20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

Allison, Margaret B.; Myers, Martin G.

doi:10.1530/joe-14-0404

Cited by 197 publications

(170 citation statements)

References 96 publications

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“…Such findings reflect a more extensive function of Site 4 beyond the accepted action on the maturation of adipocytes for energy storage, as bone growth and remodeling are substantial energy-consuming processes. Leptin's putative role is that of regulating energy homeostasis, which balances energy intake, storage and expenditure through both peripheral and central signaling managed through a group of leptin receptors, extensive hormonal signaling cascades, and neuronal control (reviewed in Allison and Myers, 2014;Ferron et al, 2013;Karsenty and Oury, 2012;Scheller et al, 2010;Mitchell et al, 2009;Frühbeck, 2006). Central signaling is accomplish through the hypothalamus and brain stem neural pathways, while peripheral signaling appears affected by nutritional status in human blood.…”

Section: Discussionmentioning

confidence: 99%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

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DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA which are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process.Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative function includes regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism and Pre-print version. Visit http://digitalcommons.wayne.edu/humbiol/ after publication to acquire the final version.reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examines the significance of variation in DNA methylation patterns along the leptin core promoter in four populations and uses biomarkers reflecting leptin's functional process in two of those populations to investigate the relevance of the ethnic variation identified in the DNA methylation. Those two populations are the Western Buryats of Siberia and the Mennonites of Central Kansas.LEP's core promoter region contains both the C/EBPα transcription binding site (TBS) which tempers the final step in adipocyte maturity and capacity to synthesize leptin and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, with others suggesting tissue-specific methylation variation at this region. We hypothesize that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers which reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system and anthropometric measures.A distinct and consistent overall pattern of differential DNA methylation across seven CpG sites of LEP core promoter is documented in all ethnicities and both sexes in our combined analyses of 313 individuals. This pattern replicates those identified in previous studies, thus suggesting a conserved core promoter region across populations. The second analyses in two of the four ...

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Section: Discussionmentioning

confidence: 99%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

View full text Add to dashboard Cite

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“…Excessive sOB-R can delay the clearance of leptin by binding leptin with an affinity similar to that of the membrane-bound receptor [12,24], which would contribute partially to the high leptin levels of the PCOS patients in our study. On the other hand, excessive sOB-R could inhibit leptin binding to membrane receptors so that leptin failed to play an effective role on reducing caloric intake, increasing energy expenditure as well as evoking GnRH and LH secretion in vivo [28,29]. Prior studies mentioned that sOB-R levels were not directly related to leptin or body fatness, and presumably mediated by other parameters related to nutrition and energy metabolism [26].…”

Section: Discussionmentioning

confidence: 99%

LEPR Gene Polymorphism and Plasma Soluble Leptin Receptor Levels are Associated with Polycystic Ovary Syndrome in Han Chinese Women

Gao

et al. 2017

Per. Med.

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Aim:To investigate the association of LEPR polymorphisms and plasma leptin and soluble leptin receptor (sOB-R) levels with polycystic ovary syndrome (PCOS) in Chinese women. Patients & methods: LEPR Lys109Arg (rs1137100) and Gln223Arg (rs1137101) polymorphisms of PCOS patients and the controls were genotyped. Plasma leptin and sOB-R levels of two groups were measured. Results: The genotypic distributions of Lys109Arg (rs1137100) differed between the PCOS and control groups. Plasma sOB-R levels increased significantly in PCOS patients and were associated with PCOS independent of BMI. Furthermore, luteinizing hormone, triglyceride and fasting blood glucose correlated significantly to PCOS patients' sOB-R levels. Conclusion: LEPR Lys109Arg (rs1137100) was associated with PCOS susceptibility and genotype AA was deduced to be a protective factor for PCOS; sOB-R levels might be recognized as a new indicator for the severity of PCOS.

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“…Indeed, the interaction between Slc38a5 and Adam7 is relevant, because Adam7 is involved in sperm maturation and the acrosome reaction [84]. Furthermore, the protein-protein interactions between Slc45a3 with StAR and between Insl3 and Lep are of particular interest because both StAR and Lep are integral to reproduction, as well as to homeostasis (reviewed in [87,91,113,114]). However, our a priori DGE analysis evaluating StAR and other reproductive hormones did not show evidence of expression changes.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the reproductive transcriptomic correlates of acute dehydration in males in the desert-adapted rodent,Peromyscus eremicus

Kordonowy

MacManes

2016

Preprint

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Background: The understanding of genomic and physiological mechanisms related to how organisms living in extreme environments survive and reproduce is an outstanding question facing evolutionary and organismal biologists. One interesting example of adaptation is related to the survival of mammals in deserts, where extreme water limitation is common. Research on desert rodent adaptations has focused predominantly on adaptations related to surviving dehydration, while potential reproductive physiology adaptations for acute and chronic dehydration have been relatively neglected. This study aims to explore the reproductive consequences of acute dehydration by utilizing RNAseq data in the desert-specialized cactus mouse (Peromyscus eremicus). Results: We exposed 22 male cactus mice to either acute dehydration or control (fully hydrated) treatment conditions, quasimapped testes-derived reads to a cactus mouse testes transcriptome, and then evaluated patterns of differential transcript and gene expression. Following statistical evaluation with multiple analytical pipelines, nine genes were consistently differentially expressed between the hydrated and dehydrated mice. We hypothesized that male cactus mice would exhibit minimal reproductive responses to dehydration; therefore, this low number of differentially expressed genes between treatments aligns with current perceptions of this species' extreme desert specialization. However, these differentially expressed genes include Insulin-like 3 (Insl3), a regulator of male fertility and testes descent, as well as the solute carriers Slc45a3 and Slc38a5, which are membrane transport proteins that may facilitate osmoregulation. Conclusions: These results suggest that in male cactus mice, acute dehydration may be linked to reproductive modulation via Insl3, but not through gene expression differences in the subset of other a priori tested reproductive hormones. Although water availability is a reproductive cue in desert-rodents exposed to chronic drought, potential reproductive modification via Insl3 in response to acute water-limitation is a result which is unexpected in an animal capable of surviving and successfully reproducing year-round without available external water sources. Indeed, this work highlights the critical need for integrative research that examines every facet of organismal adaptation, particularly in light of global climate change, which is predicted, amongst other things, to increase climate variability, thereby exposing desert animals more frequently to the acute drought conditions explored here.

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20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

Cited by 197 publications

References 96 publications

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

LEPR Gene Polymorphism and Plasma Soluble Leptin Receptor Levels are Associated with Polycystic Ovary Syndrome in Han Chinese Women

Characterizing the reproductive transcriptomic correlates of acute dehydration in males in the desert-adapted rodent,Peromyscus eremicus

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