally obese strains of mice: lean 19.8 ± 0.2 g, Lep^Ob 52.4 ± 0.6 g, Lep^Db 43.8 ± 0.5 g (P < 0.001). Of the two congenitally obese strains, Lep^Ob mice were significantly heavier than Lep^Db (P < 0.001).

Histological severity of pancreatitis. Mice of all three strains injected with vehicle (control group) did not manifest any histological changes of AP. Supramaximal stimulation by six hourly injections of 50 µg/mg ip cerulein resulted in histological changes of AP including edema, intracellular vacuolization, and inflammatory cell infiltrate. Figure 1 shows representative micrographs from each strain. The histological pancreatitis score for all animals is shown in Table 1. After cerulein hyperstimulation, both obese strains developed significantly more severe histological pancreatitis (P < 0.05) than lean animals. Of the obese mice, Lep^Db mice developed significantly more severe histological pancreatitis than Lep^Ob animals (P < 0.05).

View larger version (120K): [in this window] [in a new window]   Fig. 1. Effects of obesity on histological changes of pancreatitis. Representative hematoxylin- and eosin-stained sections of pancreas were examined by light microscopy in lean (C57BL/6J) mice receiving injection of vehicle (A) and in 3 strains of mice receiving 6 hourly intraperitoneal injections of 50 µg/kg cerulein: lean (C57BL/6J) (B), obese LepOb (C), and obese LepDb (D). Note worsening pancreatitis in both obese strains of animals compared with lean.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Pancreatic tissue concentration of proinflammatory cytokines IL-1β and IL-6. Mice received either vehicle (Control) or cerulein (50 µg/kg body wt x 6 hourly injections; Cerulein). Nine hours after the first injection, animals were euthanized, and pancreatic tissue levels of IL-1β (A) and IL-6 (B) were determined as described in the text. Data are means ± SE for 5 animals in each control strain and 10 animals in each cerulein strain.

View larger version (18K): [in this window] [in a new window]   Fig. 3. Pancreatic tissue concentration of chemokines monocyte chemoattractant protein-1 (MCP-1) and MPO. Mice received either vehicle (Control) or cerulein (50 µg/kg body wt x 6 hourly injections; Cerulein). Nine hours after the first injection, animals were euthanized, and pancreatic tissue levels of MCP-1 (A) and MPO (B) were determined as described in the text. Data are means ± SE for 5 animals in each control strain and at least 8 animals in each cerulein strain (MCP-1) or 3 animals in each cerulein strain (MPO).

View larger version (16K): [in this window] [in a new window]   Fig. 4. Serum concentration of leptin and adiponectin. Mice received either vehicle or cerulein (50 µg/kg body wt x 6 hourly injections). Nine hours after the first injection, animals were euthanized, and serum levels of leptin (A) and adiponectin (B) were determined as described in the text. Data are means ± SE for at least 9 animals in each control strain and at least 14 animals in each cerulein strain.

View larger version (13K): [in this window] [in a new window]   Fig. 5. Lung tissue concentration of MPO. Mice received either vehicle or cerulein (50 µg/kg body wt x 6 hourly injections). Nine hours after the first injection, animals were euthanized, and lung tissue levels of MPO were determined as described in the text. Data are means ± SE for at least 6 animals in each control strain and 16 animals in each cerulein strain. Concentration of MPO in the lung was significantly lower than that of MPO in the pancreatic tissues (as shown in Fig. 3B).

	DISCUSSION

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In the present study, both obese strains of mice (Lep^Ob and Lep^Db) manifest more severe pancreatitis by histological analysis, increased pancreatic tissue levels of the proinflammatory cytokines IL-1β and IL-6, increased pancreatic tissue levels of the chemokine MCP-1, and the marker of neutrophil activation MPO. Taken together, these data suggest that the increased severity of AP seen in obesity is directly related to increased inflammatory cell upregulation, activation, and infiltration into the pancreatic parenchyma. Lep^Ob mice were significantly more obese than Lep^Db animals; however, the Lep^Db mice developed the most severe pancreatitis (both histologically and biochemically). This observation suggests that the volume of adipose tissue per se is not in itself solely responsible for the increased severity of pancreatitis in obesity and that other factors such as the adipokine milieu are important modulators of the inflammatory response. It was therefore quite intriguing to observe that across all three strains of animals studied serum levels of the potent anti-inflammatory adipokine adiponectin inversely mirrored the severity of AP.

Comparative study of lean (C57BL/6J) and these two discrete strains of congenitally obese mice (both on a C57BL/6J background) affords a unique opportunity to evaluate the roles of both increased adiposity and the inflammatory modulating adipokines leptin and adiponectin in the pathogenesis of pancreatitis. Both Lep^Ob and Lep^Db mice are congenitally obese; however, they manifest this phenotype via different mechanisms. Lep^Ob mice have a spontaneous mutation of the ob (leptin) gene and produce virtually no leptin (43). Lep^Db mice, on the other hand, have a spontaneous mutation of the leptin receptor and consequently have dramatically elevated circulating levels of leptin (34). The Lep^Db mouse more closely capitulates the human situation, in which leptin resistance leads to hyperleptinemia. Thus, whereas both mice manifest the typical metabolic consequences of obesity (hyperinsulinemia and hyperglycemia), each has a dramatically different circulating adipokine milieu.

The discovery of leptin in 1994 and adiponectin shortly thereafter have been followed by an explosion in the study of adipokine biology (34, 38, 43). Both of these molecules are produced predominantly by adipocytes, but their impact on inflammation is dramatically different. In humans, circulating leptin concentration increases directly with increasing obesity, and leptin has been shown in many diverse systems to act predominantly as a proinflammatory mediator (10, 33). The proinflammatory effects of leptin are thought to be mediated mostly by mechanisms regulating differential cytokine production and leukocyte activity (21, 22). Adiponectin, on the other hand, paradoxically decreases as adipose tissue mass increases (2). In the context of obesity, the function of adiponectin as a strong anti-inflammatory molecule has been well established (11). Adiponectin exerts its anti-inflammatory effects through several distinct mechanisms: 1) downregulation of chemokines and adhesion molecules (15, 29); 2) alteration of macrophage and lymphocyte function (19, 30, 41); 3) suppression of proinflammatory cytokine production (24); and 4) upregulation of anti-inflammatory cytokine production (41).

Seven published studies have evaluated the role of leptin in lean animal models of AP. Konturek et al. (17) showed that circulating leptin levels were increased in lean rats after induction of AP by cerulein hyperstimulation, a finding that has been substantiated by two other groups (16, 42). Somewhat paradoxically, the administration of leptin (again in lean animals) has been shown to attenuate the severity of AP (13, 40). In the present experiments, circulating leptin was increased after induction of AP only in the obese Lep^Db mice. It is not surprising that there was no change in circulating leptin in Lep^Ob mice, who are unable to produce significant amounts of leptin. The observation that AP did not change circulating leptin levels in lean animals may be related to our use of a murine model (as opposed to rat models used in other reports) or use of a lower dose of cerulein than that reported in prior studies. The present experiments are the first to our knowledge that evaluate the role of adiponectin in experimental AP. In reality, the mechanisms modulating increased severity of AP in obesity are likely complex and multifactorial. The fact that adipokines are potent modulators of inflammation and that the adipokine milieu is markedly altered in the setting of obesity suggests that these molecules may play a role. Indeed, our finding that serum adiponectin concentration inversely mirrored the severity of AP suggests that downregulation of this anti-inflammatory molecule in the setting of obesity may be more important than the influence of the proinflammatory adipokine leptin.

Our finding that induction of pancreatitis increases pulmonary MPO concentration is consistent with many prior reports in small animal models of cerulein-induced pancreatitis (5, 20, 27) and indicative of a systemic inflammatory response associated with the genesis of pancreatitis. The fact that pulmonary MPO concentration was significantly elevated only in the obese Lep^Db animals may be related either to the increased severity of the local (pancreatic) insult or alternatively to the entire organism being "primed" to perpetuate a systemic inflammatory response (i.e., by the presence of a significantly altered adipokine milieu: hyperleptinemia and/or hypoadiponectenemia).

The finding of increased pancreatic MPO concentration in obese mice suggests a greater degree of neutrophil infiltration and/or activation in these animals relative to lean, wild-type mice. Although we also observed a greater degree of leukocyte infiltration in the obese mice histologically (Table 1), the role played by macrophages in this process is less obvious from our data. It is intriguing to speculate that specific leukocyte subtypes (i.e., neutrophil vs. monocyte/macrophage) may play differential roles in the pathogenesis of AP specifically in the context of obesity. We are not yet, however, confident of our ability to accurately and reliably quantify these relative subclasses of leukocytes. Further experiments using immunohistochemical staining and flow cytometry techniques may be helpful in this regard.

Serum amylase elevation is generally accepted as a marker of AP (12, 44). In the present experiments, serum amylase was found to be elevated in all three strains of mice after induction of AP. No differences in the degree of hyperamylasemia were observed among these three strains. Although some basic investigators have used the degree of amylase elevation as a surrogate for degree of pancreatic inflammation, this marker is widely variable (5, 6). Indeed, no clinical study has ever been able to correlate the degree of hyperamylasemia with the severity or duration of AP (44).

As expected, both strains of obese mice demonstrated the metabolic consequences of obesity (hyperinsulinemia and hyperglycemia) relative to lean animals. Interestingly, induction of AP led to a significant decrease in serum insulin and glucose in both obese strains of mice. Serum insulin and glucose levels were unchanged after induction of AP in lean mice. This finding may be related to increased insulin sensitivity in the face of a systemic inflammatory event; however, the reason why it would manifest differently in obese vs. lean mice is not clear.

In summary, these experiments demonstrated that congenitally obese mice developed more severe AP than lean wild-type animals when challenged by cerulein hyperstimulation. The severity of pancreatitis was not solely related to volume of adipose tissue. Thus the observation that pancreatitis severity was inversely mirrored by circulating concentrations of the anti-inflammatory adipokine adiponectin is particularly intriguing. Further dissection of the adipokine milieu's impact on the development of severe AP of obesity is clearly of high importance for two reasons. First, the prevalence of obesity in the United States (and the world) has reached epidemic proportions, and the incidence shows no sign of slowing. Second, despite over a century of research and literally billions of dollars invested in clinical therapeutic trials, the precise mechanisms involved in the pathogenesis of AP remain elusive, and currently no specific medical therapy for AP exists beyond general support. Interrogating the mechanisms by which AP develops from novel angles (such as obesity and the influence of specific adipokines like adiponectin) offers the potential for unique observations that may ultimately lead to the development of directed therapeutic agents. It is exciting to speculate that manipulation of the adipokine milieu has the potential to impact the severity of AP. Thus continued investigation along these lines is most certainly warranted.

	GRANTS

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This work was supported in part by a career development award from the Society for Surgery of the Alimentary Tract (to N. J. Zyromski).

	ACKNOWLEDGMENTS

 
The authors thank Kimberly Hoffman for excellent administrative assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: N. J. Zyromski, Dept. of Surgery, Indiana Univ. School of Medicine, 535 Barnhill Dr., RT 130, Indianapolis, IN 46202 (e-mail: nzyromsk{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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