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Übergewicht und Adipositas beeinflussen die männliche und weibliche Fertilität negativ. Im Gegensatz zur Adipositas kommt es bei Lipodystrophie zu einem selektiven Verlust von Fettgewebe. Ähnlich zur Adipositas treten auch bei Lipodystrophie metabolische und vaskuläre Folgeerkrankungen auf. Weibliche Lipodystrophie-Patientinnen leiden im Erwachsenenalter häufig an einem hypogonadotropen Hypogonadismus mit primärer oder sekundärer Amenorrhoe. Patienten mit Lipodystrophie haben signifikant niedrigere Leptinspiegel. Leptin ist ein bekannter Mediator und Modulator der Hypothalamus-Hypophysen-Gonaden-Achse und beeinflusst somit die Reproduktionsfähigkeit. Inwiefern die Gabe von Leptin die Fertilität bei Lipodystrophie beeinflusst, ist bis jetzt unzureichend untersucht. Ziel dieser Studie war die Untersuchung der Fertilität im Tiermodel der generalisierten Lipodystrophie und der Einfluss einer Leptintherapie. Hierzu wurden C57BL/6 Mäuse mit Lipodystrophie über 8 Wochen mit Kochsalz oder Leptin behandelt und mit Kontrollmäusen ohne Lipodystrophie verglichen. Die mittlere Zahl von Nachkommen war 37% geringer bei Verpaarung von weiblichen Lipodystrophie-Tieren mit männlichen Kontrollen (n = 3,3) verglichen zu männlichen Lipodystrophie-Tieren mit weiblichen Kontrollen (n = 5,2; p < 0,05). Diese Befunde sind vereinbar mit Daten beim Menschen, wo eine Lipodystrophie-assoziierte Subfertilität insbesondere bei Frauen auftritt. Das mittlere Uterusgewicht war signifikant niedriger bei Kochsalz-behandelten Lipodystrophie-Mäusen (18,8 mg) verglichen zu Kontrollen (52,9 mg; p < 0,0001). Eine Behandlung von Lipodystrophie-Mäusen mit Leptin führte zu einer deutlichen und statistisch signifikanten Erhöhung des Uterusgewichts (46,5 mg; p < 0,001) verglichen zu Kochsalz-behandelten Tieren. Die mittlere Zahl von corpora lutea pro Ovar war signifikant niedriger in Kochsalz-behandelten Lipodystrophie-Tieren verglichen zu Kontrollen (p < 0,01) und Leptin-behandelten Tieren (p < 0,05). Mechanistische Untersuchungen wiesen nach, dass die mRNA-Expression des follicle-stimulating hormone-Rezeptors (p < 0,01) und Östrogen-Rezeptors β (p < 0,05) in Ovarien sowie von luteinizing hormone β (p < 0,001) und follicle-stimulating hormone β (p < 0,05) in der Hypophyse signifikant erhöht war in Kochsalz- behandelten Lipodystrophie-Mäusen verglichen zu Kontrollen. Zusätzlich war die Zeit bis zur vaginalen Öffnung, welches als weiblicher Pubertätsmarker fungiert, um 12,5 Tage verzögert in Lipodystrophie-Tieren (50,9 Tage) verglichen zu Kontrollen (38,4 Tage; p < 0,001). Zusammenfassend wird eine weibliche Subfertilität in einem Mausmodell der Lipodystrophie nachgewiesen. Diese Subfertilität wird durch Leptingabe positiv beeinflusst. In weiterführenden Studien sollte nun bestimmt werden, ob die weibliche Subfertilität bei Patientinnen mit Lipodystrophie ebenfalls durch Leptin verbessert wird. Hierbei ist anzumerken, dass Leptin mittlerweile sowohl in der USA als auch in der EU als Therapeutikum bei Lipodystrophie zugelassen wurde, nachdem es über viele Jahre nur im Rahmen von compassionate use-Programmen verfügbar war.:INHALTSVERZEICHNIS: 1. BIBLIOGRAPHISCHE BESCHREIBUNG 2. EINFÜHRUNG IN DIE THEMATIK 2.1 LIPODYSTROPHIE 2.1.1 Definition und Klassifikation 2.1.2 Pathogenese der Metabolischen Veränderungen 2.1.3 Mausmodel für Lipodystrophie 2.2 LEPTIN 2.2.1 Geschichte 2.2.2 Struktur 2.2.3 Produktion 2.2.4 Rezeptor 2.2.5 Signalkaskade 2.2.6 Leptinmangel und einhergehende Erkrankungen 2.2.7 Leptin und Reproduktionsfunktion 2.3 FRAGESTELLUNG 3. UNTERSUCHUNGEN IM RAHMEN DER DISSERTATION 4. PUBLIKATION 5. ZUSAMMENFASSUNG 6. LITERATURVERZEICHNIS ANLAGEN A. ABKÜRZUNGSVERZEICHNIS B. ERKLÄRUNG ÜBER DIE EIGENSTÄNDIGE ABFASSUNG DER ARBEIT C. ANTEILE DER CO-AUTOREN D. DANKSAGUNG

Type 2 diabetes mellitus (T2DM) is classified as a metabolic disorder characterized by hyperglycemia that results from defects in insulin action and/or secretion, and currently affects 8.3% of the US population according to the CDC’s 2011 National Diabetes Fact Sheet. Several contributing factors have been identified to development of this disease. Published evidence indicates type 2 diabetes mellitus (T2DM) patients display lower overall paraoxonase activity and that this may be partially due to genetic variations in the paraoxonase-1 (PON-1) gene. Some bioaccumulative organochlorine (OC) pesticides have been shown to contribute to increased T2DM prevalence. In addition, these OC compound levels have been associated with alterations in adipocyte cytokine levels as well as increased inflammatory markers. Three hundred blood samples with clinical and demographic information were obtained from two US Air Force hospitals. A total of 151 non-diabetics and 149 T2DM subjects were evaluated for PON-1 activity, PON-1 Q192R and L55M genetic polymorphisms, OC compound concentrations, inflammatory marker levels and adipokine concentrations. PON-1 activity, using diazoxon as the substrate, was decreased in the T2DM subjects. Some of the PON-1 genetic polymorphisms tested were also associated with decreased PON-1 activity. OC compound levels were increased in the T2DM subjects. The non-diabetic subjects possessing elevated DDE and trans-nonachlor were associated with increased inflammation, a common hallmark of early T2DM development. Additionally, elevated OC levels were seen in association with altered adipokine concentrations. Overall, a decrease in the antioxidant properties of PON-1 as well as factors contributing to chronic low level inflammation such as elevated OC plasma concentration appear to be significant contributors to T2DM prevalence in the population studied.

One of the numerous complications of obesity is infertility. Leptin has been shown to reverse infertility; however, exact mechanism is poorly understood. Recent evidence indicates Ecadherin/ β-catenin complex, which is a structural constituent of adherens junction, is expressed in the rat ovary during folliculogenesis. We hypothesized that systemic leptin modulates the expression of E-cadherin and β-catenin in dietary-induced obese infertile rats to reverse infertility. Female Sprague-Dawley rats were fed either regular chow diet (RCD) (n=6) or high fat diet (HFD) (n=14). Oestrus cycles were monitored daily until their cycles became irregular. 100 ug/ml of leptin was given intraperitoneally to HFD-fed rats (n=5) with irregular cycles. The control rats HFD (n=9) and RCD received saline. Leptin treatment restored regular estrous cycle and increased the expression of E-cadherin and β-catenin in all the 5 rats (HFD+Leptin). This could represent the mechanism by which leptin reverses infertility in obese infertile rats.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LDand the impact of leptin treatment have not been investigated so far.Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controlsmatched for age, gender, and bodymass index. The impact ofmetreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated withmarkers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

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