No description available.

No description available.

No description available.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / While depression is a risk factor for type 2 diabetes, little is known about the effect of depression treatment on diabetes risk markers. Using data from the recently completed eIMPACT trial (NCT02458690, supported by R01 HL122245), I examined if depression intervention improves diabetes risk markers and if improvements in somatic depressive symptoms mediate potential intervention effects. 216 participants (primary care patients ≥50 years with depression and elevated cardiovascular disease risk from a safety net healthcare system) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care intervention involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants; n=107) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and affiliated psychiatrists; n = 109). Given my focus on diabetes risk, I excluded participants who did not attend the post-treatment visit (n = 17) or who had a diabetes history at pre-treatment (n = 73), leaving a final sample of 126 (n=66 intervention, n=60 usual care; Mage = 58 years, 79% women, 50% Black, 47% with income <$10k/year). I computed depressive symptom severity variables from the Hopkins Symptom Checklist-20 (SCL-20) items: hyperphagia (“overeating” item), poor appetite (“poor appetite”), hypersomnia (“sleeping too much”), disturbed sleep (“sleep that is restless or disturbed”) and SCL-15 (mean of items not pertaining to appetite or sleep). I calculated insulin resistance from fasting plasma glucose and insulin using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)-2 calculator, body mass index (BMI) from measured height and weight, and plasma concentrations of high-sensitivity C-reactive protein (hsCRP), leptin, and ghrelin using ELISA kits. Parallel mediation analyses revealed that 12 months of modernized collaborative care for depression improved both directions of sleep symptoms but did not improve poor appetite or hyperphagia – the somatic symptom most consistently linked with increases in HOMA-IR, BMI, hsCRP, and leptin. Of the five cardiometabolic biomarkers examined, the eIMPACT intervention decreased only hsCRP and ghrelin. There were no intervention effects on HOMA-IR, BMI, or leptin. In addition, no somatic depressive symptoms mediated intervention effects on the cardiometabolic biomarkers, nor did race moderate any mediation effects. Further research is warranted to determine best practices for targeting hyperphagia and reducing cardiometabolic disease risk among people with depression.

Diese Dissertation behandelt die funktionelle Charakterisierung von Varianten im Leptinrezeptor-Gen zweier pädiatrischer Patientinnen. Die Varianten wurden in vitro rekonstruiert und ihr Einfluss auf die Oberflächenexpression, Dimerisierungsfähigkeit, Ligandenbindung und den intrinsischen Signalweg untersucht. Anhand der experimentellen Charakterisierung konnte die Pathogenität der Varianten eingeschätzt werden und ob sie ursächlich für Adipositas und Hyperphagie der Patientinnen sind.:Abkürzungsverzeichnis 3 1 Einführung 5 1.1 Genetische Prädisposition für Adipositas 5 1.2 Von ob/ob-Mäusen zur Entdeckung des Adipokins Leptin 6 1.3 Der Leptinrezeptor 7 1.3.1 Proteinstruktur und Isoformen des Leptinrezeptors 7 1.3.2 Signalweg des LEPRb 8 1.3.4 Funktion des Leptin-Leptinrezeptor-Signalweges im Hypothalamus 9 1.4 Monogene Adipositas durch Leptinrezeptor-Defizit 9 1.5 Therapie des Leptinrezeptor-Defizites: Setmelanotide 11 1.6 Identifizierung von LEPR-Varianten in zwei pädiatrischen Patientinnen 12 1.6.1 Hintergrund und Fragestellung der vorliegenden Dissertation 12 1.6.2 Ergebnisse 13 2 Originalpublikation 15 3 Zusammenfassung der Arbeit 25 3.1 Identifikation einer neuen LEPR-Variante als Ursache monogener Adipositas 25 3.2 Untersuchung der LEPR-Varianten auf Funktionseinschränkungen als Grundlage der Therapieentscheidung 26 3.3 Interpretation und Ausblick 27 4 Literaturverzeichnis 29 5 Anlagen 36 5.1 Darstellung des eigenen Beitrages an der Originalpublikation 36 5.2 Eigenständigkeitserklärung 44 5.3 Lebenslauf 45 6 Danksagung 47

Autonomic nervous system (ANS) activity is related to body weight regulation. Based on the hypothesis that Most Obesities kNown Are Low In Sympathetic Activity (MONA LISA), it has been suggested that most obese subjects and animals have low sympathetic nervous system activity. Leptin, leptin receptor, and ghrelin genes influence the ANS regulation of body weight and food intake. The aim of this study was to investigate whether there are differences in leptin, the leptin receptor, or ghrelin regulation between lines of chickens selected for high (HWS) or low body weight (LWS). Intraperitoneal injections of reserpine were administrated to chickens from the HWS and LWS lines. Body weight and food intake were then compared to evaluate ANS regulation. While reserpine caused a transitory decrease in food intake and body weight in both lines, the magnitude of the change was greater in the HWS than in the LWS chickens. However, chickens from the LWS line exhibited greater catecholamine and indoleamine level changes in response to reserpine than those from the HWS line. Therefore, HWS chickens were more sensitive to the body weight-reducing effects of reserpine than LWS lines, while LWS chickens appeared to have greater sympathetic nervous system activity. Food and water intakes were differentially affected in HWS and LWS chickens in response to intracerebroventricular administration of human recombinant leptin. Leptin caused a linear decrease in food intake in the LWS line, but no effect on food intake in the HWS lines. The HWS chickens tended to have reduced water intake following leptin administration. These results suggest that the leptin receptor, or the down-stream neuropeptide regulation pathway mediating the effect of leptin; may be different between chickens from the HWS and LWS lines. Leptin, insulin like growth factor (IGF)-1, and IGF-2 concentrations in the plasma of HWS and LWS lines of chickens were evaluated. Leptin, IGF-1 and IGF-2 levels were significantly higher in the LWS than HWS chickens. The HWS female leptin concentrations were significantly lower than in HWS males or LWS females. Male chickens had greater IGF-1 concentrations in the plasma than female chickens. However, the concentration of IGF-2 did not differ between sexes. The difference in leptin concentrations in these lines and sexes may explain the differences in age of sexual maturity. Different IGF-1 and IGF-2 concentrations may be involved in the obese and anorexic conditions, fast and slow growth, and high and low food consumption found in these two lines of chickens. Differences in the gene sequence of the leptin receptor were observed in HWS and LWS lines of chickens. A single nucleotide polymorphism (SNP) in the intron between exon 8 and 9 introduced a restriction site for the enzyme Sel I in the HWS, but not the LWS line. Two SNP were detected in the leptin receptor cDNA region at nucleotides 189 and 234. At nucleotide 189, the LWS line has both a homozygous (T-T) and heterozygous (C-T), whereas the HWS line has only homozygous (T-T) form. The SNP found in nucleotide 234 introduces a restriction site Mse I in the HWS, but not the LWS line. These specific changes may be directly involved or closely linked to differences between the two lines in either the coding or regulatory domains of the leptin receptor. Differences in the leptin receptor gene expression between HWS and LWS lines of chickens in various organs and ages were observed. Leptin receptor expression in the whole brain was significantly different between sexes at 28 days-of-age in the HWS and LWS lines. The LWS line had higher leptin receptor gene expression in the liver at 2 days-of-age than at 56 and 363 days-of-age, but no differences were observed in the HWS line. In addition, at 2 days-of age, liver leptin receptor gene expression was higher in LWS than HWS chickens, but the reverse was observed at 363 days-of age. In adipose tissue, leptin receptor expression was higher in the LWS than HWS line. Leptin receptor expression in adipose tissue was greater at 363, than 28 and 56 days-of-ages. Our results showed that changes in the regulation of leptin and the leptin receptor were associated with sex, age, and growth. Differences in the ghrelin gene in the HWS and LWS lines under different feeding conditions were investigated. Both HWS and LWS chickens have six extra base pairs in the 5'-untranslated region. The LWS male ghrelin gene expression was significantly lower than in the LWS female and HWS male. The 84 day-old males had lower gene expression than 84 day-old females and 363 day-old males. When comparing different feeding methods, females allowed ad libitum feed consumption had a lower cycle threshold cycle number (CT) ratio than males allowed ad libitum feeding or fasted females. However, the inflection point cycle number of ad libitum fed females was lower than that of the ad libitum fed males, but greater than the fasted females. Ghrelin gene expression was different between the two lines of chickens, and the expression of ghrelin in chickens was influenced by body weight selection, sex, age, and feeding condition. / Ph. D.

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

High body weight seems protective of bone mass, specifically bone mineral content (BMC) and bone mineral density (BMD), thereby reducing the risk of osteoporosis. Cognitive eating restraint (CER), diet composition, and the satiety hormone, leptin, produced by adipocytes, are associated with body mass and may also influence bone mass. Few studies have examined these relationships. To investigate the relationship between leptin and CER score, 36 premenopausal, healthy weight women, as defined by body mass index (BMI) of 18-25 kg/m², aged 18-25 years were studied. Women were categorized by baseline Eating Inventory questionnaire scores into either the high CER group (score > 9, n = 20) or low CER group (score < 9, n = 16). Serum leptin concentration was significantly lower in the low CER group versus high CER group at baseline. A positive relationship between serum leptin concentration and body fat mass and body fat % in normal weight women despite differences in CER scores was observed. In a separate study, overweight and obese women, (BMI > 25 to < 43 kg/m²), aged 32-45 years, were randomly assigned to either a low-carbohydrate, high-protein (LCHP) or low-fat, high-carbohydrate (LFHC) diet for 12 weeks. Serum leptin concentration was significantly greater in the LCHP versus the LFHC diet group at 12 weeks (p < 0.05). Over time, significant decreases in serum leptin concentration, BMI, body weight, total lean mass, total fat mass, and body fat % were observed in both diet groups. Serum leptin concentration was positively associated with body weight, fat mass, and body fat % regardless of diet consumed. Both studies are novel in their respective populations and show no direct link between leptin and bone mass when considered in the context of CER or diet composition. / Master of Science

INTRODUÇÃO: A obesidade na infância e adolescência representa uma epidemia global e figura como um problema de saúde pública proeminente de prevalência crescente. A obesidade frequentemente está associada à compulsão alimentar periódica (CAP) e componentes genéticos participam de sua etiologia multifatorial. Polimorfismos de nucleotídeo único (SNPs) no gene da leptina (LEP) e do receptor da leptina (LEPR) podem modificar a expressão da leptina e de suas vias de sinalização e, consequentemente, alterar a regulação do apetite e da saciedade, contribuindo assim para a etiopatogenia e manutenção da CAP. O objetivo deste trabalho foi investigar a influência dos polimorfismos rs7799039 (G > A) no gene LEP e rs1137100 (A > G), rs1137101 (A > G) e rs8179183 (G > C) no gene LEPR sobre a CAP em crianças e adolescentes obesos, além de caracterizar a população quanto à CAP e verificar a associação dos SNPs com o risco cardiometabólico (RCM) e a obesidade. MÉTODOS: Estudo transversal que incluiu 465 crianças e adolescentes obesos com idade entre 7 e 19 anos avaliados quanto a variáveis antropométricas e metabólicas. Os fatores de RCM consistiram de hipertensão arterial sistêmica, glicemia de jejum alterada, HDL-colesterol baixo e hipertrigliceridemia. A CAP foi avaliada por meio da Escala de Compulsão Alimentar Periódica (ECAP). Para investigar o efeito dos SNPs no risco para a obesidade foi incluído um grupo controle composto por 135 crianças e adolescentes eutróficos. A genotipagem foi realizada por PCR em tempo real e para análise dos SNPs, adotou-se o modelo dominante. Foi calculado o desequilíbrio de ligação entre os SNPs e estimada as frequências dos haplótipos. As comparações entre os grupos foram realizadas estratificadamente por gênero e estádio puberal. Para avaliar a magnitude do risco dos SNPs sobre a CAP e a obesidade foi realizada regressão logística ajustada para variáveis de confusão (idade, Z-IMC e estádio puberal). RESULTADOS: As crianças e adolescentes obesos (12,5 ± 2,9 anos; 52,7% meninas) classificados com CAP apresentaram maior adiposidade e a frequência da CAP foi mais elevada no gênero feminino (OR= 2,146; IC 95% 1,461-3,152; p < 0,001). A frequência do alelo A do rs7799039 foi mais elevada no grupo de obesos (OR= 1,530; IC 95% 1,022-2,292; p= 0,039) e o alelo associou-se ao maior nível de leptina e colesterol total em meninas e à maior glicemia em meninos (p < 0,05). No rs1137100 e o rs1137101, a presença do alelo G em meninas conferiu risco para a hipertrigliceridemia (OR= 1,926; IC 95% 1,010-3,673; p= 0,047 e OR= 2,039; IC 95% 1,057-3,931; p= 0,033, respectivamente). O alelo C do rs8179183 relacionou-se, em meninas, à relação cintura-estatura e glicemia mais elevadas e, em meninos, ao maior percentil de pressão arterial diastólica, glicemia, colesterol total e LDL-colesterol (p <0,05). CONCLUSÃO: Os polimorfismos não foram associados à compulsão alimentar periódica. A CAP foi relacionada ao pior grau de adiposidade e o maior risco foi observado no gênero feminino. O SNP rs7799039 no gene LEP conferiu risco para obesidade, enquanto o rs1137100, rs1137101 e rs8179183 no gene LEPR relacionaram-se ao pior perfil cardiometabólico em crianças e adolescentes obesos / INTRODUCTION: Obesity during childhood and adolescence represents a global epidemic and consists in a prominent public health issue of increasing prevalence. Obesity is frequently associated with binge eating (BE) and genetic factors participate of its multifactorial etiology. Single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes may modify the leptin expression and its signaling pathways and, consequently, alter appetite and satiety regulation, thus contributing to the etiopathogeny and maintenance of BE. The aim of this study was to investigate the influence of polymorphisms rs7799039 (G > A) in the LEP gene and rs1137100 (A > G), rs1137101 (A > G) and rs8179183 (G > C) in the LEPR gene on BE in obese children and adolescents, besides characterize the population regarding to BE and examine the association of SNPs with cardiometabolic risk (CMR) and obesity. METHODS: Cross-sectional study in which 465 obese children and adolescents aged from 7 to 19 years were enrolled and had anthropometric and metabolic variables assessed. The CMR factors consisted of systemic hypertension, impaired fasting glucose, low HDL-cholesterol levels and hypertriglyceridemia. The BE was evaluated through the Binge Eating Scale (BES). To investigate the effect of SNPs on obesity risk, a control group of 135 eutrophic children and adolescents was enrolled. Genotyping was performed by real-time PCR and for the SNPs analysis, the dominant model was adopted. The linkage disequilibrium between SNPs was calculated and the haplotype frequencies were estimated. Comparisons between groups were performed stratified by gender and pubertal stage. To assess the risk magnitude for the SNPs on BE and obesity, logistic regression adjusted for confounding variables (age, Z-BMI and pubertal stage) was performed. RESULTS: Obese children and adolescents (12.5 ± 2.9 years, 52.7% girls) classified with BE showed greater adiposity and BE frequency was higher among females (OR= 2.146; 95% CI 1.461-3.152; p < 0.001). The observed frequency of A allele of rs7799039 was a higher in the obese group (OR= 1.530; 95% CI 1.022-2.292; p= 0.039) and the allele was associated with higher leptin and total cholesterol levels in girls and higher glucose levels in boys (p < 0.05). For the rs1137100 and rs1137101, the presence of the G allele among girls, conferred risk for hypertriglyceridemia (OR= 1.926; 95% CI 1.010-3.673; p= 0.047 and OR= 2.039; 95% CI 1.057-3.931; p= 0.033, respectively). The C allele of rs8179183 was associated, among girls, with a higher waist-to-height ratio and glucose levels and, among boys, with greater diastolic blood pressure percentile, glucose, total cholesterol and LDL-cholesterol levels (p < 0.05). CONCLUSION: Polymorphisms were not associated with binge eating. BE was related with a more severe adiposity and an increased risk was observed among females. The SNP rs7799039 in the LEP gene contributed to the risk of obesity, whereas the rs1137100, rs1137101 and rs8179183 in LEPR gene were related to a worse cardiometabolic profile in obese children and adolescents