Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniformquality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3, 495 anorexia nervosa cases and 10, 982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2 SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. Results: Results were obtained for 10, 641, 224 SNPs and insertion-deletion variants with minor allele frequencies.&gt;1% and imputation quality scores &gt;0.6. The h2 SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genomewide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.</p

Polypharmakologische Strategien zur Behandlung von Adipositas und zur Verbesserung mehrerer Aspekte des metabolischen Syndroms bei Mäusen

Obesity and its comorbidities, such as type 2 diabetes mellitus (T2DM), are major threats to worldwide health. In this PhD thesis, I tested the efficacy of two novel polypharmacological approaches to induce body weight loss and ameliorate associated metabolic complications in diet-induced obese mice. In the first approach, we aimed to in vivo pharmacologically mimic the hormonal changes that occur upon bariatric surgery. In the second approach, we aimed to in vivo mimic the two canonical modulators of human energy metabolism – tobacco smoking and cold exposure. Most importantly, with the presented PhD thesis, I contributed to the preclinical evaluation of urgently needed novel pharmacological options to treat obesity and associated diseases.Adipositas und Begleiterkrankungen wie Typ-2-Diabetes mellitus stellen eine gesundheitliche Bedrohung für die Bevölkerung dar. In dieser Doktorarbeit habe ich die Wirksamkeit zweier neuer polypharmakologischer Ansätze getestet in Diät-induzierten fettleibigen Mäusen das Körpergewicht zu reduzieren und assoziierte metabolische Komplikationen zu verbessern. In unabhängigen Studien habe ich sowohl die hormonellen Veränderungen, die nach bariatrischen Operationen auftreten, als auch die beiden kanonischen Modulatoren des menschlichen Energiestoffwechsels - Tabakrauchen und Kälteexposition - pharmakologisch nachgeahmt. Zusammenfassend habe ich mit der Doktorarbeit zur präklinischen Evaluation dringend benötigter neuer pharmakologischer Optionen zur Behandlung von Fettleibigkeit und damit verbundenen metabolischen Erkrankungen beigetragen

Polypharmakologische Strategien zur Behandlung von Adipositas und zur Verbesserung mehrerer Aspekte des metabolischen Syndroms bei Mäusen

Obesity and its comorbidities, such as type 2 diabetes mellitus (T2DM), are major threats to worldwide health. In this PhD thesis, I tested the efficacy of two novel polypharmacological approaches to induce body weight loss and ameliorate associated metabolic complications in diet-induced obese mice. In the first approach, we aimed to in vivo pharmacologically mimic the hormonal changes that occur upon bariatric surgery. In the second approach, we aimed to in vivo mimic the two canonical modulators of human energy metabolism – tobacco smoking and cold exposure. Most importantly, with the presented PhD thesis, I contributed to the preclinical evaluation of urgently needed novel pharmacological options to treat obesity and associated diseases.Adipositas und Begleiterkrankungen wie Typ-2-Diabetes mellitus stellen eine gesundheitliche Bedrohung für die Bevölkerung dar. In dieser Doktorarbeit habe ich die Wirksamkeit zweier neuer polypharmakologischer Ansätze getestet in Diät-induzierten fettleibigen Mäusen das Körpergewicht zu reduzieren und assoziierte metabolische Komplikationen zu verbessern. In unabhängigen Studien habe ich sowohl die hormonellen Veränderungen, die nach bariatrischen Operationen auftreten, als auch die beiden kanonischen Modulatoren des menschlichen Energiestoffwechsels - Tabakrauchen und Kälteexposition - pharmakologisch nachgeahmt. Zusammenfassend habe ich mit der Doktorarbeit zur präklinischen Evaluation dringend benötigter neuer pharmakologischer Optionen zur Behandlung von Fettleibigkeit und damit verbundenen metabolischen Erkrankungen beigetragen

Polypharmakologische Strategien zur Behandlung von Adipositas und zur Verbesserung mehrerer Aspekte des metabolischen Syndroms bei Mäusen

Obesity and its comorbidities, such as type 2 diabetes mellitus (T2DM), are major threats to worldwide health. In this PhD thesis, I tested the efficacy of two novel polypharmacological approaches to induce body weight loss and ameliorate associated metabolic complications in diet-induced obese mice. In the first approach, we aimed to in vivo pharmacologically mimic the hormonal changes that occur upon bariatric surgery. In the second approach, we aimed to in vivo mimic the two canonical modulators of human energy metabolism – tobacco smoking and cold exposure. Most importantly, with the presented PhD thesis, I contributed to the preclinical evaluation of urgently needed novel pharmacological options to treat obesity and associated diseases.Adipositas und Begleiterkrankungen wie Typ-2-Diabetes mellitus stellen eine gesundheitliche Bedrohung für die Bevölkerung dar. In dieser Doktorarbeit habe ich die Wirksamkeit zweier neuer polypharmakologischer Ansätze getestet in Diät-induzierten fettleibigen Mäusen das Körpergewicht zu reduzieren und assoziierte metabolische Komplikationen zu verbessern. In unabhängigen Studien habe ich sowohl die hormonellen Veränderungen, die nach bariatrischen Operationen auftreten, als auch die beiden kanonischen Modulatoren des menschlichen Energiestoffwechsels - Tabakrauchen und Kälteexposition - pharmakologisch nachgeahmt. Zusammenfassend habe ich mit der Doktorarbeit zur präklinischen Evaluation dringend benötigter neuer pharmakologischer Optionen zur Behandlung von Fettleibigkeit und damit verbundenen metabolischen Erkrankungen beigetragen

Pirt deficiency has subtle female-specific effects on energy and glucose metabolism in mice

Objective: The contribution of brown adipose tissue (BAT) to adult human metabolic control is a topic of ongoing investigation. In context, understanding the cellular events leading to BAT uncoupling, heat production, and energy expenditure is anticipated to produce significant insight into this endeavor. The phosphoinositide interacting regulator of transient receptor potentials (Pirt) was recently put forward as a key protein regulating cold sensing downstream of the transient receptor potential melastatin 8 (TRPM8). Notably, TRPM8 has been identified as a non-canonical regulator of BAT thermogenesis. The aim of this investigation was to delineate the role of Pirt in energy homeostasis and glucose metabolism - and the possible involvement of Pirt in TRPM8-elicited energy expenditure. Methods: To this end, we metabolically phenotyped male and female Pirt deficient (Pirt−/−) mice exposed to a low-fat chow diet or to a high-fat, high-sugar (HFHS) diet. Results: We identified that chow-fed female Pirt−/− mice have an increased susceptibility to develop obesity and glucose intolerance. This effect is abrogated when the mice are exposed to a HFHS diet. Conversely, Pirt−/− male mice display no metabolic phenotype on either diet relative to wild-type (WT) control mice. Finally, we observed that Pirt is dispensable for TRPM8-evoked energy expenditure. Conclusion: We here report subtle metabolic abnormalities in female, but not male, Pirt−/− mice. Future studies are required to tease out if metabolic stressors beyond dietary interventions, e.g. temperature fluctuations, are interacting with Pirt-signaling and metabolic control in a sex-specific fashion. Keywords: Signaling molecule, Sex differences, Body weight, Energy metabolism, TRPM8, Brown adipose tissu