The adipocyte-secreted hormone leptin is considered a keyplayer in the regulatory mechanisms underlying obesity, since, among other functions, it induces satiety and thereby controls energy homeostasis. The mechanisms of leptin’s effects, as well as the regulation of its synthesis, remain the subject of recent studies. Several publications point to the involvement of long non-coding RNAs (lncRNA) in the regulation of leptin synthesis. Furthermore, in 2016 a genome-wide association study (GWAS) identified a single nucleotide polymorphism (SNP), rs10487505, in the proximal promoter region of the Leptin gene in humans, which was associated with decreased leptin levels and increased BMI.
We analyzed an as yet uninvestigated lncRNA (termed LncR) and tested the hypothesis that LncR expression in subcutaneous and visceral adipose tissue (SCAT and VAT) affects Leptin mRNA expression, circulating leptin levels and other metabolic and anthropomorphic parameters. We also analyzed whether the SNP rs10487505 is associated with the above-mentioned parameters as well as with the LncR and Leptin gene expression levels.
We report that lncR negatively correlates with circulating leptin levels in women. LncR did not correlate with Leptin mRNA expression, therefore, we assume that its regulatory mechanism might act downstream of the protein synthesis process. Since the effect was specific to women, we stratified the female patients into a pre- and postmenopausal group. We did not find any evidence that the effect on circulating leptin levels was influenced by female hormonal status. Furthermore, LncR correlated with parameters of obesity and inflammation. The effects were highly gender-specific and dependent on the fat depot in which LncR was expressed.
We confirmed the leptin-depleting effect of the C allele of the SNP rs10487505 in women, as described in the 2016 GWAS. However, we found a BMI decreasing effect of the C allele in women in our highly obese cohort, in contrast to the mainly population-based cohort of the GWAS. We suggest a model in which the leptin depletion via rs10487505 enhances weight gain in normal weight and low obese individuals but prevents leptin resistance and further dysregulation of appetite and satiety in morbidly obese patients. The BMI-decreasing effect seems to be a postmenopausal phenomenon. Further, the leptin-depleting allele of rs10487505 was associated with parameters of obesity and inflammation, such as decreased FPI, gGT and IL-6 in women, and decreased body fat, FPI and increased adiponectin in men. In general, these results point to a rather protective role of the leptin-depleting allele in our cohort.:List of Figures III
List of Tables IV
Index of Abbreviations V
1. Introduction
1.1. Overweight and obesity
1.1.1. Definition
1.1.2. Epidemiology
1.2. Adipose tissue
1.2.1. Adipose tissue in energy homeostasis
1.2.2. Adipose tissue as endocrine organ
1.2.3. Body fat distribution
1.3. Leptin
1.3.1. Neuroendocrine effects
1.3.2. Metabolic effects of leptin
1.3.3. Leptin deficiency vs. leptin resistance
1.3.4. Regulation of leptin expression
1.3.5. Leptin regulation by a long non-coding RNA
2. Aim of this study
3. Material and Methods
3.1. Methods
3.1.1. Study participants
3.1.2. Defining the LncR gene locus
3.1.3. Analysis of LEP and LncR expression in human adipose tissue
3.1.4. Genotyping for SNP analysis of rs10487505
3.1.5. Statistical analyses
4. Results
4.1. Gene expression measurement
4.1.1. Characteristics of LEP gene expression
4.1.2. Characterization of LncR gene expression
4.1.3. Gender-specific correlation of LEP and LncR gene expression with anthropomorphic and metabolic parameters
4.1.4. The LncR/LEP ratio influences circulating leptin
4.1.5. Correlation analysis in pre- and postmenopausal women
4.2. SNP-Analysis
4.2.1. Effects of rs10487505 in pre- and postmenopausal women
5. Discussion
5.1. LncR expression in AT
5.2. LncR expression affects circulating leptin but only in women
5.3. LncR expression affects the metabolic and inflammatory state in women
5.4. Correlation of LncR with circulating leptin levels is not dependent on menopausal state
5.5. Rs10487505 affects circulating leptin levels but not via LEP or LncR gene expression
5.6. Rs10487505 C allele decreases BMI in a highly obese cohort
5.7. Rs10487505 correlates with obesity-related and inflammatory parameters
5.8. Conclusion
6. Summary
7. References
8. Supplements
8.1. LEP and LncR gene expression
8.2. SNP-Analysis
9. Selbstständigkeitserklärung
10. Danksagung
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:90851 |
| Date | 11 April 2024 |
| Creators | Molder, Janine |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English, German |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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