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Effect of adiponectin and leptin administration on Con Ainduced alterations in hepatic histology. Lipodystrophic mice received a chronic infusion of vehicle, adiponectin (ADP), leptin (LEP), or their combination (ADP LEP) for 6 d. Untreated WT mice were used as controls. On d 7, mice received an iv injection of Con A. The liver was removed 24 h later for histological evaluation (left panels) and TUNEL staining (right panels). One representative staining of five performed in each group is shown.
Source publication
Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was o...
Context in source publication
Context 1
... effects of adiponectin and leptin administration on liver histology and hepatocyte cell death were also evaluated (Fig. 8). As demonstrated by hematoxylin and eosin staining, Con A induced cell infiltration and necrosis to a similar degree in WT and LD mice. TUNEL staining also indicated a similar degree of cell death in the two groups. Admini- stration of adiponectin protected LD mice from immune cell infiltration and liver necrosis and completely ...
Citations
... 10 Leptin and adiponectin play important roles in NAFLD etiology since leptin is believed to act as a pro-inflammatory factor that increases hepatotoxicity by regulating cytokine production and T-cell activation. 11 Additionally, leptin augments the oxidation of fatty acids in the liver by activating peroxisome proliferator-activated receptor-alpha and increasing NAFLD severity. 12 In contrast, adiponectin enhances glucose and fatty acid oxidation, improves insulin sensitivity, and plays a role in the hepatoprotective effects of adiponectin, including antisteatotic, anti-inflammatory, and antifibrogenic effects. ...
Background/aims:
Nonalcoholic fatty liver disease (NAFLD) is a common disease with severe inflammatory processes associated with numerous gastrointestinal diseases, such as inflammatory bowel disease (IBD). Therefore, we investigated the relationship between NAFLD and IBD and the possible risk factors associated with the diagnosis of IBD.
Methods:
This longitudinal nationwide cohort study investigated the risk of IBD in patients with NAFLD alone. General characteristics, comorbidities, and incidence of IBD were also compared.
Results:
Patients diagnosed with NAFLD had a significant risk of developing IBD compared to control individuals, who were associated with a 2.245-fold risk of the diagnosis of IBD and a 2.260- and 2.231-fold of increased diagnosis of ulcerative colitis and Crohn's disease, respectively (P< 0.001). The cumulative risk of IBD increased annually during the follow-up of patients with NAFLD (P< 0.001).
Conclusions:
Our results emphasize that NAFLD significantly impacts its incidence in patients with NAFLD. If patients with NAFLD present with risk factors, such as diabetes mellitus and dyslipidemia, these conditions should be properly treated with regular follow-ups. Furthermore, we believe that these causes may be associated with the second peak of IBD.
... With respect to innate immunity, leptin increases the cytotoxicity of natural killer cells, as well as increases the activation of granulocytes, macrophages, and dendritic cells [122][123][124][125][126][127][128]. As for adaptive immunity, leptin limits the proliferation of regulatory T cells but increases the production of naïve T cells and B cells [53,[129][130][131][132][133]. Although the exact mechanism is unclear, the presence of leptin is believed to influence cell survival, as exogenous leptin was found to delay apoptosis via intracellular JAK, NF-kB, and MAPK pathways [134][135][136]. ...
... Although the exact mechanism is unclear, the presence of leptin is believed to influence cell survival, as exogenous leptin was found to delay apoptosis via intracellular JAK, NF-kB, and MAPK pathways [134][135][136]. Overall, leptin induces an inflammatory response via immune cell activation, inducing chemotaxis and the release of cytokines [53,[129][130][131][132][133]. Likewise, leptin plays a role in immunity by maintaining the balance of Type I and Type II Helper T cells [137][138][139]. ...
Leptin is a well-known hunger-sensing peptide hormone. The role of leptin in weight gain and metabolic homeostasis has been explored for the past two decades. In this review, we have tried to shed light upon the impact of leptin signaling on health and diseases. At low or moderate levels, this peptide hormone supports physiological roles, but at chronically higher doses exhibits detrimental effects on various systems. The untoward effects we observe with chronically higher levels of leptin are due to their receptor-mediated effect or due to leptin resistance and are not well studied. This review will help us in understanding the non-anorexic roles of leptin, including their contribution to the metabolism of various systems and inflammation. We will be able to get an alternative perspective regarding the physiological and pathological roles of this mysterious peptide hormone.
... Increased leptin levels act as a pro-inflammatory stimulus [20], and leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation [21]. On the other hand, leptin augments the oxidation of fatty acids in the liver by activating peroxisome proliferator-activated receptor-alpha (PPAR-α) [22]. ...
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer‐associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole‐body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low‐grade systemic inflammation characterized by altered adipokine regulation. Obesity‐related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non‐alcoholic fatty liver disease, viral hepatitis‐related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
... Previous studies showed a positive association between obesity and leptin and resistin concentrations [45][46][47][48]. Moreover, both leptin and resistin may stimulate the production of pro-inflammatory cytokines such as TNF-α and IL-6 via NF-κB activation [49][50][51]. Therefore, decreasing leptin and resistin concentrations may be considered a therapeutic target to reduce the inflammatory state associated with obesity [44]. ...
We examined the effects of six weeks of dark chocolate supplementation combined with interval jump rope exercise (JRE) on inflammatory cytokines, adipokines, and body composition in obese adolescent boys. Forty-eight obese adolescent boys (age = 15.4 ± 1.1 years and body mass index = 32.2 ± 2.4 kg/m 2) were randomly assigned into one of four groups: JRE + white chocolate (JW; n = 13), JRE + dark chocolate supplementation (JD; n = 13), dark chocolate supplementation (DS; n = 12), or control (C; n = 12). Participants in JW and JD groups performed JRE for three times per week for six weeks. Participants in the DS and JD groups consumed 30 g of dark chocolate containing 83% of cocoa. Body composition, pro-inflammatory cytokines ((hs-CRP, TNF-α, IL-6), adipokines (leptin, resistin, RBP-4, chemerin, MCP-1), and anti-inflammatory adipokines (irisin, adiponectin)) were evaluated prior to and after the intervention trials. All three intervention trials significantly (p < 0.05) decreased body mass, waist-hip ratio, fat mass, hs-CRP, TNF-α, IL-6, leptin, resistin, RBP-4, and MCP-1, and increased irisin and adiponectin concentrations. The improvements in these parameters were greater in the JD group, and additionally, chemerin concentrations decreased only in the JD group. JD enhanced adiponectin concentrations and decreased IL-6 concentrations compared to C. Moreover, JD significantly reduced chemerin concentrations, an effect not observed in any of the other interventions. We demonstrated that dark chocolate supplementation potentiated JRE-induced decreases in body mass, WHR, FM, hs-CRP, TNF-α, IL-6, leptin, resistin, RBP-4, and MCP-1, chemerin as well as increases irisin and adiponectin concentrations in obese adolescent boys. Therefore, JRE combined with dark chocolate supplementation could be a beneficial in reducing obesity-induced inflammation in adolescent boys.
... Functions in adaptive immunity include thymic homeostasis, naïve CD4 + cell proliferation, promotion of T helper 1 (T H 1) responses and suppression of CD4 + CD25 high regulatory T cells (Tregs) [18]. Consequently, leptin can contribute to the onset and progression of several T cell-controlled autoimmune diseases, including Crohn's disease [19,20], rheumatoid arthritis [21,22], multiple sclerosis [23,24] and autoimmune hepatitis [25][26][27]. Furthermore, clinical reports unequivocally link elevated serum leptin levels (caused by obesity) to an increased risk of certain cancers including prostate [28], breast [29,30], colorectal [31], renal cancers [32] and multiple myeloma [33,34]. ...
Leptin links body energy stores to high energy demanding processes like reproduction and immunity. Based on leptin’s role in autoimmune diseases and cancer, several leptin and leptin receptor (LR) antagonists have been developed, but these intrinsically lead to unwanted weight gain. Here, we report on the uncoupling of leptin’s metabolic and immune functions based on the cross talk with the epidermal growth factor receptor (EGFR). We show that both receptors spontaneously interact and, remarkably, that this complex can partially overrule the lack of LR activation by a leptin antagonistic mutein. Moreover, this leptin mutant induces EGFR phosphorylation comparable to wild-type leptin. Exploiting this non-canonical leptin signalling pathway, we identified a camelid single-domain antibody that selectively inhibits this LR-EGFR cross talk without interfering with homotypic LR signalling. Administration in vivo showed that this single-domain antibody did not interfere with leptin’s metabolic functions, but could reverse the leptin-driven protection against starvation-induced thymic and splenic atrophy. These findings offer new opportunities for the design and clinical application of selective leptin and LR antagonists that avoid unwanted metabolic side effects.
... Some studies have reported an increase in serum leptin levels in HBV infection because of the action of inflammatory cytokines, adipose tissues, and phagocytosis of macrophages. In addition, leptin stimulates macrophages to secrete inflammatory cells, such as TNF-α, IL-6, and IL-12, which can promote liver degeneration and necrosis [9]. However, no differences in serum leptin levels were observed between HBV patients and healthy people in some studies [10]. ...
... Kronik viral hepatitlerde inflamatuar süreçte artmış leptin üretiminin, CD4 T lenfositleri ve makrofajları uyararak sitokin salınımına yol açtıkları öne sürülmüştür (20). Bazı hayvan modellerinde ise leptinin aktifleştirdiği T hücrelerinin ya direkt hepatosit üzerine sitotoksik etki göstererek ya da aktif haldeki T hücrelerinin saldıkları mediatörler sayesinde hepatositleri hasara uğrattıkları tespit edilmiştir (21). Yine bir başka çalışmada, kronik viral hepatitli hastalarda leptin sisteminin, immunpatogenezde rolü olduğu gösterilmiştir (22). ...
Objective: Although the steatogenic effect of hepatitis B virus (HBV) has been established in several studies, it is not yet known whether it leads to hepatosteatosis in anti-HBc IgG-positive patients. This study aimed to investigate the relationship between the frequency of HBV and levels of serum adipokines in patients with hepatosteatosis and insulin resistance. Methods: Eighty patients diagnosed with hepatosteatosis by ultrasonography, who were admitted to our polyclinic between July 2011 and June 2012 for various reasons, and who had insulin resistance were included. Homeostasis model assessment-insulin resistance of >2.7 was considered as insulin resistance, and these patients was investigated for anti-HBc IgG. The anti-HBc IgG level was analyzed by enzyme-linked immunosorbent assay. Levels of adiponectin, resistin, and leptin in serum samples were analyzed in anti-HBc IgG (+) and anti-HBc IgG (-) groups. Results: Anti-HBc IgG was positive in 29 (36.2%) patients and negative in 51 (63.8%). While the level of leptin in the anti-HBc IgG (+) group was 31569.72 +/- 14027.64 ng/mL, it was 25410.73 +/- 10978.26 ng/mL in the anti-HBc IgG (-) group. The levels of leptin in the anti-HBc IgG (+) and anti-HBc IgG (-) groups were statistically significant (p=0.047). However, levels of adiponectin and resistin were not different between the groups. Conclusion: These results suggest that anti-HBc IgG positivity is involved in the etiology of hepatosteatosis and insulin resistance as well.
... The effect of leptin on circulating adiponectin concentrations has been previously studied with contradictory results. In this sense, leptin-deficient ob/ob mice, in which leptin's effect are absent, exhibit either decreased 18,19 , increased 20,21 , or unchanged 22 adiponectin circulating concentrations. Moreover, many previous studies have used supraphysiological or even pharmacological doses of leptin 18,23 that may overestimate its effects or, alternatively, exert no effect since it has been reported that pharmacological doses of leptin may lose its effect due to saturation or downregulation of receptors 24 or even elicit opposite effects to those observed after the administration of a low leptin dose around the physiological level 25 . ...
The circulating concentrations of adiponectin, an antidiabetic adipokine, have been shown to be reduced in obesity, in relation to an increase in inflammation. The aim of the present work was to assess the effect of leptin replacement on adiponectin levels and expression as well as on markers of oxidative stress and inflammation in leptin-deficient ob/ob mice. Twelve-week-old male mice (n = 7–10 per group) were treated with either saline (wild type and ob/ob mice) or leptin (ob/ob mice) for 18 days. A third group of ob/ob mice was treated with saline and pair-fed to the amount of food consumed by the leptin-treated group. Leptin replacement restored values of adiponectin (P < 0.001), reduced circulating 8-isoprostane and serum amyloid A (SAA) levels (P < 0.05 for both), and significantly downregulated the increased gene expression of osteopontin (Spp1, P < 0.05), Saa3 (P < 0.05), Cd68 (P < 0.01), Il6 (P < 0.01) and NADPH oxidase (Nox1 and Nox2, P < 0.01) in the perirenal WAT and Spp1 (P < 0.05) in the liver of ob/ob mice. In cultured adipocytes from ob/ob mice, leptin increased (P < 0.05) the mRNA expression and secretion of adiponectin. We concluded that circulating concentrations of adiponectin are positively regulated by leptin and ameliorate obesity-associated oxidative stress and inflammation in mice.
... Francois et al. 18 and Sennello et al. 19 ...
... Leptin also regulates immune surveillance in gastrointestinal cancers, including EAC, by inhibiting the activity of regulatory T cells. 19 Although subcutaneous tissue contributes significantly to the production of adipokines, their primary source in obese individuals is visceral adipose tissue. 50,51 Adipokinemediated carcinogenic effects resulting from increasing visceral fat levels have been observed in several gastrointestinal cancers, including EAC. 52 In addition to releasing adipokines, visceral fat is also associated with insulin resistance, and a key role for insulin and IGF-1 in regulating the malignant progression of esophageal cancer has recently been reported 15 (Table 1 and Figure 1). ...
The prevalence of obesity has steadily increased over the past few decades. Previous studies suggest that obesity is an oncogenic factor and that over 20% of all cancers are obesity-related. Among such cancers, digestive system malignancies (including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, liver, and pancreas) are reported most frequently. While the 5-year survival rates of cancers of the breast and prostate are 90%, that rate is only 45% for digestive cancers. In this review, the mechanisms of obesity-associated digestive cancers are discussed, with an emphasis on obesity-related gene mutations, insulin and insulin-like growth factor signaling pathways, chronic inflammation, and altered adipokine levels. Evidence that these factors often function interdependently rather than independently in carcinogenesis is presented. Recommended interventions that may reduce the burden of obesity-associated digestive cancers, such as participation in physical activity, diet modulation, and calorie restriction, are also described.
... Whereas we observed CD4 þ levels in the blood of wild-type mice between the trauma/sepsis-leptin1-group and the trauma/sepsis leptin2 group which were only higher by tendency as compared with the trauma/sepsis vehicle group, we observed an increase of splenic CD4 þ T-cells after leptin administration in a dose of 2.5 mg/g body weight in the sham model and in the trauma/sepsis model. The role of leptin in the maturation of Ly49þ NK cells has already been confirmed by their decreased number in leptin receptordeficient mice (30). In accordance with this finding, our study indicated a significant dose-dependent impact of leptin on the number of splenic Ly49þ NK cells in wild-type mice of the sham model. ...
Introduction:
Leptin is thought to play an important role in the regulation of the immune system. In patients, leptin is inversely proportional to interleukin-6 (IL-6) levels. Thus, the objective of our study was to evaluate a dose-dependent therapeutic impact of leptin with possible IL-6-dependency on immune actions and outcome in a trauma/sepsis model.
Materials and methods:
Sixty-nine wild-type and 63 IL-6 mice were subdivided into three groups: trauma/sepsis group (first hit: femur fracture and hemorrhage; second hit: cecal ligation and puncture 2 days later), trauma group (first hit and laparotomy), sham group (laparotomy only). Each group received vehicle or leptin (2.5 μg/g (leptin1) or 5 μg/g (leptin2)) subcutaneously and was observed for 8 days after induction of the first hit. Mortality, humoral, and cellular immune markers were determined.
Results:
We revealed a dose-dependent anti-inflammatory effect of exogenous leptin in the sepsis groups and to some extent a pro-inflammatory effect in the sham groups. Leptin administration resulted in a decreased mortality in septic wild-type mice (trauma/sepsis vehicle group: 36.4%, trauma/sepsis leptin1 group: 25%, trauma/sepsis leptin2 group: 0%) and in an increased mortality in septic IL-6 mice (53.8%, 83.4%, 100%). All mice of the trauma groups and sham groups survived. In wild-type trauma/sepsis mice, exogenous leptin led to increased levels of CD4 and CD8 in the spleen, and a less pronounced type IV hypersensitivity (P ≤ 0.039). Furthermore, it decreased the levels of tumor necrosis factor-α and IL-6, not reaching statistical significance.
Conclusions:
Due to the fact that leptin administration to traumatized and septic mice seems to have a positive effect on their outcome via IL-6 and does not negatively impact their medical condition if applied preventively, leptin might be a therapeutic agent for the prevention, or treatment of sepsis-related detrimental outcome after initial trauma.
