Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism

Häusl, Alexander S.; Bajaj, Thomas; Brix, Lea M.; Pöhlmann, Max L.; Hafner, Kathrin; Angelis, Meri De; Nagler, Joachim; Dethloff, Frederik; Balsevich, Georgia; Schramm, Karl‐Werner; Giavalisco, Patrick; Chen, Alon; Schmidt, Mathias V.; Gassen, Nils C.

doi:10.1126/sciadv.abi4797

Cited by 12 publications

(7 citation statements)

References 75 publications

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“…Moreover, pharmacological modulation of FKBP51 or genetic manipulation of Fkbp5 in rodents has already demonstrated its implications in stress resilience mechanisms ( 19 , 20 , 24 – 27 ). However, the contribution of FKBP51 to stress resilience processes may vary largely between different brain regions, or even so, between specific cell types, which has already been highlighted by previous work from our group and others ( 25 – 31 ).…”

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confidence: 55%

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

van Doeselaar,

Stark,

Mitra

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic ( Fkbp5 Nex ) and GABAergic ( Fkbp5 Dlx ) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

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mentioning

confidence: 55%

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

van Doeselaar,

Stark,

Mitra

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…In animal models of Huntington disease, reduction of FKBP5 expression increased LC3-II levels and autophagic flux [ 27 ]. Recently, Nils C. Gassen and his colleges demonstrated that FKBP5-regulated autophagy play a crucial role in mediobasal hypothalamus (MBH) under metabolic stress [ 28 , 29 ]. However, whether FKBP5 regulates autophagy in β cells was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling

Liu

Cao

et al. 2023

Cell Death Discov.

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The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone—insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal NIT-1 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β-cell survival, improved insulin secretion, and upregulated β-cell functional gene expressions (MAFA and NKX6.1) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance in improving islet function, in accordance with its protective effect against inflammation. Molecular studies found that FKBP5 is an important regulator for FOXO1 phosphorylation at Serine 256, and silencing of FOXO1 abrogated the protective effect of FKBP5 inhibition, suggesting that it is the key downstream effector of FKBP5 in β cells. At last, in situ detection of FKBP5 protein expression on human and mice pancreases revealed a reduction of FKBP5 expression in β cells in human T2D patients, as well as T2D mice model (db/db), which may indicate a FKBP5-inhibition-mediated pro-survival mechanism against the complex stresses in T2D milieus.

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“…In animal models of Huntington disease, reduction of FKBP5 expression increased LC3-II levels and autophagic ux [28] . Recently, Nils C. Gassen and his colleges demonstrated that FKBP5-regulated autophagy play a crucial role in mediobasal hypothalamus (MBH) under metabolic stress [29,30] . However, whether FKBP5 regulates autophagy in β cells was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

Liu

Cao

et al. 2023

Preprint

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The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone—insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal βTC-6 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β cell survival, improved insulin secretion, and upregulated β cell functional gene expressions (Pdx1 and NKX6.1) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance in improving islet function, in accordance with its protective effect against inflammation. Molecular studies found that FKBP5 is an important regulator for FOXO1 phosphorylation at Serine 256 and the subsequent nuclear translocation; Combining with the abundant expression of FKBP5 in β cells, this finding explains, as least partially, the unique constitutively cytoplasmic sub-cellular localization of FOXO1 protein. Meanwhile, silencing of FOXO1 abrogated the protective effect of FKBP5 inhibition, suggesting that it is the key downstream effector of FKBP5 in β cells. At last, taking advantage of pancreatic specimens from T2D patients and non-diabetic organ donors, we found a reduction of FKBP5 expression in β cells in T2D, which may indicate a FKBP5-inhibition mediated pro-survival mechanism against the complex stresses in T2D milieus.

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Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism

Cited by 12 publications

References 75 publications

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

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