Leptin Effects on Pancreatic β-Cell Gene Expression and Function

Seufert, Jochen

doi:10.2337/diabetes.53.2007.s152

Cited by 245 publications

(205 citation statements)

References 82 publications

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“…During fetal life, insulin is one of the major growth factors and it has been shown that leptin inhibits insulin release in pancreatic b-cells. 6,8 A possible peripheral effect of leptin during fetal development is further supported by the observation that functional leptin receptors are already expressed in pancreatic islets of fetal rats. 47 Studying the relation between the LEPR SNPs and umbilical cord insulin levels might support the proposed mechanism.…”

Section: Discussionmentioning

confidence: 96%

“…The hormone and its receptor are also expressed in other tissues, including pancreatic b-cells where it inhibits insulin secretion. [7][8][9] During pregnancy, leptin is produced by maternal and fetal adipose tissue and also by the placenta, and in contrast to maternal leptin levels, umbilical cord leptin levels are positively correlated with birth weight. 10,11 The association between single nucleotide polymorphisms (SNPs) in the leptin (LEP)/leptin receptor (LEPR) gene and birth weight has not been studied, this in contrast to the large number of (inconclusive) studies on the association with type 2 diabetes and obesity.…”

Section: Introductionmentioning

confidence: 99%

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Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

et al. 2008

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Objective: Children born small for gestational age are at increased risk of developing type 2 diabetes in adulthood. The satiety signal leptin that regulates food intake and energy expenditure might be a possible molecular link, as umbilical cord leptin levels are positively correlated with birth weight. In the present study, we examined whether common single nucleotide polymorphisms (SNPs) in the leptin (LEP; 19G4A) gene and its receptor (LEPR; Q223R and K109R) are associated with birth weight and adult metabolic risk factors for type 2 diabetes in twins. Design: SNPs were genotyped in 396 monozygotic and 232 dizygotic twins (286 men and 342 women, mean age 25 years) recruited from the East Flanders Prospective Twin Survey. Data were analysed using linear mixed models. Results: The LEPR K109R SNP was associated with birth weight (KK, KR and RR (95% confidence interval, CI): 2511 (2465-2557), 2575 (2516-2635) and 2726 (2606-2845) gram; P additive ¼ 0.001). Also the LEPR Q223R SNP showed a significant association with weight at birth (QQ, QR and RR (95% CI): 2492 (2431-2554), 2545 (2495-2595) and 2655 (2571-2740) gram; P additive ¼ 0.003). Furthermore, an interaction between the LEPR K109R and the Q223R SNP on birth weight was observed (P ¼ 0.014). G allele carriers of the LEP 19G4A SNP had higher high-density lipoprotein (HDL) cholesterol levels compared to 19A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol l À1 ; P recessive ¼ 0.013). Conclusions: This study indicates that leptin may act as a growth-promoting signal during fetal development, and suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adulthood. Additionally, these results suggest that the LEP 19G4A SNP affect HDL cholesterol levels.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

et al. 2008

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“…Indeed, PPAR- is a transcription factor preferentially expressed in adipose tissue [37] and it is known that its activation, as we have observed in adipocytes exposed to hyperoxia, could improve insulin resistance [46]. HIF-1 leptin are important regulators of hundreds of target genes involved in several biological functions, such as cellular metabolism, cell growth and apoptosis and restoration of the oxygen supply [44,45]; nevertheless, their expression was not modified by hyperoxia. Finally, ANGPTL4 is a gene involved in glucose and lipid metabolism, mainly involved in the regulation of plasma triacylglycerides metabolism by inhibition of LPL [35].…”

Section: Discussionmentioning

confidence: 75%

Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes

et al. 2012

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Adipose tissue often becomes poorly oxygenated in obese subjects. This feature may provide cellular mechanisms involving chronic inflammation processes such as the release of proinflammatory cytokines and macrophage infiltration. In this context, the purpose of the present study was to determine whether a hyperoxia exposure on mature adipocytes may influence the expression of some adipokines and involve favorable changes in specific metabolic variables. 3T3-L1 adipocytes (14 days differentiated) were treated with 95% oxygen for 24 h. Cell viability, intra and extracellular reactive oxygen especies (ROS) content, glucose uptake and lactate and glycerol concentrations were measured in the culture media. Also, mRNA levels of HIF-1, leptin, IL-6, MCP-1, PPAR-, adiponectin, and ANGPTL-4 were analyzed.Hyperoxia treatment increased intra and extracellular ROS content, reduced glucose uptake and lactate release and increased glucose release. It also led to an upregulation of the expression of IL-6, MCP-1 and PPAR-, while ANGPTL4 was downregulated in the hyperoxia group with respect to control. The present data shows that hyperoxia treatment seems to provoke an inflammatory response due to the release of ROS and the upregulation of pro-inflammatory adipokines, such as IL-6 and MCP-1. On the other hand, hyperoxia may have an indirect effect on the improvement of insulin sensitivity, due to the upregulation of PPAR- gene expression as well as a possible modulation of both glucose and lipid metabolic markers. To our knownledge, this is the first study analyzing the effect of hyperoxia in 3T3-L1 adipocytes.

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“…The effect of elevated leptin levels on the so-called 'adipoinsular axis' may also provide another potential mechanism for the impaired insulin secretion in Alox5 −/− mice. For example, since leptin has been shown to inhibit insulin biosynthesis and secretion [35,36], the increased plasma leptin in Alox5 −/− mice could also decrease insulin production and secretion from beta cells, in addition to what is directly affected by 5-LO itself. This could be particularly relevant in older mice in which adiposity has substantially increased.…”

Section: Discussionmentioning

confidence: 99%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

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Leptin Effects on Pancreatic β-Cell Gene Expression and Function

Abstract: The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [

Cited by 245 publications

References 82 publications

Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

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