leptin and Hepatitis

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

Topics: Adipokines; Adiponectin; Blood Proteins; Chemokines; Cytokines; Galectin 3; Galectins; GPI-Linked Proteins; Hepatitis; Humans; Hypertension, Portal; Intercellular Signaling Peptides and Proteins; Interleukin-6; Lectins; Leptin; Liver; Liver Cirrhosis; Nicotinamide Phosphoribosyltransferase; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Resistin

Topics: Fatty Liver; Female; Hepatitis; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Oxidative Stress; Risk Factors; Tumor Necrosis Factor-alpha

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

Topics: Adolescent; Adult; Aged; Fatty Liver; Female; Hepatitis; Hormone Replacement Therapy; Humans; Leptin; Lipodystrophy; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Pilot Projects; Transaminases; Triglycerides

Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which, although usually relatively mild, may in some cause fibrosis, cirrhosis, and premature death resulting from liver failure. Its prevalence is increasing, and it is probably underestimated as a cause for cirrhosis. The need for an effective treatment is clear and urgent. Although several small, pilot, and randomized studies have been reported, large-scale studies are yet to be performed in patients with NASH. The aim of therapy is to intervene early in patients at risk of progression of liver disease. In this review, we summarize the extant literature on the management of NASH and discuss the potential future therapies and prophylactic recommendations in patients with NASH.

Topics: Diabetes Mellitus; Fatty Liver; Hepatitis; Humans; Hyperinsulinism; Iron; Leptin; Liver Transplantation; Risk Factors; Silymarin; Triglycerides; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid; Vitamin E

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer's disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.

Topics: Animals; Diabetes Mellitus, Type 2; Hepatitis; Inflammation; Kidney; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Receptors, Leptin

Liver function abnormalities are common in patients with inflammatory arthritis. However, the precise mechanism is still unclear. In this study, inflammatory arthritis was established in mice by subcutaneous injection of complete Freund's adjuvant, and the intravenous injection of concanavalin A (Con A) was employed to induce acute immune-mediated hepatitis in mice. The result showed that the arthritis mice were more susceptible to ConA-induced hepatitis than the control mice, as evidenced by increased hepatic necrosis, elevated serum alanine aminotransferase activity, and raised inflammatory cytokines. Besides, the in vitro assay demonstrated that the T cells from arthritis mice were more sensitive to the Con A stimulation than those from control mice. Moreover, we determined that the level of leptin, a kind of adipokine, was significantly increased in the serum and hepatic T cells of arthritis mice. Interestingly, the data indicated that the enhanced expression of leptin in hepatic T cells is responsible for the hypersensitivity of arthritis mice-derived T cells to Con A challenge. Collectively, our findings demonstrate an unexpected role of leptin in the connection between inflammatory arthritis and acute immune-mediated hepatitis, thus providing new insight into the clinical therapy of arthritis-related liver dysfunction.

Topics: Acute Disease; Animals; Arthritis; Concanavalin A; Cytokines; Disease Susceptibility; Hepatitis; Hypersensitivity; Inflammation; Inflammation Mediators; Leptin; Liver; Lymphocyte Activation; Mice, Inbred C57BL; Signal Transduction; T-Lymphocytes

How obesity affects the response to sepsis was not completely understood. It was hypothesized that obesity alters adipose and hepatic tissue inflammation through signal transducer and activator of transcription (STAT3) activation.. Male C57BL/6 mice at 6 weeks of age were randomized to a high-fat diet (60% kcal fat) or normal diet (16% kcal fat) for 6 to 7 weeks. Sepsis was then induced by cecal ligation and puncture, and animals were monitored for survival or sacrificed and tissue collected.. High-fat diet-fed mice gained more weight, had increased fat mass, and were glucose intolerant compared with normal diet-fed mice. Obesity increased hepatic neutrophil infiltration and injury after sepsis. Mice with obesity had higher plasma leptin levels compared with mice without obesity. Adipose tissue expression of adiponectin receptor 2, tumor necrosis factor-α, and peroxisome proliferator activated receptor gamma was altered during sepsis and affected by obesity, but the greatest change in adipose tissue expression was in leptin. Septic mice with obesity had lower plasma interleukin-17a, interleukin-23, and tumor necrosis factor-α levels and increased hepatic STAT3 and activator protein-1 activation compared with septic mice without obesity. Ultimately, mice with obesity had a lower probability of survival following sepsis.. Mice with obesity are more susceptible to sepsis and have higher mortality, in part, through activation of the STAT3 signaling pathway and through activator protein-1 activation.

Topics: Adipose Tissue; Animals; Cecum; Diet, High-Fat; Hepatitis; Inflammation; Interleukin-17; Interleukin-23; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Sepsis; Signal Transduction; STAT3 Transcription Factor; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells.. The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice.. The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin.. Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.

Topics: Adipocytes; Adipose Tissue; Animals; Cell Communication; Disease Susceptibility; Hepatitis; Leptin; Lymphocyte Activation; MAP Kinase Signaling System; Mice; Natural Killer T-Cells; Receptors, Antigen, T-Cell; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes

High-protein (HP) diets are effective anti-steatotic treatment options for patients with non-alcoholic fatty liver disease, but whether these diets also decrease steatosis in hyperlipidaemic conditions is not known. The aim of the present study was to determine the effects of a HP diet on hepatic steatosis and inflammation in hyperlipidaemic mice. Hyperlipidaemic male and female APOE2 knock-in (APOE2ki) mice were fed a semi-synthetic low-protein (LP) or HP diet in combination with a low-fat diet or a high-fat diet for 3 weeks. The HP diets reduced hepatic fat and cholesterol concentrations to 40-55 % of those induced by the corresponding LP diets and attenuated hepatic inflammation mildly. The VLDL-associated plasma cholesterol concentrations decreased to 60-80 %, but those of TAG increased 3-4-fold. APOE2-mediated restriction of fat import into the liver did not modify the effects of a HP diet previously observed in wild-type mice. Female APOE2ki mice exhibited a higher expression of lipogenic, cholesterol-synthesising, inflammatory and cell-stress genes than wild-type female or male APOE2ki mice, but a similar response to HP diets. Low Apob expression and unchanged plasma APOB100 concentrations suggest that HP diets increase the plasma concentrations of TAG by slowing their clearance. The decrease in plasma leptin and hepatic fat and glycogen concentrations and the increase in fatty acid-oxidising gene and phosphoenolpyruvate carboxykinase 1 protein expression suggest a HP diet-mediated increase in mitochondrial metabolism. In conclusion, a HP diet reduces hepatic lipid content in dyslipidaemic mice and lowers the activation status of inflammatory cells in the liver.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein E2; Cholesterol; Diet, Fat-Restricted; Diet, High-Fat; Diet, Protein-Restricted; Dietary Proteins; Female; Gene Knock-In Techniques; Hepatitis; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Liver Glycogen; Male; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Triglycerides

There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH.. Male Sprague-Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined.. In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR.. We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.

Topics: Adiponectin; Animals; Chemokines; Disease Models, Animal; Disease Progression; Fatty Liver; Gene Expression Regulation; Hepatitis; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Resistin; RNA; Severity of Illness Index

Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 +/- 0.3 g, while HFD mice gained 6.8 +/- 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 +/- 0.3 g and 3.3 +/- 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-alpha, MCP-1, PAI-1 and IKKbeta was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD.

Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Weight; Cytokines; Diet; Dietary Fats; Glucose Tolerance Test; Hepatitis; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Physical Conditioning, Animal; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction

Topics: Animals; Dietary Fats; Disease Models, Animal; Fatty Liver; Hepatitis; Leptin; T-Lymphocytes, Regulatory

Alteration of the leptin system appears to play a role in the inflammatory-metabolic response in catabolic diseases such as chronic liver diseases.. To investigate the association between leptin components, inflammatory markers and hepatic energy and substrate metabolism.. We investigated in vivo hepatic substrate and leptin metabolism in 40 patients employing a combination of arterial and hepatic vein catheterization techniques and hepatic blood flow measurements. In addition to metabolic, inflammatory and neuroendocrine parameters, circulating levels of free leptin, bound leptin and soluble leptin receptor were determined.. Compared with controls, bound leptin and soluble leptin receptor levels were significantly elevated in cirrhosis, while free leptin did not increase. In cirrhosis bound leptin was correlated with soluble leptin receptor (r = 0.70, P < 0.001). Free leptin was positively correlated with metabolic parameters such as energy storage (body fat mass; r = 0.36, P < 0.05), insulin and insulin resistance (r = 0.48; r = 0.46, P < 0.01) as well as with hepatic glucose and energy release (r = 0.35 and r = 0.40, P < 0.05). In contrast, bound leptin and soluble leptin receptor were linked to proinflammatory cytokines and sympathetic activity (r = 0.61 and r = 0.56, P < 0.01).. The components of the leptin system (free leptin, bound leptin and soluble leptin receptor) have distinct roles in metabolic and inflammatory processes in patients with liver cirrhosis. The better understanding of this metabolic and inflammatory tissue-repair response may lead to innovative new therapeutic strategies in liver disease as well as in various other catabolic diseases.

Topics: Adult; Case-Control Studies; Cytokines; Female; Hepatitis; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Receptors, Leptin

Experimental T cell-mediated hepatitis induced by concanavalin A (ConA) results in the initiation of an inflammatory response and the production of cytokines. Adiponectin is an adipocytokine produced by adipose tissue that is involved in the reciprocal regulation of other cytokines, including tumor necrosis factor alpha (TNF-alpha). Concanavalin A administration to C57BL/6J mice reduced circulating levels of adiponectin, whereas leptin was markedly increased. Adiponectin messenger RNA expression in adipose tissue was also decreased; however, the expression of both the adiponectin receptors remained unchanged. Neutralization of TNF-alpha reduced ConA-induced liver damage, and this was associated with restored circulating levels of adiponectin. These findings indicate that inflammation-induced TNF-alpha is a critical mediator of adipose-tissue-derived adiponectin in vivo.

Topics: Adiponectin; Adipose Tissue; Animals; Concanavalin A; Hepatitis; Leptin; Mice; Mice, Inbred C57BL; Mitogens; Receptors, Adiponectin; Receptors, Cell Surface; RNA, Messenger; T-Lymphocytes; Tumor Necrosis Factor-alpha

Topics: Adoptive Transfer; Animals; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Cell Transplantation; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Hepatitis; Immunity, Innate; Interleukin-10; Killer Cells, Natural; Leptin; Mice; Mice, Obese; Nuclear Magnetic Resonance, Biomolecular; Spleen

Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH) and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27%) had diabetes mellitus (n = 5) or impaired glucose tolerance (n = 5). Body mass index (BMI) was less than 30 kg/m(2) in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m(2). Serum adiponectin, leptin, TNF-alpha, and ghrelin were determined. Serum leptin (15.49 +/- 4.84 vs 10.31 +/- 2.53) and TNF-alpha (12.1 +/- 2.7 vs 10.31 +/- 2.56) levels were significantly higher in the NASH group compared to in the control group (P < .001 for each). Nevertheless, adiponectin (11.1 +/- 2.1 vs 17.3 +/- 2.8) and ghrelin (6.46 +/- 1.1 vs 7.8 +/- 1.1) levels were lower in the NASH group than in the control group (P < .001 for each). Serum levels of the adipokines and ghrelin, however, were comparable in the subgroups of patients regardless of whether BMI was < 30 or > 30 or glucose tolerance was impaired or not (P > .05). Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P > .05). In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.

Topics: Adiponectin; Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus; Fatty Liver; Female; Ghrelin; Glucose Intolerance; Hepatitis; Humans; Leptin; Male; Middle Aged; Peptide Hormones; Reference Values; Tumor Necrosis Factor-alpha

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 observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNF alpha protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNF alpha was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNF alpha-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNF alpha-induced death.

Topics: Adiponectin; Animals; Apoptosis; Autoimmune Diseases; CCAAT-Enhancer-Binding Proteins; Concanavalin A; Cytokines; DNA-Binding Proteins; Hepatitis; In Situ Nick-End Labeling; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Leptin; Lipodystrophy; Lymphocyte Activation; Mice; Mice, Obese; Mice, Transgenic; Obesity; Sterol Regulatory Element Binding Protein 1; T-Lymphocytes; Transcription Factors; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Hepatitis; Humans; Immunity; Inflammation; Intercellular Signaling Peptides and Proteins; Leptin; Lipodystrophy; Mice; Mice, Transgenic; Obesity; T-Lymphocytes; Tumor Necrosis Factor-alpha

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.

Topics: Animals; Apoptosis; CD4-Positive T-Lymphocytes; Colitis; Colon; Concanavalin A; Hepatitis; Intestinal Mucosa; Leptin; Leukocyte Common Antigens; Leukocytes, Mononuclear; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, SCID

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.

Topics: Adiponectin; Adult; Antigens, CD; Case-Control Studies; Diagnosis, Differential; Fatty Liver; Female; Hepatitis; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Multivariate Analysis; Necrosis; Prognosis; Proteins; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Solubility; Tumor Necrosis Factor-alpha

As anorexia and hypermetabolism are common in cirrhosis, leptin levels may be increased in this disease. In this study, we investigated the relation between the severity of disease and serum leptin levels in post-hepatitis cirrhosis and the role of body composition, gender and viral aetiology of cirrhosis in this association.. Thirty-five cases with post-hepatitis cirrhosis and 15 healthy controls were enrolled in this study. Body composition including body mass index, body fat percentage and body fat mass were determined. Serum leptin levels were assayed.. Leptin levels were significantly higher among cirrhotic patients independent of sex compared to controls (p = 0.001). Female patients in both groups have had higher leptin levels than males (in cirrhotics p = 0.029, in controls p = 0.02). Cirrhotic patients in each of A, B and C subgroups according to the Child- Pugh classification revealed significantly different levels compared to controls (p = 0.046, p = 0.004, p = 0.0001, respectively). Male cirrhotics in Child-Pugh Class B and C subgroups had significantly higher leptin levels compared to male controls (p = 0.006, p = 0.008). On the other hand, female patients only in Child Pugh class C subgroup have had higher levels of serum leptin compared to controls (p = 0.022).Child-Pugh classification has been found to be the sole discriminator in determination of leptin levels in cirrhotics by linear regression (beta: 0.435 p = 0.015).. Serum leptin levels increase in advanced liver disease independently of gender, body composition in posthepatitic cirrhosis. The increase is more abundant among patients that belong to C subgroup according to the Child- Pugh classification.

Topics: Body Composition; Case-Control Studies; Female; Fibrosis; Hepatitis; Humans; Leptin; Male; Middle Aged; Severity of Illness Index; Sex Factors

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").

Topics: Adult; Aged; C-Peptide; Fatty Liver; Female; Hepatitis; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Severity of Illness Index; Sex Factors; Triglycerides

Topics: Animals; CCAAT-Enhancer-Binding Proteins; Chromans; Diabetes Mellitus; DNA-Binding Proteins; Fatty Liver; Hepatitis; Hypoglycemic Agents; Islets of Langerhans; Leptin; Liver; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone