The tissue-specific action of FKBP51 in the regulation of the acute stress response and metabolism

Häusl, Alexander (2022): The tissue-specific action of FKBP51 in the regulation of the acute stress response and metabolism. Dissertation, LMU München: Fakultät für Biologie

Abstract

Obesity and stress related disorders are a major burden to modern societies and significantly impact public health worldwide. The FK506 binding protein 51 (FKBP51) has been identified as an essential regulator of signaling pathways associated with stress-related disorders and metabolic diseases. This thesis demonstrates further molecular and physiological evidence that FKBP51 acts in a tissue-specific manner to mediate the acute stress response, body weight control, and glucose metabolism. In the first set of experiments, we investigated the role of global FKBP51 deletion on high-fat diet (HFD) exposure. We could show that FKBP51 knockout (KO) mice are protected from high-fat diet-induced weight gain, have improved glucose tolerance, and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulated the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Mechanistically, we identified that FKBP51 regulates glucose uptake in muscle through the association between FKBP51 and AS160, a substrate of AKT2. Next, we were interested in the role of FKBP51 in the hypothalamus, a key brain area involved in regulating whole-body metabolism. We investigated the impact of FKBP51 via hypothalamic-specific overexpression and deletion and observed an opposing phenotype compared to the global FKBP51 KO animals, which display a lean phenotype upon a high-fat diet. In fact, hypothalamic FKBP51 deletion strongly induced obesity on a regular chow diet, while its overexpression protected against HFD induced body weight gain. We further identified FKBP51 as a critical mediator for the LKB1/AMPK complex recruitment to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. In the last study, we manipulated FKBP51 in the paraventricular nucleus of the hypothalamus (PVN) and investigated its role in the acute stress response. The study demonstrated that FKBP51 deletion dampens the acute stress response and increases GR sensitivity, while its overexpression results in a chronic hypothalamic-pituitary adrenal (HPA) axis overactivation. Furthermore, we identified a cell- type specific expression pattern of FKBP51 in the PVN and showed that FKBP51 expression is most upregulated in Crh+ neurons after acute stress. Interestingly, Crh-specific FKBP51 overexpression alters Crh neuronal activity but only partially recapitulates the PVN-specific FKBP51 overexpression phenotype. In summary, this thesis significantly extends the knowledge about the tissue-specific action of FKBP51 in the regulation of the acute stress response and whole-body metabolism and provides novel molecular binding partners of FKBP51.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 24. November 2022
• 1. Bericht­erstatter:in: Schmidt, Mathias