Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Gallardo, Nilda; Bonzón-Kulichenko, Elena; Fernández-Agulló, Teresa; Moltó, Eduardo; Gómez‐Alonso, Sergio; Blanco, Pablo J.; Carrascosa, J.M.; Ros, Manuel; Andrés, Antonio

doi:10.1210/en.2007-0933

Cited by 94 publications

(78 citation statements)

References 39 publications

(28 reference statements)

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“…52 Leptin has also been shown to attenuate liver TG secretion and fatty acid synthesis, although increasing hepatic fatty acid b-oxidation. 53,54 Leptin deficiency suppressed both the innate and acquired immune response, thereby favoring T-helper cell lymphocyte polarization and making the liver steatosis. 55 In the present study, daidzein supplementation augmented leptin and adiponectin mRNA levels, and reduced the levels of TNFa mRNA in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

et al. 2010

Int J Obes

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Introduction: Globally, non-alcoholic fatty liver disease (NAFLD) continues to rise and isoflavones exert antisteatotic effects by the regulation of hepatic lipogenesis/insulin resistance or adiposity/a variety of adipocytokines are related to hepatic steatosis. However, there is very little information regarding the potential effects of daidzein, the secondary abundant isoflavone, on NAFLD. Here, we have assessed the hepatic global transcription profiles, adipocytokines and adiposity in mice with high fat-induced NAFLD and their alteration by daidzein supplementation. Methods: C57BL/6J mice were fed with normal fat (16% fat of total energy), high fat (HF; 36% fat of total energy) and HF supplemented with daidzein (0.1, 0.5, 1 and 2 g per kg diet) for 12 weeks. Results: Daidzein supplementation (X0.5 g per kg diet) reduced hepatic lipid concentrations and alleviated hepatic steatosis. The hepatic microarray showed that daidzein supplementation (1 g per kg diet) downregulated carbohydrate responsive element binding protein, a determinant of de novo lipogenesis, its upstream gene liver X receptor b and its target genes encoding for lipogenic enzymes, thereby preventing hepatic steatosis and insulin resistance. These results were confirmed by lower insulin and blood glucose levels as well as homeostasis model assessment insulin resistance scores. In addition, daidzein supplementation inhibited adiposity by the upregulation of genes involved in fatty acid b-oxidation and the antiadipogeneis, and moreover augmented antisteatohepatitic leptin and adiponectin mRNA levels, whereas it reduced the mRNA or concentration of steatotic tumor necrosis factor a and ghrelin. Conclusions: These findings show that daidzein might alleviate NAFLD through the direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by the alteration of adipocyte metabolism.

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Section: Discussionmentioning

confidence: 99%

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

et al. 2010

Int J Obes

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“…Some data suggest that hypothalamic malonyl-CoA plays a significant role in the regulation of muscle and liver FAO [62][63][64][65][66][67], although the downstream factor remains elusive. In this context, we would like to suggest that CPT1C could be that factor, and act as a malonyl-CoA sensor in the hypothalamus to regulate FAO in peripheral tissues.…”

Section: Regulation Of Peripheral Lipid Metabolismmentioning

confidence: 99%

Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

105

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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“…Central treatment with leptin decreased mRNA expression of the hepatic gluconeogenic enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) in streptozotocin-induced diabetic rats [15]. In addition, chronic icv administration of leptin caused the down-regulation of genes encoding stearoyl-CoA desaturase-1 (SCD1), acetyl-coenzyme A-carboxylase (ACC), and fatty acid synthase (FAS) in the liver when compared with vehicle-infused pair-fed rats [16]. This suggests that leptin acts in the brain to suppress liver lipogenic gene expression independent of feeding.…”

Section: Introductionmentioning

confidence: 99%

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Cheng

Szabo

et al. 2015

The Journal of Nutritional Biochemistry

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X. (2015). Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. Journal of Nutritional Biochemistry, 26 (5), 541-548. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice AbstractThe consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6 J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling ( JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Abstract:The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules, and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1), and a pro-inflammatory response (TNF-α, IL1-β, IL-6, and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei.Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2), ...

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Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Cited by 94 publications

References 39 publications

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

Carnitine palmitoyltransferase 1C: From cognition to cancer

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

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