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Obesity is a global health problem of the first order. In my thesis, I aimed to elucidate the role of histone deacetylase 5 in controlling thermogenesis and body weight. My studies in male HDAC5-KO mice revealed an impaired thermogenic PVH-SNS-BAT/eWAT axis that induced mature-onset obesity under non-obesogenic conditions. By developing pipelines for the sorting of specific cellular subpopulations in the CNS, I unraveled chronic hyperactivation of dopaminergic neurons in the dorsomedial arcuate nucleus as likely driver for the obesity phenotype of HDAC5-KO males, Adipositas ist ein Problem globaler Ausprägung. Meine Doktorarbeit beleuchtet die Rolle des Enzyms Histon Deacetylase 5 in der Adipositas-Ätiologie. Mäuse mit HDAC5 Deletion entwickelten Adipositas wegen verminderter, durch die PVH-SNS-BAT/eWAT-Achse gesteuerter Thermogenese bzw. Lipolyse. In meiner Arbeit entwickelte Techniken zur spezifischen Isolation von Zellpopulationen im ZNS deuten zudem auf eine entscheidende Rolle dopaminerger Neuronen des dorsomedialen Hypothalamus für die Ausprägung des Adipositas-Phänotyps hin.

Obesity is a global health problem of the first order. In my thesis, I aimed to elucidate the role of histone deacetylase 5 in controlling thermogenesis and body weight. My studies in male HDAC5-KO mice revealed an impaired thermogenic PVH-SNS-BAT/eWAT axis that induced mature-onset obesity under non-obesogenic conditions. By developing pipelines for the sorting of specific cellular subpopulations in the CNS, I unraveled chronic hyperactivation of dopaminergic neurons in the dorsomedial arcuate nucleus as likely driver for the obesity phenotype of HDAC5-KO males, Adipositas ist ein Problem globaler Ausprägung. Meine Doktorarbeit beleuchtet die Rolle des Enzyms Histon Deacetylase 5 in der Adipositas-Ätiologie. Mäuse mit HDAC5 Deletion entwickelten Adipositas wegen verminderter, durch die PVH-SNS-BAT/eWAT-Achse gesteuerter Thermogenese bzw. Lipolyse. In meiner Arbeit entwickelte Techniken zur spezifischen Isolation von Zellpopulationen im ZNS deuten zudem auf eine entscheidende Rolle dopaminerger Neuronen des dorsomedialen Hypothalamus für die Ausprägung des Adipositas-Phänotyps hin.

p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.