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HPA-Axis Suppression Drives Durable Metabolic Improvements In Murine Multiple Models Of Metabolic Disease Via Central And Peripheral Mechanisms V

ABSTRACT: The HPA-Axis and systemic glucocorticoid metabolism influence cellular and metabolic function in nearly every cell type in mammals. Chronic exposure to excess glucocorticoid levels results in broad metabolic derangements, while suppression of glucocorticoid levels leads to improvements in multiple aspects of metabolic health despite remaining difficult to target pharmacologically. Here, we utilize a monoclonal antibody against CRF, the parent activator of the HPA-Axis, to achieve durable suppression of plasma glucocorticoid levels without inducing adrenal failure. In multiple mouse models of metabolic disease and obesity, including in diet-induced obese animals treated for up to 8 consecutive months, long-term treatment with this antibody resulted in significant reductions in weight trajectory, significantly improved body composition, and broad improvement in metabolic parameters. Parallel assessments were performed in lean animals. Using multi-tissue transcriptomic and proteomic assessments, we identified glucocorticoid responsive genes that were strongly correlated with metabolic efficacy and drug treatment. We also generated multi-organ omic datasets in middle aged animals maintained on a high-fat diet versus a chow diet for 8 months. Collectively, our study demonstrates a putative role for HPA-Axis suppression as an efficacious metabolic therapy, and we supply a unique dataset from which transcriptomic changes following prolonged diet-induced metabolic disease in mice can be further investigated.

ORGANISM(S): Mus musculus

PROVIDER: GSE317099 | GEO | 2026/09/16

REPOSITORIES: GEO

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Project description:This a model from the article: Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability. Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Theor Biol Med Model 2007 Feb 14;4:8 17300722 , Abstract: BACKGROUND: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS). CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. (2007) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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HPA-Axis Suppression Drives Durable Metabolic Improvements In Murine Multiple Models Of Metabolic Disease Via Central And Peripheral Mechanisms V

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