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Abstract

Our world is facing a pandemic of stress-related disorders, ranging from mental health to cardiovascular and metabolic diseases, and there is an urgent need for effective and selective treatments. Despite enormous efforts and decades of research, we are still far from finding targeted interventions for most psychiatric but also metabolic diseases. The identification of genetic risk factors and subsequently deciphering their tissue- and cell type-specific role in physiology is an indispensable step towards a more comprehensive understanding of the molecular mechanisms underlying these disorders. One prominent example is the co-chaperone FKBP51, which has been linked to the development of psychiatric and metabolic disorders in humans. It has been shown to be involved in a plethora of cellular signaling pathways that modulate our hormonal stress response system, the hypothalamic-pituitary-adrenal (HPA axis), and whole-body metabolism. To dissect the tissue-specific role of FKBP51 in the HPA axis, we selectively manipulated FKBP51 expression in mouse paraventricular nucleus (PVN), the master regulator of the central stress response, and assessed the behavioral and endocrine phenotypes of these animals. We were further interested in whether loss of FKBP51 in corticotrope pro-opiomelanocortin (POMC) cells in the pituitary gland (PIT) affects negative feedback control of the HPA axis and age-related dysregulation of the stress response. Both cell type-specific studies on the involvement of FKBP51 in HPA axis (re)activity revealed a beneficial effect of attenuating Fkbp5 expression, which is consistent with systemic endogenous knockout (KO) studies in rodents. To expand the existing knowledge on the role of FKBP51 in autophagy signaling, we knocked out and overexpressed (OE) the gene in the mediobasal hypothalamus (MBH), which is known for its key role in energy homeostasis and feeding behavior. Our study identified a novel group of molecular players called phosphoinositide protein family (WIPI proteins) that interact with FKBP51 to control autophagy signaling in the rodent MBH. Since the MBH is a heterogeneous structure with multiple neuronal subpopulations that all individually and synergistically contribute to shaping homeostasis, we set out to investigate the cell type-specific role of FKBP51 in steroidogenic factor 1 (Sf1) expressing neurons of the ventromedial hypothalamus (VMH) and Pomc-expressing cells of the arcuate nucleus (ARC). Intriguingly, KO of FKBP51 in these two MBH subnuclei had opposite effects on high-fat diet (HFD) induced body weight (BW) gain: KO of FKBP51 in VMH-SF1 neurons adversely affects whole-body metabolism, corresponding to an MBH-wide KO of this co-chaperone. However, attenuation of Fkbp5 expression in POMC neurons had positive effects on BW regulation under a HFD challenge. Thus, the collective results of this work highlight the importance of cell type-specific studies on the role of FKBP51 in homeostatic control and pave the way for future pharmacological intervention studies.