Effects of Short-Term Leptin Exposure on Triglyceride Deposition in Rat Liver

Roden, Michael; Anderwald, Christian; Fürnsinn, Clemens; Waldhäusl, W.; Lohninger, Alfred

doi:10.1053/jhep.2000.18712

Cited by 29 publications

(24 citation statements)

References 38 publications

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“…The current study demonstrates that leptin effects on liver lipid metabolism can be mediated by hepatic leptin receptors at physiological leptin concentrations, confirming observations from previous studies (14,15,51). Because we were unable to detect ObRb protein or mRNA (data not shown), similar to previous studies (26,52), it is most likely the predominant ObRa that mediates the lipid-lowering effects of leptin.…”

Section: Figsupporting

confidence: 91%

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Huang

Dedousis

Bhatt

et al. 2004

Journal of Biological Chemistry

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Obesity is associated with the development of leptin resistance. However, the effects of leptin resistance on leptin-regulated metabolic processes and the biochemical defects that cause leptin resistance are poorly understood. We have addressed in rats the effect of dietinduced obesity (DIO), a situation of elevated tissue lipid levels, on the well described lipid-lowering effect of leptin in liver, an action that is proposed to be important for the prevention of tissue lipotoxicity and insulin resistance. In addition, we have addressed the role of phosphatidylinositol 3-kinase (PI 3-kinase) in mediating the acute effects of leptin on hepatic lipid levels in lean and DIO animals. A 90-min leptin (ϳ10 ng/ml) perfusion of isolated livers from lean animals decreased triglyceride levels by 42 ؎ 5% (p ‫؍‬ 0.006). However, leptin concentrations ranging from ϳ10 to ϳ90 ng/ml had no effect on triglyceride levels in livers from DIO animals. The acute lipid-lowering effect of leptin on livers from lean animals was mediated by a PI 3-kinase-dependent mechanism, because wortmannin and LY294002, the PI 3-kinase inhibitors, blocked the effects of leptin on hepatic triglyceride levels and leptin increased liver PI 3-kinase activity by 183 ؎ 6% (p ‫؍‬ 0.003) and insulin receptor substrate 1 tyrosine phosphorylation by 185 ؎ 30% (p ‫؍‬ 0.02) in the absence of PI 3-kinase inhibitors. Contrary to the effects of leptin in lean livers, leptin did not activate PI 3-kinase in livers from DIO rats. These data present evidence for a role for 1) leptin resistance in contributing to the excessive accumulation of tissue lipid in obesity, 2) PI 3-kinase in mediating the acute lipid-lowering effects of leptin in liver, and 3) defective leptin activation of PI 3-kinase as a novel mechanism of leptin resistance.Human obesity and diet-induced obesity in rodents are associated with the development of leptin resistance (1-3). However, despite substantial progress, our understanding of the consequences of leptin resistance for the metabolic actions of leptin and the molecular defects causing leptin resistance remains vague. Metabolic abnormalities arising from defective leptin action are most clear in leptin-deficient states caused by leptin gene mutations or lipodystrophy in humans or rodents. These states are characterized by hyperlipidemia, excessive storage of lipid in tissues such as liver and skeletal muscle, and insulin resistance, defects that are markedly improved by administration of leptin (4 -8). Similar effects on lipid metabolism and/or insulin sensitivity are obtained in normal rodents with acute (9, 10) or prolonged (11-13) hyperleptinemia. In the ZDF rat characterized by non-functional leptin receptors and obesity, elevated hepatic lipid levels are reduced by adenovirusmediated expression of functional wild-type leptin receptors in liver (14), whereas administration of leptin to gold-thioglucosetreated mice that lack hypothalamic leptin function decreases hepatic lipogenesis (15). Taken together, these studies demonstrate potent l...

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Section: Figsupporting

confidence: 91%

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Huang

Dedousis

Bhatt

et al. 2004

Journal of Biological Chemistry

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“…The histological mechanism of non alcoholic fatty liver disease (NAFLD) is yet not understood (18). In many of obese people, increase of hepatic triglyceride levels, causes hepatic steatosis (24). The aim of this study was to investigate the effects of high fat diet (30%) on NAFLD histologically, in order to achieve this objective, obese rat model was constituted by means of fatty diet administration.…”

Section: Discussionmentioning

confidence: 99%

Effects of High Fat Diet Induced Obesity on Female Rat Livers (A Histochemical Study)

Altunkaynak

2005

ELECTRON J GEN MED

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Aim:Obesity is an important, complex and chronic disease. Fatty diet is a significant factor causing obesity. It is known that obesity is associated with many chronic disorders such as NonAlcoholic Fatty Liver Disease (NAFLD). However, mechanism of this event is yet unclear. In this study, it was purposed to examine histological effects of fatty diet induced obesity on liver from female obese rats.Methods: Within scope of this aim, the obesity model was performed on animals of the study group, (Sprague Dawley rats), by feeding them with a diet comprised highly of fat, for a duration of 2-3 months. After this controlled nutritional process, livers were removed from all sacrificed rats and viewed under light microscope.Results: In study groups' slides; mononuclear cell infiltrations, foci of necrosis, vascular dilatation, an increase in hepatic connective tissue, hepatocellular steatosis and shrinkage, additional cytoplasmic acidophily and nuclear density in the hepatocytes were determined. Finally, it was observed that fat-rich diet (%30) had caused a liver damage.Conclusion: We think that our light microscopical finding would contribute clarifying the histopathological mechanism of obesity.

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“…A portal perfusion of leptin in rats induced hypertriglyceridemia and contributed to hepatic steatosis by increasing the levels of free fatty acids accumulation in the liver [31]. Lines of evidence indicated that leptin modulated proinflammatory responses induced by endotoxin (lipopolysaccharide; LPS) [32] or tumor necrosis factor-α (TNF-α) [33].…”

Section: Animal Modelsmentioning

confidence: 99%

Leptin in the Field of Hepatic Fibrosis: A Pivotal or an Incidental Player?

Bethanis

Theocharis

2006

Dig Dis Sci

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Leptin is a 16-kDa nonglycosylated protein primarily secreted from the adipocytes of white fat; minor levels of regulated leptin expression also occurs at other sites such as placenta, skeletal muscle, the stomach fundus, and culture-activated hepatic stellate cells (HSCs). Leptin is primarily involved in the regulation of food intake and body composition through a central feedback mechanism linking food ingestion, hypothalamus, and adipose tissue mass. In recent years, however, emerging evidence has suggested a critical role of leptin in hepatic inflammation and fibrogenesis and the influence of leptin on chronic liver disease has been an area of active research worldwide. In this review the data on the in vivo and in vitro actions of leptin on liver cells in experimental animal models of liver injury and the effects of leptin on human liver are discussed, with a focus on three distinct fields of chronic liver diseases: nonalcoholic steatohepatitis, alcoholic liver disease, chronic viral hepatitis, and, especially, hepatitis C.

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Effects of Short-Term Leptin Exposure on Triglyceride Deposition in Rat Liver

Cited by 29 publications

References 38 publications

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Effects of High Fat Diet Induced Obesity on Female Rat Livers (A Histochemical Study)

Leptin in the Field of Hepatic Fibrosis: A Pivotal or an Incidental Player?

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