Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

Sharma, Ashok; Bartell, Shoshana M.; Baile, Clifton A.; Chen, Bin; Podolsky, Robert H.; McIndoe, Richard A.; She, Jin Xiong

doi:10.1371/journal.pone.0012147

Cited by 22 publications

(19 citation statements)

References 45 publications

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“…These findings are consistent with reports showing that leptin infusion in the brain of ob/ob mice regulates hepatic lipid metabolism, including plasma and liver TG and cholesterol (40)(41)(42)(43)(44)(45). Our data suggest that leptin action on POMC neurons is one site where this regulation occurs.…”

Section: Figuresupporting

confidence: 93%

Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

et al. 2012

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Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelanocortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr loxTB allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia.Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR. IntroductionLeptin is an adipose-derived hormone that acts on its cognate receptors (LEPR) expressed by multiple neuronal groups in distinct areas of the brain (1). The canonical effect of leptin action in the brain is to regulate food intake and energy expenditure and thus body weight (2-4). In addition, leptin regulates several other physiological processes, including hepatic glucose production, insulin action, and glucagon levels (5-10). It is still unclear, however, which neurons mediate the varied physiological effects of leptin.One population of neurons targeted by leptin is proopiomelanocortin (POMC) cells in the arcuate nucleus of the hypothalamus (ARH) and nucleus of the solitary tract (NTS) (2, 3). Leptin action on POMC neurons in the ARH is considered a prototypical site of action in the control of energy balance. This view is partly based on results showing that loss of LEPR in POMC neurons increases body weight (8,11,12). Conversely, LEPR reexpression in the ARH (13), overexpression in the ARH (14-17), and transgenic expression in POMC neurons (18) lower body weight. Interestingly, these latter studies also show lowered blood glucose, suggesting that leptin-sensitive POMC neurons in the ARH directly modulate metabolism (13-18). In the current study, we developed what we believe to be a novel LEPR-null mouse model in which endogenous LEPR expression can be reexpressed in cells that normally express leptin receptors. Here, we reexpress LEPR only in POMC neurons to delineate the physiological effects on energy and metabolic homeostasis.

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Section: Figuresupporting

confidence: 93%

Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

et al. 2012

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“…In comparison with a previous study where exogenous leptin was administered for 12 days, only Cyp17a1 features among the top downregulated genes with FC being O2 in both studies (Sharma et al 2010). In concordance with the study of Sharma et al, Gck was downregulated, which is associated with decreased lipogenesis and decreased IR.…”

Section: Known Pathways Relevant To Nafldsupporting

confidence: 84%

Molecular pathways involved in the improvement of non-alcoholic fatty liver disease

Paz-Filho

Mastronardi

Parker

et al. 2013

Journal of Molecular Endocrinology

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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are components of the metabolic syndrome. Serum leptin levels are elevated in obesity, but the role of leptin in the pathophysiology of the liver involvement is still unclear. To identify the effects and mechanisms by which leptin influences the pathogenesis of NAFLD, we performed epididymal white adipose tissue (eWAT) transplantation from congenic wild-type mice into the subcutaneous dorsal area of Lep ob/ob recipient mice and compared the results with those of the Lep ob/ob sham-operated mice. The mice were followed for 102-216 days. During killing, the transplanted mice had significantly lost body weight and exhibited significantly higher leptin levels, improved glucose tolerance, and lower liver injury scores than the shamoperated mice. Liver microarray analysis showed that novel pathways related to GA-binding protein (GABP) transcription factor targets, pheromone binding, and olfactory signaling were differentially expressed in the transplanted mice. Our data also replicate pathways known to be involved in NAFLD, such as those involved in the regulation of microRNAs, lipid, glucose, and glutathione metabolism, peroxisome proliferator-activated receptor signaling, cellular regulation, carboxylic acid processes, iron, heme, and tetrapyrrole binding, immunity and inflammation, insulin signaling, cytochrome P450 function, and cancer. Conclusion: wild-type eWAT transplantation into Lep ob/ob mice led to improvements in metabolism, body weight, and liver injury, possibly attributed to the production of leptin by the transplanted eWAT. These improvements were accompanied by the differential expression of novel pathways. The causal relationship between GABP downregulation and NAFLD improvement remains to be determined.

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“…These pathways, indicating a higher cellular turnover, activity, and reactivity, were also found to correlate with leptinmediated weight loss in ob/ob mice after leptin administration ( 45 ).…”

Section: Canonical Pathway Analysismentioning

confidence: 76%

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Ponsuksili

Muráni

Brand

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org lated to body composition, leanness, and obesity. Traits related to fatness are important not only as economic factors in pork production but also because of their association with serious diseases in humans ( 1, 2 ). Pigs share many similarities with humans in physiology and genomes and, therefore, provide a good model to study the genetic determination of complex traits ( 3 ). The study of a porcine model is benefi cial because a number of fatness traits (e.g., "fat area") can be determined quantitatively with great accuracy and reproducibility post mortem, and RNA samples are available for transcriptomic approaches. In humans, indices for obesity are obtained intra vitam (i.e., body mass index or body fat percentage are estimated based on statistical models of measures of near-infrared interactance, body average density measurement, bioelectrical impedance analysis, or anthropometric methods) ( 4 ).Functional genomics provides an insight into the molecular processes underlying phenotypic differences. The analysis of trait-correlated expression levels reveals genes belonging to pathways or networks relevant for the control of quantitative traits. However, holistic expression profi ling does not often discriminate differential expression of the genes as either an effect or a cause of variation.Genome-wide association studies (GWAS) in large natural populations of unrelated individuals have resulted in the association of many genes with complex traits (http:// www. genome.gov/gwastudies). Unfortunately, for a conAbstract Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain×(German Large White × German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression signifi cantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defi ned in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10 The metabolic activities of the liver are essential for providing fuel to the peripheral organs. Most components absorbed by the intestine pass through the liver, which enables it to regulate the levels of many metabolites in the blood. Storage, ...

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Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

Cited by 22 publications

References 45 publications

Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

Molecular pathways involved in the improvement of non-alcoholic fatty liver disease

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

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