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

Huang, Wan; Dedousis, Nikolaos; Bhatt, Bankim A.; O’Doherty, Robert M.

doi:10.1074/jbc.m401546200

Cited by 66 publications

(84 citation statements)

References 52 publications

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“…The leptin-mediated phosphatidylinositol-3-OHkinase (PI3K) activation pathway may be one candidate [23,24]. Indeed, impaired activation of PI3K by leptin has been indicated as a novel mechanism of hepatic leptin resistance in diet-induced obesity [25]. However, the role of the central leptin-PI3K pathway in long-term energy homeostasis regulation has not been identified.…”

Section: Discussionmentioning

confidence: 99%

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

et al. 2005

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Aims/hypothesis: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats. Materials and methods: Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344×BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 μg leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined. Results: The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptinresistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls. Conclusions/interpretation: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.

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Section: Discussionmentioning

confidence: 99%

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

et al. 2005

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“…Isolated perfused rat liver preparation has been described previously (37). Livers were perfused with 400 ml of re-circulating oxygenated Krebs-Henseleit buffer with or without leptin (9-fold above basal) for 90 min in the presence or absence of phosphatidylinositol 3-kinase inhibitors wortmannin (100 nM) or LY294002 (10 M).…”

Section: Liver Perfusion Studiesmentioning

confidence: 99%

CCAAT/Enhancer-binding Protein β Deletion Reduces Adiposity, Hepatic Steatosis, and Diabetes in Lepr Mice

Schroeder-Gloeckler¹,

Rahman²,

Janssen³

et al. 2007

Journal of Biological Chemistry

Self Cite

120

101

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CCAAT/enhancer-binding protein ␤ (C/EBP␤) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBP␤ in hepatic lipogenesis remains undefined. Here we show that C/EBP␤ inactivation in Lepr db/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBP␤ ؊/؊ x Lepr db/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP␤ deletion in Lepr db/db mice down-regulated peroxisome proliferator-activated receptor ␥2 (PPAR␥2) and stearoyl-CoA desaturase-1 and up-regulated PPAR␣ independent of SREBP1c. Conversely, C/EBP␤ overexpression in wild-type mice increased PPAR␥2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP␤ or C/EBP␤ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR␥2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP␤ expression in hepatocytes, whereas fatty acids up-regulate C/EBP␤ expression. These data provide novel evidence linking C/EBP␤ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.Obesity is the most common nutritional disorder in Western societies. Today in the United States, more than 60% of people are either overweight (body mass index (BMI) Ͼ 25) or obese (BMI Ͼ 30) (1). Obesity is frequently associated with type II diabetes, hypertension, and hyperlipidemia, all known risk factors for cardiovascular disease (2). Obesity is also a major risk factor for non-alcoholic fatty liver disease, one of the most common emerging liver diseases in Western countries coinciding with the worldwide obesity epidemic (3, 4). The underlying transcriptional events that contribute to obesity and its associated disorders are not well understood. Some of the genes that regulate body weight have been identified as well as additional neuropeptides, hormones, and nutritional factors that play a role in body weight regulation, particularly through the ␤-adrenergic system (5, 6). Discovery of the hormone leptin and its receptors, which suppress appetite and reduce fat mass, has dramatically increased our understanding of the regulation of energy balance (7,8). More recently, the study of specific transcription factor genes and their metabolism has provided powerful new tools for understanding the integrated mechanisms underlying obesity and diabetes (9 -11). This is most elegantly illustrated using tissue-specific gene knockouts and overexpression models to elucidate the mechanism of action of the PPAR 5 family of nuclear hormone receptors (12). The CCAAT/enhancer-binding protein (C/EBP) family includes five nuclear transcription factors, C/EBP ␣, ␤, ␥, ␦, and ⑀, encoded by separate genes located on different chromosomes (13,14). Collectively, C/EBPs are expressed across a variety of cell types, and...

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“…Direct effects of leptin on hepatic insulin signaling and glycogenolysis have been previously reported in isolated hepatocytes or in perfused liver (35)(36)(37). Thus, it is important to delineate whether the potent melanocortin-independent effects of leptin on hepatic glucose fluxes can also be elicited in response to the central rather than systemic administration of leptin.…”

Section: Activation Of Central Melanocortin Receptors Leads To a Markmentioning

confidence: 99%

“…It should be pointed out that these insulin-like effects of systemic leptin on hepatic glucose fluxes could be mediated via direct effects on the liver as well as via extrahepatic (presumably hypothalamic) actions of leptin. In this regard, leptin has also been shown to directly modulate insulin signaling, lipid metabolism, and glycogenolysis in some studies conducted in isolated liver cells (35,36) or perfused liver (37). Conversely, the effects of a physiological increase in systemic leptin on the hepatic expression of gluconeogenic enzymes as well as on gluconeogenesis are centrally mediated because they were abolished by the central antagonism of melanocortin receptors.…”

Section: Fig 5 Effect Of Central (Icv) Leptin On Glucose Metabolismmentioning

confidence: 99%

Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes

Gutiérrez‐Juárez¹,

Obici

Rossetti

2004

Journal of Biological Chemistry

104

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Leptin and insulin share some hypothalamic signaling molecules, but their central administration induces different effects on hepatic glucose fluxes. Acute insulin infusion in the third cerebral ventricle inhibits endogenous glucose production (GP), whereas acute leptin infusion stimulates gluconeogenesis but does not alter GP because of a compensatory decrease in glycogenolysis. Because melanocortin agonists also stimulate hepatic gluconeogenesis, here we examined whether central melanocortin blockade modifies the acute effects of leptin on GP, on gluconeogenesis, on glycogenolysis, and/or on the hepatic expression of the gluconeogenic enzymes glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Systemic or central administration of leptin alone did not alter GP, despite increasing both the rate of gluconeogenesis and the expression of Glc-6-Pase and PEPCK. When activation of the central melanocortin pathway was prevented, the effects of leptin on gluconeogenesis, Glc-6-Pase, and PEPCK were abolished, and a marked suppression of glycogenolysis resulted in decreased GP. We conclude that leptin regulates hepatic glucose fluxes through a melanocortin-dependent pathway leading to stimulation of gluconeogenesis and a melanocortin-independent pathway causing inhibition of GP and glycogenolysis.Leptin, the 167-amino acid polypeptide product of the ob gene, is secreted by the adipose tissue and acts mainly on the central nervous system to regulate energy balance (1). Leptin regulates food intake and body adiposity partly via activation of melanocortin receptors in the hypothalamus and in other areas within the central nervous system (2, 3). It is now well recognized that leptin also plays an important role in the regulation of insulin action and intermediate metabolism (4 -9). Indeed, prolonged administration of recombinant leptin to nondiabetic and diabetic rats (10 -13) as well as to lipodystrophic humans and mice (4, 14) markedly improves in vivo insulin action. Similarly, bi-directional modulation of the activity of the central melanocortin pathway leads to significant changes in hepatic and peripheral insulin action (15). On the other hand, the prolonged administration of either leptin or melanocortin agonists or antagonists also impacts on the distribution of body adiposity and on lipid homeostasis (10, 15-18). These effects are in turn likely to secondarily influence the in vivo action of insulin on metabolic parameters (15). Thus, it is important to delineate the acute effects of leptin and melanocortins on metabolic fluxes prior to the onset of changes in energy balance, body composition, and lipid storage.In this regard, acute administration of leptin to postabsorptive rats causes a marked redistribution of intrahepatic glucose fluxes, with a marked increase in the relative contribution of gluconeogenesis and a parallel decrease in the contribution of glycogenolysis to hepatic glucose output (5, 6). This effect is seen following either systemic or central administration of the hor...

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

Cited by 66 publications

References 52 publications

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

CCAAT/Enhancer-binding Protein β Deletion Reduces Adiposity, Hepatic Steatosis, and Diabetes in Lepr Mice

Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes

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