Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.20
Obesity is pervasive in western society, and its systemic effects extend to pancreatic disease. This chapter reviews the effects of obesity on pancreatic disease – specifically acute pancreatitis and pancreatic adenocarcinoma. Special focus is directed toward the influence of adipokines, biologically active proteins produced by adipose tissue.
1. Obesity and Adipose Tissue as a Metabolic Organ
Obesity has become a global epidemic in the 21st century. In America alone, over one-third of adults are currently obese, the incidence of obesity continues to rise, and obesity is occurring at younger ages (30,92). Obesity significantly increases the risk for numerous chronic diseases including insulin resistance, diabetes, cardiovascular disease, stroke, hyperlipidemia, arthritis, asthma, non-alcoholic steatohepatitis (NASH), and some forms of cancer (100). Adipose tissue expansion and infiltration into body tissues is accompanied by an altered leukocyte profile and subsequent induction of the local proinflammatory cytokine milieu. This milieu in turn generates a systemic proinflammatory state, the end results of which have been well documented in the pathogenesis of disease processes such as atherosclerosis (63) and NASH (39). It is intuitive that a similar process would affect the pancreas in obesity.
Early autopsy and radiology studies correlated obesity with increased pancreatic fat deposition (96,131). Fatty replacement of the pancreas in cystic fibrosis leads to severe exocrine insufficiency (51). In addition, in vitro studies have suggested that lipotoxicity in pancreatic β cells contributes to type II diabetes, though in vivo studies have been less convincing (128, 144). Moreover, clinical studies have shown obesity to be a risk factor for increased severity of acute pancreatitis (AP) and for developing pancreatic ductal adenocarcinoma (PDAC).
The increased incidence of obesity has led to a surge in basic obesity research. As a result, a greater understanding of the specific mechanisms by which obesity impacts clinical disease has begun to emerge. For many years, adipose tissue was viewed primarily as an inert storage depot where excess energy was packaged in the form of triglycerides, and released when needed in the peripheral tissues. The discovery of leptin in 1994 (143) and adiponectin shortly thereafter (109) marked the beginning of a dramatic change in this established concept. Leptin and adiponectin are proteins produced predominantly by adipocytes that have a broad ranging impact on diverse metabolic and inflammatory processes, and were thus termed adipokines. Over the subsequent decades, a number of other adipokines have been identified, and the paradigm of adipose tissue as an active metabolic organ has become widely accepted.
Adipose tissue is now recognized not simply as an energy storage depot, but as an active metabolic organ (44). Prominent among the 100 individual proteins produced by adipocytes are adipokines: small, cytokine-like molecules that modulate metabolism, inflammation, angiogenesis, and the immune response (68,122). The obese state is characterized by alteration in adipokine concentration and function. Adipokines’ position upstream from several mechanisms that influence cancer growth, invasion, and metastasis make the perturbed adipokine milieu of obesity a logical link between obesity and accelerated cancer growth. Similarly, this position makes adipokines an attractive target for intervention – not simply at the level of the cancer cell, but upstream of several overlapping mitogenic pathways. Not surprisingly, a moderate amount of investigation has evaluated adipokines’ role in tumor biology (5,37,48,113). The best studied adipokines to date are leptin and adiponectin.
Adiponectin is expressed in full length, multimeric, and globular forms; the precise role of these isoforms remains to be defined. Circulating adiponectin levels are in the microgram per milliliter range, which is about 2-5 orders of magnitude greater than observed with other adipokines and cytokines. This fact, along with its long half-life (about 14 hours), have positive implications for potential use as a therapeutic agent (101). Circulating adiponectin concentration paradoxically decreases with increasing obesity, a feedback loop that appears to be regulated by tumor necrosis factor alpha (TNF-α) (2,13,107). Two receptors for adiponectin, AdipoR1 and AdipoR2 were discovered in 2003 (139). AdipoR1 has been shown in several models to be expressed strongly in skeletal muscle and widely throughout various organ systems, while AdipoR2 appears to be predominantly expressed in liver. Both AdipoR1 and AdipoR2 have been identified in human and rodent pancreatic β cells, as well as throughout the embryonic murine gut (62,115,145). Our research group has recently documented the presence of AdipoR1 and AdipoR2 in murine pancreas. Adiponectin also modulates metabolism. Increased adiponectin enhances insulin sensitivity and increases fatty acid oxidation, effects that appear to be mediated through adenosine monophosphate kinase (AMPK) (33,123). In humans, decreased adiponectin levels lead to insulin resistance and development of cardiovascular disease (47,67).
In addition to its metabolic effects, emerging evidence has shown that adiponectin plays an important role in regulating the immune and inflammatory response (Figure 1). The initial anti-inflammatory effects of adiponectin were described in endothelial cells. In this system, adiponectin potently downregulates the expression of adhesion molecules intracellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) by inhibiting TNF-α (98,59). Adiponectin markedly reduces macrophage phagocytic activity andTNF-α production by inhibiting nuclear transcription factor κB (NF-κB) activation (80). Adiponectin also induces production of the important anti-inflammatory cytokines IL-10 and IL-1ra by human monocytes and macrophages, and repressed production of interferon-γ (IFN-γ) by LPS-stimulated human macrophages (97,137). Inhibition of NF- κB appears to be at least partly responsible for these effects, as well.
In vivo, adiponectin has been shown to have anti-inflammatory effects in various models of liver inflammation (80) and acute intestinal inflammation (28,87). These protective effects are mediated by downregulation of TNF-α and chemokine production, as well as by induction of anti-inflammatory IL-10. In obese humans, circulating adiponectin concentration correlates negatively with the inflammatory marker c-reactive protein and with levels of the pro-inflammatory cytokines TNF-α and IL-6 (13,107).
In the context of obesity, the function of adiponectin as a strong anti-inflammatory modulator has been well established. Adiponectin exerts these anti-inflammatory effects by 1) downregulating chemokine and adhesion molecules, 2) altering lymphocyte and macrophage function, and 3) suppressing production of proinflammatory and upregulating production of anti-inflammatory cytokines.
Leptin, the first adipokine discovered in 1994, is widely known for its role in maintaining energy balance and the central regulation of satiety (143). Obesity (specifically increased adipocyte mass) leads to characteristic hyperleptinemia with subsequent leptin resistance (9,76). Leptin is a cellular mitogen, and also directly affects angiogenesis, the inflammatory profile, and immune cellular function. Leptin exerts downstream signaling primarily through the long form of its receptor (ObRl also known as Lep-Rb), which stimulates the Janus kinase 2/signal transducer and activator of transcription (JAK/STAT) pathway. This strategic position leads to downstream effects including increased angiogenesis (such as increased production of vascular endothelial growth factor [VEGF]) and decreased apoptosis. (8,10,18,120).
2. Acute Pancreatitis
Each year in the United States, over 240,000 patients are hospitalized with the primary diagnosis of acute pancreatitis, at a cost of over 2.3 billion dollars to the health care system (27). AP generates local inflammation as well as a systemic inflammatory response that affects remote organ systems to variable degrees, resulting in a broad spectrum of disease severity. Importantly, despite the investment of a tremendous amount of basic and clinical research, no specific therapy has been shown to attenuate the clinical course of acute pancreatitis, and current treatment remains entirely supportive (127).
The central position of inflammatory cell infiltration and cytokine production in the development of acute pancreatitis is well established; many of the inflammatory changes observed in pancreatitis such as upregulation of chemoattractant and adhesion molecules, altered leukocyte function, and increased production of proinflammatory cytokines parallel changes seen in the generalized proinflammatory state induced by obesity, and thus offer a potentially attractive mechanistic link between these conditions.
Obesity and Clinical Acute Pancreatitis
A substantial amount of clinical evidence has confirmed obesity to have a significant negative impact on the course of acute pancreatitis. Autopsy studies performed nearly 50 years ago generated the observation that many patients with pancreatitis were obese (26). In 1985 Nordback and colleagues suggested that obesity was a risk factor for developing extensive pancreatic necrosis (90), and the seminal study of Lankisch and Schirren in 1990 showed that obesity was associated with the development of an increase in local complications of pancreatitis (69). Since the early 1990s, over a dozen published reports have evaluated the impact of obesity on the severity of acute pancreatitis (21,35,42,45,57-59,79 82,83,99,104,119,121,125). Nearly all of these studies have shown obesity to be associated with increased severity of pancreatitis as assessed by organ dysfunction. Additionally, many of these reports demonstrated that obese patients with pancreatitis have a significantly increased mortality rate relative to those with normal body mass (58,83). Martinez et al recently performed a well-controlled meta-analysis that included data from 739 patients (78). This analysis showed that both severity of disease (OR 2.9, CI 1.8-4.6) and mortality (OR 2.1, CI 1.0-4.8) were significantly higher in obese patients with pancreatitis. Thus, the collective weight of clinical evidence strongly supports the concept that obesity exacerbates acute pancreatitis.
Four clinical studies have examined adipokine levels in humans with acute pancreatitis; however, results from these studies are conflicting. Konturek and colleagues found serum leptin levels to be significantly elevated in 15 patients with mild acute pancreatitis as compared to healthy control patients matched for body mass index (BMI) (64). Similar results were reported by Schaffler et al, who studied 23 patients with pancreatitis and found that the circulating concentration of leptin and resistin correlated positively with severity of acute pancreatitis measured by radiological scoring scales (108). In this study, leptin also correlated positively with c-reactive protein (an inflammatory marker known to be elevated in pancreatitis), but not with a clinical pancreatitis severity score. These investigators also measured serum adiponectin concentrations, which were decreased in patients with more severe pancreatitis but did not reach statistical significance in most groups. Patients in this small study exhibited a broad range of obesity; however, no attempt was made to correlate BMI with either severity of pancreatitis or adipokine concentration.
In contrast to these studies, two other reports failed to find significant correlation of leptin with severity of pancreatitis. Duarte-Rojo et al measured serum leptin levels in 56 patients with acute pancreatitis (27% of whom had severe pancreatitis) (22). The average BMI in the mild and severe groups was similar, and no correlation existed between leptin concentration and severity of pancreatitis. Tukiainen and colleagues measured serum leptin and adiponectin levels in 24 patients with acute pancreatitis (126). Patients were divided into those with mild and severe disease, and matched by age, sex, etiology, and BMI. No differences were observed in the average circulating level of leptin or adiponectin between patients with mild and severe pancreatitis. While it is somewhat difficult to compare the results of these small, heterogeneous studies, it is clear that the role of adipokines in the pathogenesis of human acute pancreatitis remains incompletely understood.
Obesity and Experimental Acute Pancreatitis
A few studies have evaluated the role of obesity on acute pancreatitis in experimental animal models. In one study of pancreatitis in an obese animal model, Swedish investigators studied three groups of rats: lean control animals, genetically obese (Zucker fa/fa), and animals in which obesity was generated by high fat diet (110). Pancreatits was induced by retrograde infusion of sodium taurocholate into the pancreatic duct. Genetically obese rats had significantly increased mortality, while animals with diet-induced obesity displayed more severe histologic pancreatitis relative to lean animals. These experiments confirmed the impact of obesity on severity of pancreatitis, but did not provide any mechanistic information.
Our laboratory performed experiments in lean and congenitally obese (LepOb and LepDb) mice. Animals were subjected to acute pancreatitis generated by cerulein hyperstimulation. These experiments showed that both obese strains of mice sustained more severe pancreatitis than lean animals, and that severity of pancreatitis was inversely mirrored by circulating adiponectin concentration (147). Follow-up studies showed that 1) modest increases in adiponectin modulated the pancreatic chemokine and cytokine milieu in pancreatitis, and 2) central blockade of the cannabinoid-1 receptor increased circulating adiponectin concentration and significantly attenuated severity of pancreatitis in obese (LepDb) mice (146). These experiments confirmed the negative influence of obesity on the severity of pancreatitis, and strongly suggest that this effect is mediated at least in part by an alteration in the adipokine milieu (specifically a decrease in adiponectin).
Seven published studies have examined the role of adipokines in lean animal models of acute pancreatitis. Four reports are from a single Polish group, and focused on the proinflammatory adipokine leptin. These investigators have shown that circulating leptin is elevated in cerulein-induced pancreatitis, and that administration of exogenous leptin 1) decreases exocrine pancreatic secretion in vitro and in vivo and 2) attenuates the severity of acute pancreatitis induced by two discrete models using cerulein hyperstimulation and ischemia (53,54,64,134). Kerem et al confirmed the observation that circulating leptin concentration is elevated in lean rats subjected to pancreatitis by injection of cerulein or arginine (60). Yavuz et al also reported increased serum leptin levels in rats after pancreatitis was induced by ethanol injection into the common bile duct (140). Finally, Gultekin and colleagues demonstrated that exogenous leptin administration attenuates both pancreatic inflammation and lung injury in a rat model of cerulein-induced pancreatitis (43). Taken together, these studies suggest that 1) circulating leptin concentration is elevated in lean rats subjected to pancreatitis, and 2) though somewhat paradoxical, exogenous leptin administration appears to attenuate the severity of acute pancreatitis in animal models using lean rats.
Opportunities for Intervention in Pancreatitis
Both obesity and acute pancreatitis individually represent substantial health problems. Clinical studies have consistently identified obesity to be an independent risk factor for increased severity of acute pancreatitis. This combination results in a particularly devastating impact, as no specific therapy for pancreatitis currently exists. The concept that downregulating the anti-inflammatory adipokine adiponectin in obesity may potentiate the severity of acute pancreatitis appears quite plausible;understanding the mechanisms by which obesity contributes to the severity of acute pancreatitis are critical to identify novel therapeutic and preventative treatments.
3. Pancreatic Adenocarcinoma
Pancreatic cancer is devastating: virtually every patient diagnosed with pancreatic cancer will die as a consequence of the disease (7,40,49,55). Advances in surgical technique and perioperative care have improved short term outcomes after resection of pancreatic cancer. Unfortunately, long-term survival after resection remains remarkably poor – fewer than 20% of patients will survive to 5 years (1,49,88). These dismal results clearly reflect aggressive (and poorly understood) tumor biology, highlighting the desperate need to develop novel therapeutic approaches.
Viewed in this context, the platform of obesity provides an opportunity to evaluate cancer biology from a novel angle. The mechanisms by which obesity promotes pancreatic cancer are poorly understood. Study of pancreatic cancer in obesity therefore presents a golden opportunity to gain insight into unique aspects of pancreatic tumor biology, and thus identify novel targets for directed therapeutic intervention.
Epidemiology of Obesity-Related Pancreatic Adenocarcinoma
Numerous epidemiologic studies have evaluated the relationship between obesity and increased risk of developing pancreatic cancer. Together, the vast majority of these studies confirm a clear association between increasing obesity (generally measured as BMI) and increased risk of developing pancreatic cancer, similar to the influence of obesity on other solid organ malignancies (3,15,17,24,32,34,36,38,46,50,56,70-75,84-86, 91,95,102,105,106,111,112,117,118,138,142).
Clinical Observations of Obesity and Pancreatic Adenocarcinoma
One clinical study evaluated visceral fat - as measured by retrorenal fat measured on cross-sectional imaging and found that patients with increased visceral fat had nearly twofold increased incidence of any complication of pancreatic resection. A second study evaluated 240 patients having pancreatoduodenectomy for pancreatic adenocarcinoma. In this study, obesity was associated with increased operative time and blood loss, but not with increased overall complication rate or perioperative death (136).
Four clinical reports have specifically addressed the impact of obesity on long-term outcomes after pancreatic resection for adenocarcinoma. Results from these reports are heterogeneous. Fleming et al were the first to draw attention to the potential negative impact of obesity on long term survival of pancreatic cancer patients (31). Their report documented a nearly twofold increase in the risk of recurrence and disease-related death in a subset of patients (21% of their population) with BMI > 35. A second study included 306 resected pancreatic cancer patients, 22% of whom were obese (BMI > 30) (6). These patients had increased blood loss and perioperative complication rates; however, no difference in long-term survival (non-obese 12.6 months vs obese 11.3 months) between these groups. A third study reported outcomes in 795 patients undergoing pancreatoduodenectomy for cancer, 14% of whom were obese (124). Obese patients had increased blood loss and pancreatic fistula rates, but improved 5-year survival (22% vs 15% in non-obese patients).
A recent study from the Mayo Clinic included 586 pancreatic cancer patients resected over a 26 year period (61). Twenty-one percent of these patients were obese. Obesity correlated with increased operative duration and blood loss. Perioperative morbidity and mortality were similar in obese and non-obese patients, and no difference in long-term survival was seen.
These studies highlight several challenges associated with obesity research. Firstly, BMI, while relatively easy to calculate and follow, is a very blunt instrument with which to measure the true effects of obesity. Although BMI is well accepted as an obesity measurement, it results in somewhat artificial segregation. Better measures may include volumetric analysis of visceral fat (66). For example, a small pilot study by Balentine et al suggested that increased intraabdominal fat correlated with poorer survival in pancreatic cancer, irrespective of BMI (4).Along these lines, our group showed a correlation between increased intrapancreatic adipocyte volume at the cut neck margin and poor long term survival (81).
Basic Mechanisms in Obesity Related Cancer
Broadly speaking, obesity may impact tumor growth at multiple different levels: systemically, by influencing the inflammatory milieu and immune response; locally (i.e. the peri-pancreatic and/or retroperitoneal adipocyte mass) by paracrine hormonal/inflammatory mediator production; and directly at the tumor level via intratumoral adipocytes within the microenvironment (Figure 2).
Leptin, Adiponectin, and Cancer
Leptin receptors have been identified in numerous cancer tissues and cell lines, including breast, colon, esophageal, genitourinary, endocrine, and lymphoma/leukemia (37,52). Our group has documented leptin receptor presence on murine pancreatic cancer cells. In vitro studies have generally shown leptin to be mitogenic in cancer cell systems, including breast, colon, ovarian, lung, prostate and esophageal (37). However, some inconsistencies exist. For example, exogenous leptin administration did not affect adrenal cancer cells in culture (41), and while leptin promoted the growth of hepatocellular cancer cells in vitro, exogenous leptin suppressed growth of this tumor in nude mice (25,133).
Epidemiologic studies have shown an association between increased serum leptin and increased tumor growth in a wide range of cancers including breast, colorectal, ovarian, and genitourinary (39). Though not all epidemiologic studies have been uniformly conclusive, these clinical data largely support the relationship between elevated leptin concentration and an increased incidence of cancer.
Adiponectin receptors have been identified on a wide variety of cancer cell lines and human tumors, including breast, colon, gastric, endometrial, neuroblastoma, and hepatocellular carcinoma. We and others have documented adiponectin receptor presence in murine pancreatic cancer cells. In vitro studies have shown that adiponectin suppresses the growth of leukemia, breast, prostate, and hepatocellular carcinoma (14,65,132,141). In contrast, exogenous adiponectin stimulated proliferation of colonic HT29 epithelial cells (94). Far fewer in vivo studies have been reported; however, increased adiponectin (either by exogenous administration or by adenovirus upregulation) has decreased mammary tumorigenesis, fibrosarcoma, and hepatocellular carcinoma (11,65,77). On the other hand, adiponectin transgenic mice did not show reduced susceptibility to developing carcinogen-stimulated colon cancer (23). Interesting recent studies have explored the potential interaction between adiponectin and leptin: adiponectin has been shown to inhibit leptin-stimulated proliferation of esophageal, colon, and hepatocellular cancer cell lines (29,89,93) .
Clinical and epidemiologic studies have shown a strong and consistent inverse association between adiponectin and cancer development, including breast, endometrial, prostate, gastric, colon, and leukemia (39). Thus, while fewer data regarding adiponectin and cancer are available, the majority of clinical and experimental studies support the relationship between decreased adiponectin and increased carcinogenesis.
Leptin and Adiponectin in Pancreatic Adenocarcinoma
Several reports have evaluated leptin and adiponectin in pancreatic cancer. Brown et al were the first to measure preoperative serum leptin concentration in PDAC patients (12). Two other smaller studies showed decreased serum leptin concentration in pancreatic cancer patients relative to control patients (20,103). Patients in both of these studies were lean, which may explain why these small clinical studies conflict with the majority of other reports of leptin in cancer.
In experimental studies addressing leptin’s effect on pancreatic cancer growth, exogenous leptin (in subphysiological doses) decreased the growth of two human pancreatic cancer cell lines (114). In contrast, our group has shown increased pancreatic cancer growth in obese mice that are hyperleptinemic (LepDb and diet-induced obese mice) as well as in those without leptin (LepOb) (135,148). These conflicting findings highlight the need to study the isolated effects of leptin on pancreatic cancer. Leptin receptors are present in human pancreatic cancers; in preliminary studies, we have documented the presence of leptin receptor mRNA in murine pancreatic cancers.
Clinical studies evaluating adiponectin in pancreatic cancer have generated inconsistent data. Two studies reported increased serum adiponectin concentration in patients with pancreatic cancer relative to controls (19,20). All patients in these studies were lean, and at least half had jaundice and/or cholestasis (which significantly affects adiponectin measurement). Another small study reported no difference in circulating adiponectin concentration between pancreatic cancer patients and controls (10). The largest study of adiponectin in pancreatic cancer patients documented an inverse relationship between circulating adiponectin and risk of pancreatic cancer (116).
In experimental studies, our group found a significant negative correlation between circulating adiponectin and proliferation of murine pancreatic cancers in a congenital obesity model, as well as a significant negative correlation between adiponectin and tumor weight in a diet-induced obesity model (135,148). Adiponectin receptors are present in human pancreatic cancer (20); we have also documented the presence of AdipoR1 and AdipoR2 in murine pancreas (130) as well as in murine pancreatic cancer cell lines.
From currently available data, elevated leptin in general is associated with increased tumorigenesis in clinical studies and is mitogenic in in vitro cancer systems, while decreased adiponectin in general is associated with increased tumorigenesis in clinical studies and adiponectin administration attenuates cancer growth in vitro.
Other Mechanisms Linking Obesity and Cancer
In addition to altered adipokine milieu, several other mechanisms offer attractive links between obesity and cancer. These mechanisms include adipocyte production of growth factors and proangiogenic factors, mitochondrial dysfunction related to oxidation-reduction potential, changes in the inflammatory profile, steroid hormone imbalance, obesity-regulated immune cell modulation, and dysregulation of the insulin axis (16,129). Hyperinsulinemia and alteration of insulin-like growth factors present in the obese state may either interact with or obscure other direct and indirect effects of adipokines.
Obesity clearly exerts a negative effect on patients with acute pancreatitis and pancreatic cancer. Strong epidemiologic data show that obesity is associated with increased development of pancreatic cancer. The mechanisms modulating the effects of obesity on pancreatic disease are partly defined, but offer exciting paths for study, and an opportunity to discover much needed therapy for these devastating problems.
- Allison DC, Piantadosi S, Hruban RH, Dooley WC, Fishman EK, Yeo CJ, et al. DNA content and other factors associated with ten-year survival after resection of pancreatic carcinoma. J Surg Oncol 67: 151-159, 1998. PMID: 9530884.
- Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257(1):79-83, 1999. PMID: 10092513.
- Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB et al. Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med 170: 791-802, 2010. PMID: 20458087.
- Balentine CJ, Enriquez J, Fisher W, Hodges S, Bansal V, Sansgiry S, et al. Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg 14: 1832-1837, 2010. PMID: 20725799.
- Barb D, Williams CJ, Neuwirth AK, Mantzoros CS. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am. J. Clin. Nutr 86: s858-866, 2007. PMID: 18265479.
- Benns M, Woodall C, Scoggins C, McMasters K, Martin R. The impact of obesity on outcomes following pancreatectomy for malignancy. Ann Surg Oncol 16: 2565-2569, 2009. PMID: 19557479.
- Bilimoria KY, Bentram DJ, Tomlinson JS, Merkow RP, Stewart AK, Ko CY, et al. Quality of pancreatic cancer care at Veterans Administration compared with non-Veterans Administration hospitals. Am J Surg 194(5): 588-593, 2007. PMID: 17936418.
- Bjorbaek C, Kahn, B.B. Leptin signaling in the central nervous system and the periphery. Recent Prog. Horm. Res 59: 305- 331, 2004. PMID: 14749508.
- Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab 81: 3419-3423, 1996. PMID: 8784108.
- Bouloumie A.; Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ. Res 83: 1059-1066, 1998. PMID: 9815153.
- Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 101: 2476-2481, 2004. PMID: 14983034.
- Brown DR, Berkowitz DE, Breslow MJ. Weight loss is not associated with hyperleptinemia in humans with pancreatic cancer. J Clin Endocrinol Metab 86: 162-166, 2001. PMID: 11231995.
- Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, et. al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285(3): E527-533, 2003. PMID: 12736161.
- Bub JD, Miyazaki T, Iwamoto Y. Adiponectin as a growth inhibitor in prostate cancer cells. Biochem Biophys Res Commun 340: 1158-1166, 2006. PMID: 16403434.
- Bueno de Mesquita HB, Moerman CJ, Runia S, Maisonneuve P. Are energy and energy-providing nutrients related to exocrine carcinoma of the pancreas? Int J Cancer 46(3):435-444, 1990. PMID: 2394510.
- Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4: 579-591, 2004. PMID: 15286738.
- Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348: 1625-1638, 2003. PMID: 12711737.
- Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc. Natl. Acad. Sci. U S A 98: 6390-6395, 2001. PMID: 11344271.
- Chang MC, Chang YT, Su TC, Yang WS, Chen CL, Tien YW, et al. Adiponectin as a potential differential marker to distinguish pancreatic cancer and chronic pancreatitis. Pancreas 35: 16-21, 2007. PMID: 17575540.
- Dalamaga M, Migdalis I, Fargnoli JL, Papadavid E, Bloom E, Mitsiades N, et al. Pancreatic cancer expresses adiponectin receptors and is associated with hypoleptinemia and hyperadiponectinemia: a case-control study. Cancer Causes Control 20: 625-633, 2009. PMID: 19051043.
- De Waele B, Vanmierlo B, Van Nieuwenhove Y, Delvaux G. Impact of body overweight and class I,II and III obesity on the outcome of acute biliary pancreatitis. Pancreas 32 (4): 343-345, 2006. PMID: 16670615.
- Duarte-Rojo A, Lezama-Barreda A, Ramierz-Iglesias MT, Pelaez-Luna M, Robles Diaz G. Is leptin related to systemic inflammatory response in acute pancreatitis? World J Gastroenterol 12(27): 4392-4396, 2006. PMID: 16865784.
- Ealey KN, Lu S, Lau D, Archer MC. Elevated circulating adiponectin and elevated insulin sensitivity in adiponectin transgenic mice are not associated with reduced susceptibility to colon carcinogenesis. Int J Cancer 124: 2226-2230, 2009. PMID: 18174274.
- Eberle CA, Bracci PM, Holly EA. Anthropometric factors and pancreatic cancer in a population-based case-control study in the San Francisco Bay area. Cancer Causes Control 16(10):1235-1244, 2005. PMID: 16215874.
- Elinav E, Abd-Elnabi A, Pappo O, Bernstein I, Klein A, Engelhardt D, et al. Suppression of hepatocellular carcinoma growth in mice via leptin, is associated with inhibition of tumor cell growth and natural killer cell activation. J Hepatol 44: 529-536, 2006. PMID: 16310278.
- Enquist IF, Gliedman ML. Gross autopsy findings in cases of fatal acute pancreatitis. AMA Arch Surg 77(6):985-991, 1958. PMID: 13594003.
- Fagenholz PJ, Fernandex-del Castillo C, Harris NS, Pelletier AJ, Camargo CA Jr. Direct medical costs of acute pancreatitis hospitalizations in the United States. Pancreas 35 (4): 302-307, 2007. PMID: 18090234.
- Fayad R, Pini M, Sennello JA, Cabay RJ, Chan L, Xu A, et al. Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology 132(2):601-614, 2007. PMID: 17258715.
- Fenton JI, Birmingham JM, Hursting SD, Hord NG. Adiponectin blocks multiple signaling cascades associated with leptin-induced cell proliferation in Apc Min/+ colon epithelial cells. Int J Cancer 122: 2437-2445, 2008. PMID: 18338750.
- Flegal K.M, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA 303: 235-241, 2010. PMID: 20071471.
- Fleming JB, Gonzalez RJ, Petzel MQ, Lin E, Morris JS, Gomez H, et al. Influence of obesity on cancer-related outcomes after pancreatectomy to treat pancreatic adenocarcinoma. Arch Surg 144: 216-221, 2009. PMID: 19289659.
- Friedman GD, van den Eeden SK. Risk factors for pancreatic cancer: an exploratory study. Int J Epidemiol 22(1): 30-37, 1993. PMID: 8449644.
- Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FR, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98(4): 2005-2010, 2001. PMID: 11172066.
- Fryzek JP, Schenk M, Kinnard M, Greenson JK, Garabrant DH. The association of body mass index and pancreatic cancer in residents of southeastern Michigan, 1996-1999. Am J Epidemiol 162(3): 222-228, 2005. PMID: 15987732.
- Funnell IC, Bornman PC, Weakley SP, Terblanche J, Marks IN. Obesity: an important prognostic factor in acute pancreatitis. Br J Surg 80(4): 484-286, 1993. PMID: 8495317.
- Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283(19): 2552-2558, 2000. PMID: 10815119.
- Garofalo C, Surmacz E. Leptin and cancer. J. Cell Physiol 207: 12-22, 2006. PMID: 16110483.
- (38). Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol 207: 12-22, 2006.
- Ghadirian P, Simard A, Baillargeon J, Maisonneuve P, Boyle P. Nutritional factors and pancreatic cancer in the francophone community in Montreal, Canada. Int J Cancer 47(1):1-6, 1991. PMID: 1845960.
- Giovannucci E, Michaud D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132: 2208-2225, 2007. PMID: 17498513.
- Glasgow RE, Jackson HH, Neumayer L. Pancreatic resection in Veterans Affairs and selected university medical centers: results of the patient safety in surgery study J Am Coll Surg 204(6): 1252-1260, 2007. PMID: 17544083.
- Glasow A, Bornstein SR, Chrousos GP, Brown JW, Scherbaum WA. Detection of Ob-receptor in human adrenal neoplasms and effect of leptin on adrenal cell proliferation. Horm Metab Res 31: 247-251, 1999. PMID: 10333078.
- Gloor B, Muller CA, Worni M, Martignoni ME, Uhl W, Buchler MW. Late mortality in patients with severe acute pancreatitis. Br J Surg 88(7): 975-979, 2001. PMID: 11442530.
- Gultekin FA, Kerem M, Tatlicioglu E, Aricioglu A, Unsal C, Bukan N. Leptin treatment ameliorates acute lung injury in rats with cerulean-induced acute pancreatitis. World J Gastroenterol 13 (21): 2932-2938, 2007. PMID: 17589942.
- Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab. Clin North Am 37: 753-768, x-xi, 2008. PMID: 18775362.
- Halonen KI, Leppaniemi AK, Puolakainen PA, Lundin JE, Kemppainen EA, Hietaranta AJ, et al. Severe acute pancreatitis: prognostic factors in 270 consecutive patients. Pancreas 21 (3): 266-271, 2000. PMID: 11039471.
- Hanley AJ, Johnson KC, Villeneuve PJ, Mao Y. Physical activity, anthropometric factors and risk of pancreatic cancer: results from the Canadian enhanced cancer surveillance system. Int J Cancer 94(1):140-147, 2001. PMID: 11668489.
- Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20(6):1595-1599, 2000. PMID: 10845877.
- Housa D, Housova J, Vernerova Z, Haluzik M. Adipocytokines and cancer. Physiol. Res 55: 233-244, 2006. PMID: 16238454.
- Howard TJ, Krug JE, Yu J, Zyromski NJ, Schmidt CM, Jacobson LE, et al. A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon's contribution to long-term survival in pancreatic cancer. J Gastrointest Surg 10: 1338-1345; discussion 45-6, 2006. PMID: 17175452.
- Howe GR, Jain M, Miller AB. Dietary factors and risk of pancreatic cancer: results of a Canadian population-based case-control study. Int J Cancer 45(4):604-608, 1990. PMID: 2157670.
- Iannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cytic fibrosis: an immunohistochemical study. Hum Pathol 15(3): 278-284, 1984. PMID: 6365738.
- Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10: 4325-4331, 2004. PMID: 15240518.
- Jaworek J, Bonio J, Leja-Szpa A, Nawrot K, Tomaszewska MR, Stachura J, et al. Sensory nerves in central and peripheral control of pancreatic integrity by leptin and melatonin. J Physiol Pharmacol 53(1): 51-74, 2002. PMID: 11939719.
- Jaworek J, J. Bonior Konturek S J, Bilski J, Szlachcic A, Pawlik WW. Role of leptin in the control of postprandial pancreatic enzyme secretion. J Physiol Pharmacol 54 (4): 950-955, 2003. PMID: 14726613.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 59: 225-249, 2009. PMID: 19474385.
- Johansen D, Borgstrom A, Lindkvist B, Manjer J. Different markers of alcohol consumption, smoking and body mass index in relation to risk of pancreatic cancer. A prospective cohort study within the Malmo Preventive Project. Pancreatology 9(5): 677-686, 2009. PMID: 19684432.
- Johnson CD, Toh SK, Campbell MJ. Combination of APACHE-II score and an obesity score (APACHE-O) for the prediction of severe acute pancreatitis. Pancreatology 4(1): 1-6, 2004. PMID: 14988652.
- Karimgani I, Porter KA, Langevin RE, Banks PA. Prognostic factors in sterile pancreatic necrosis. Gastroenterology 103(5): 1636-1640, 1992. PMID: 1426885.
- Kawanami D, Maemura K, Takeda N, Harada, T, Nojiri R, Imai Y, et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res 314(2):415-419, 2004. PMID: 14733921.
- Kerem M, Bedirli A, Pasaoglu, H, Unsal C, Yilmaz TU, Ofluoglu E, et al. Role of ghrelin and leptin in predictin the severity of acute pancretitis. Dig Dis Sci 52 (4): 950-955, 2007. PMID: 17333355.
- Khan S, Sclabas G, Reid-Lombardo K, Sarr MG, Nagorney D, Kendrick M, et al. Does body mass index/morbid obesity influence outcome in patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma? J Gastrointest Surg 14: 1820-1825, 2010. PMID: 20676790.
- Kharroubi I, Rasschaert J, Eizirik DL, Cnop M. Expression of adiponectin receptors in pancreatic beta cells. Biochem Biophys Res Commun 312(4):1118-1122, 2013. PMID: 14651988.
- Kistorp C, Faber J, Galatius S, Gustafsson F, Frustyk J, Flyvbjerb A, et al. Plasma Adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 112(12): 1756-1762, 2005. PMID: 16157772.
- Konturek PC, Jaworek J, Maniatoglou A, Bonior J, Meixner H, Konturek SJ, et al. Leptin mondulates the inflammatory response in acute pancreatitis. Digestion 65(3): 149-160, 2002. PMID: 12138320.
- Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, et al. Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies. J Clin Endocrinol Metab 92: 1041-1048, 2007. PMID: 17192291.
- Kovanlikaya AC, Guclu C, Desai C, Becerra R, Gilsanz V. Fat quantification using three-point Dixon technique: in vitro validation. Acad Radio 12(5): 636-639, 2005. PMID: 15866138.
- Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109(17):2046-2049, 2004. PMID: 15096450.
- Lago, F.; Dieguez, C.; Gomez-Reino, J.; Gualillo, O. The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev 18: 313-325, 2007. PMID: 17507280.
- Lankisch PG, Schirren CA. Increased body weight as a prognostic parameter for complications in the course of acute pancreatitis. Pancreas 5(5): 626-629, 1990. PMID: 2235973.
- Larsson SC, Permert J, Hakansson N, Naslund I, Bergkvist L, Wolk A. Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. Br J Cancer 93(11):1310-1315, 2005. PMID: 16288300.
- Lee IM, Sesso HD, Oguma Y, Paffenbarger RS, Jr. Physical activity, body weight, and pancreatic cancer mortality. Br J Cancer 88(5):679-683, 2003. PMID: 12659113.
- Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 301: 2553-2562, 2009. PMID: 19549972.
- Lin Y, Kikuchi S, Tamakoshi A, Yagyu K, Obata Y, Inaba Y, et al. Obesity, physical activity and the risk of pancreatic cancer in a large Japanese cohort. Int J Cancer 120: 2665-2671, 2007. PMID: 17304505.
- Luo J, Margolis KL, Adami HO, LaCroix A, Ye W, Women's Health Initiative Investigators.. Obesity and risk of pancreatic cancer among postmenopausal women: the Women's Health Initiative (United States). Br J Cancer 99(3):527-531, 2008. PMID: 18628761.
- Luo J, Iwasaki M, Inoue M, Sasazuki S, Otani T, Ye W, et al. Body mass index, physical activity and the risk of pancreatic cancer in relation to smoking status and history of diabetes: a large-scale population-based cohort study in Japan--the JPHC study. Cancer Causes Control 18(6): 603-612, 2007. PMID: 17401636.
- Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1: 1155-1161, 1995. PMID: 7584987.
- Man K, Ng KT, Xu A, Cheng Q, Lo CM, Xiao JW, et al. Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling. Clin Cancer Res 16: 967-977, 2010. PMID: 20103676.
- Martinez J, Johnson CD, Sanchez-Paya, J, De Madaria E, Robles-Diaz G, Perez-Mateo M. Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis. Pancraetology 6(3): 206-209, 2006. PMID: 16549939.
- Martinez J, Sanchez-Paya J, Palazon JM, Aparicio JR, Pico A, Perez-Mateo M, Obesity: a prognostic factor of severity in acute pancreatitis. Pancreas 19(1):15-20, 1999. PMID: 10416686.
- Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology 40(1):177-184, 2004. PMID: 15239101.
- Mathur A, Zyromski NJ, Pitt HA, Al-Azzawi H, Walker JJ, Saxena R, et al. Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. J Am Coll Surg 208: 984-994, 2009. PMID: 19476877.
- Mentula P, Kuylanpaa ML, Kemppainen E, Repo H, Puolakkainen P. Early inflammatory response in acute pancreatitis is little affected by body mass index. Scand J Gastroenterol 42(11): 1362-1368, 2007. PMID: 17852885.
- Mercy CM, Rubio V, Duarte-Rojo A, Suazo-Barahona J, Pelaez-Luna M, Milke P, et al. Android fat distribution as predictor of severity in acute pancreatitis. Pancreatology 2(6): 543-549, 2002. PMID: 12435867.
- Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 286: 921-929, 2001. PMID: 11509056.
- Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 30A(3):344-350, 1994. PMID: 8204357.
- Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in Nord-Trondelag, Norway. Cancer Causes Control 11(7):645-652, 2000. PMID: 10977109.
- Nishihara T, Matsuda M, Araki H, Oshima K, Kihara S, Funahashi T, et al. Effect of adiponectin on murine colitis induced by dextran sulfate sodium. Gastroenterology 131(3): 853-861, 2006. PMID: 16952554.
- Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221: 59-66, 1995. PMID: 7826162.
- Nkhata KJ, Ray A, Schuster TF, Grossmann ME, Cleary MP. Effects of adiponectin and leptin co-treatment on human breast cancer cell growth. Oncol Rep 21: 1611-1619, 2009. PMID: 19424644.
- Nordback I, Pessi T, Auvinen O, Autio V. Determination of necrosis in necrotizing pancreatitis.Br J Surg 72(3): 225-227, 1985. PMID: 3978385.
- Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Body mass index and physical activity as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Cancer Causes Control 18(2):165-175, 2007. PMID: 17219012.
- Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295: 1549-1555, 2006. PMID: 16595758.
- Ogunwobi OO, Beales IL. Globular adiponectin, acting via adiponectin receptor-1, inhibits leptin-stimulated oesophageal adenocarcinoma cell proliferation. Mol Cell Endocrinol 285: 43-50, 2008. PMID: 18313838.
- Ogunwobi OO, Beales IL. Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Pept 134: 105-113, 2006. PMID: 16529829.
- Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 23(21): 4742-4754, 2005. PMID: 16034050.
- Olsen TS. Lipomatosis of the pancreas in autopsy material and its relation to age and overweight. Acta Pathol Microbiol Scand 86A(5): 367-373, 1978. PMID: 716899.
- Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103(8):1057-1063, 2001. PMID: 11222466.
- Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100(25): 2473-2476, 1999. PMID: 10604883.
- Papachristou GI,Papchristou DJ, Avula H, Slivka A, Whitcomb DC. Obesity increases the severity of acute pancreatitis: performance of APACHE-O score and correlation with the inflammatory response. Pancreatology 6(4): 279-285, 2006. PMID: 16636600.
- Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol. Biomarkers Prev 14: 459-466, 2005. PMID: 15734973.
- Peake PW, Kriketos AD, Campbell LV, Shen Y, Charlesworth JA. The metabolism of isoforms of human adiponectin: studies in human subjects and in experimental animals. Eur J Endocrinol 153(3): 409-417, 2005. PMID: 16131604.
- Pezzilli R, Morselli-Labate AM, Migliori M, Manca M, Bastagli L, Gullo L. Obesity and the risk of pancreatic cancer: an italian multicenter study. Pancreas 31(3): 221-224, 2005. PMID: 16163052.
- Pezzilli R, Barassi A, Corsi MM, Morselli-Labate AM, Campana D, Casadei R, et al. Serum leptin, but not adiponectin and receptor for advanced glycation end products, is able to distinguish autoimmune pancreatitis from both chronic pancreatitis and pancreatic neoplasms. Scand J Gastroenterol 45: 93-99, 2010. PMID: 19883273.
- Porter KA, Banks PA. Obesity as a predictor of severity in acute pancreatitis. Int J Pancreatol 10(3-4): 247-52, 1991. PMID: 1787336.
- Rapp K, Schroeder J, Klenk J, Stoehr S, Ulmer H, Concin H, et al. Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria. Br J Cancer 93(9):1062-1067, 2005. PMID: 16234822.
- Samanic C, Chow WH, Gridley G, Jarvholm B, Fraumeni JF, Jr. Relation of body mass index to cancer risk in 362,552 Swedish men. Cancer Causes Control 17(7): 901-909, 2006. PMID: 16841257.
- Santosa S, Demonty I, Lichtenstein AH, Cianflone K, Jones PJ. An investigation of hormone and lipid associations after weight loss in women. J Am Coll Nutr 26(3): 250-258, 2007. PMID: 17634170.
- Schaffler A, Landfriend K, Volk M, Furst A, Buchler C, Scholmerich J, et al. Potential of adipocytokines in predicting peripancratic necrosis and severity in acute pancreatitis: pilot study. J Gastroenterol Hepatol 22(3): 326-334, 2007. PMID: 17295762.
- Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. JBiol Chem 270(45): 26746-26749, 1995. PMID: 7592907.
- Segersvard R, Sylvan M, Herrington M, Larsson J, Permert J. Obesity increases the severity of acute experimental pancreatitis in the rat. Scand J Gastroenterol 36(6): 658-663, 2001. PMID: 11424327.
- Shibata A, Mack TM, Paganini-Hill A, Ross RK, Henderson BE. A prospective study of pancreatic cancer in the elderly. Int J Cancer 58(1):46-49, 1994. PMID: 8014014.
- Silverman DT, Swanson CA, Gridley G, Wacholder S, Greenberg RS, Brown LM, et al. Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst 90(22):1710-1719, 1998. PMID: 9827525.
- Somasundar P, McFadden DW, Hileman SM, Vona-Davis L. Leptin is a growth factor in cancer. J Surg Res 116, 337- 349, 2004. PMID: 15013374.
- Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res 113: 50-55, 2003. PMID: 12943810.
- Staiger K, Stefan N, Staiger H, Brendel MD, Brandhorst D, Bretzel RG, et al. Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis. J Clin Endocrinol Metab 90(12): 6707-6713, 2005. PMID: 16204361.
- Stolzenberg-Solomon RZ, Weinstein S, Pollak M, Tao Y, Taylor PR, Virtamo J, et al. Prediagnostic adiponectin concentrations and pancreatic cancer risk in male smokers. Am J Epidemiol 168: 1047-1055, 2008. PMID: 18801887.
- Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes D. A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland). Cancer Causes Control 13(5): 417-426, 2002. PMID: 12146846.
- Stolzenberg-Solomon RZ, Adams K, Leitzmann M, Schairer C, Michaud DS, Hollenbeck A, et al. Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort. Am J Epidemiol 167(5): 586-597, 2008. PMID: 18270373.
- Suazo-Barahona J, Carmona-Sanchez R, Robels-Diaz G, Milke-Garcia P, Vargas-Vorackova, F, Uscanga-Dominguez L, et al. Obesity: a risk factor for severe acute biliary and alcoholic pancreatitis. Am J Gastroenterol 93(8): 1324-1328, 1998. PMID: 9707059.
- Sweeney G. Leptin signaling. Cell Signal 14(8):655-663, 2002. PMID: 12020765.
- Talamini G, Bassi C, Falconi M, Sartori N, Frulloni L, DiFrancesco V, et al. Risk of death from acute pancreatitis. Role of early, simple "routine" data. Int J Pancreatol 19(1):15-24, 1996. PMID: 8656023.
- Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772-783, 2006. PMID: 16998510.
- Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 99(25): 16309-16313, 2002. PMID: 12456889.
- Tsai S, Choti MA, Assumpcao L, Cameron JL, Gleisner AL, Herman JM, et al.. Impact of Obesity on Perioperative Outcomes and Survival Following Pancreaticoduodenectomy for Pancreatic Cancer: A Large Single-Institution Study. J Gastrointest Surg 14: 1143-1150, 2010. PMID: 20431978.
- Tsai CJ. Is obesity a significant prognostic factor in acute pancreatitis? Dig Dis Sci 43(10): 2251-2254, 1998. PMID: 9790461.
- Tukiainen E, Kylanpaa ML, Ebeling P, Kemppainen E, Puolakkainen P, Reoim H. Leptin and adiponectin levels in acute pancreatitis. Pancreas 32(2): 211-214, 2006. PMID: 16552343.
- Uhl W, Warshaw A, Imrie C, Bassi C, McKay CJ, Lankisch PG, et al. IAP Guidelines for the Surgical Management of Acute Pancreatitis. Pancreatology 2(6):565-573, 2002. PMID: 12435871.
- Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44(8): 863-870, 1995. PMID: 7621989.
- van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 18: 2569-2578, 2009. PMID: 19755644.
- Wade TE, Mathur A, Lu D, Swartz-Basile DA, Pitt HA, Zyromski NJ. Adiponectin receptor-1 expression is decreased in the pancreas of obese mice. J Surg Res 154: 78-84, 2009. PMID: 19062045.
- Walters MN. Adipose atrophy of the exocrine pancreas. J Pathol Bateriol 92(2): 547-557, 1966. PMID: 5964381.
- Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, et al. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 66: 11462-11470, 2006. PMID: 17145894.
- Wang XJ, Yuan SL, Lu Q, Lu YR, Zhang J, Liu Y, Wang WD. Potential involvement of leptin in carcinogenesis of hepatocellular carcinoma. World J Gastroenterol 10: 2478-2481, 2004. PMID: 15300888.
- Warzecha Z, Dembinski A, Ceranowicz P, Jaworek J, Konturek PC, Dembinski M, et al.. Influence of leptin administration on the course of acute ischemic pancreatitis. J Physiol Pharmacol 53(4 Pt 2): 775-790, 2002. PMID: 12510863.
- White PB, True EM, Ziegler KM, Wang SS, Swartz-Basile DA, Pitt HA, et al. Insulin,leptin, and tumoral adipocytes promote murine pancreatic cancer growth. J Gastrointest Surg 14(12): 1888-1893, 2010. PMID: 20859700.
- Williams TK, Rosato EL, Kennedy EP, Chojnacki KA, Andrel J, Hyslop T, et al. Impact of obesity on perioperative morbidity and mortality after pancreatoduodenectomy. J Am Coll Surg 208: 210-217, 2009. PMID: 19228532.
- Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 323(2):630-635, 2004. PMID: 15369797.
- Wolk A, Gridley G, Svensson M, Nyren O, McLaughlin JK, Fraumeni JF, et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 12(1):13-21, 2001. PMID: 11227921.
- Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloningof adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423(6941):762-769, 2003. PMID: 12802337.
- Yavuz N, Unal E, Memisoglu K, Krand O, Kiziler AR, Aydemir B, et al. Plasma leptin levels in rats with pancreatitis. Tohoku J Exp Med 204(4):243-248, 2004. PMID: 15572849.
- Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96: 1723-1732, 2000. PMID: 10961870.
- Zatonski W, Przewozniak K, Howe GR, Maisonneuve P, Walker AM, Boyle P. Nutritional factors and pancreatic cancer: a case-control study from south-west Poland. Int J Cancer 48(3):390-394, 1991. PMID: 2040534.
- Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505): 425-432, 1994. PMID: 7984236.
- Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.;Friedman, J.M. Positional cloning of the mouse obese gene and its human homologue. Nature, 1994, 372, 425-432.
- Zhou YP, Ling ZC, Grill VE. Inhibitory effects of fatty acids on glucose –regulated B-cell function: association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism. Metabolism 45(8): 981-986, 1996. PMID: 8769356.
- Zhou Y, Sun X, Jin L, Stringfield T, Lin L, Chen Y. Expression profiles of adiponectin receptors in mouse embryos. Gene Expr Patterns 5(5): 711-715, 2005. PMID: 15939384
- Zyromski NJ, Mathur A, Wade TE, Pitt HA, Wang S, Swartz-Basile DA, et al. Cannabinoid receptor-1 blockade attenuates acute pancreatitis in obesity by an adiponectin mediated mechanism. J Gastrointest Surg ;13(5):831-838, 2009. PMID: 19225848.
- Zyromski NJ, Mathur A, Yancey K, Gripe JT, Walker JJ, Lu D, et al. A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 295(3): G552-558, 2008. PMID: 18583460.
- Zyromski NJ, Mathur A, Pitt HA, Wade TE, Wang S, Nakshatri P, et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery 146: 258-263, 2009. PMID: 19628082.