Neuroendocrine-immune perturbations in metabolic disease: pathophysiological mechanisms underlying cognitive impairment

Aviva Fraer; Sanaz Saleh; Dana Tasabehji; Durga Shankar Sharma; Mohamad Mokadem

doi:10.3389/fnhum.2026.1857087

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Neuroendocrine-immune perturbations in metabolic disease: pathophysiological mechanisms underlying cognitive impairment

Journal article

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Neuroendocrine-immune perturbations in metabolic disease: pathophysiological mechanisms underlying cognitive impairment

Aviva Fraer, Sanaz Saleh, Dana Tasabehji, Durga Shankar Sharma and Mohamad Mokadem

Frontiers in human neuroscience, Vol.20, 1857087

07/13/2026

DOI: 10.3389/fnhum.2026.1857087

PMID: 42517056

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Abstract

The escalating global prevalence of obesity and associated metabolic disorders has catalyzed intensive investigation into their multisystemic ramifications. Recent scientific investigations elucidate the sophisticated bidirectional relationship between systemic metabolic aberrations and central nervous system (CNS) dysfunction, orchestrated via complex neuro–immune–endocrine signaling cascades. This integrative analysis consolidates extant literature regarding the mechanisms by which adiposity, metabolic-associated steatotic liver disease (MASLD), and systemic metabolic perturbations disrupt neuro–immune–endocrine communication networks, consequently precipitating neuroinflammatory processes, cognitive dysfunction, and enhanced vulnerability to neurodegenerative disorders. We examine the molecular and cellular mechanisms underlying this pathophysiological cascade, including adipokine dysregulation, systemic inflammatory mediator elevation, hypothalamic inflammation, microglial activation, blood-brain barrier disruption, and subsequent neuronal dysfunction. Furthermore, we analyze the modulatory roles of key endocrine axes—including the hypothalamus, the pituitary and the adrenal glands-, and growth hormone/insulin-like growth factor systems—in metabolic-neural crosstalk. By elucidating these complex pathways, we aim to highlight mechanistically informed therapeutic targets and combinatorial strategies that may attenuate neuroinflammatory processes and cognitive deterioration in metabolically compromised individuals.

adipokines

cognitive impairment

cytokines

hypothalamic inflammation

metabolic-associated steatotic liver disease

microgliosis

neurodegeneration

neuro-immune-endocrine axis

Details

Title: Subtitle: Neuroendocrine-immune perturbations in metabolic disease: pathophysiological mechanisms underlying cognitive impairment
Creators: Aviva Fraer - University of Iowa
Sanaz Saleh - University of Iowa
Dana Tasabehji - University of Iowa
Durga Shankar Sharma - University of Iowa
Mohamad Mokadem - University of Iowa
Resource Type: Journal article
Publication Details: Frontiers in human neuroscience, Vol.20, 1857087
DOI: 10.3389/fnhum.2026.1857087
PMID: 42517056
ISSN: 1662-5161
eISSN: 1662-5161
Publisher: Frontiers Media
Grant note: US Department of Veterans Affairs, VA Merit Review Program: I01 BX004774-05
The author(s) declared that financial support was received for this work and/or its publication. MM is supported by funds from the US Department of Veterans Affairs, VA Merit Review Program (I01 BX004774-05).
Language: English
Date published: 07/13/2026
Academic Unit: Gastroenterology and Hepatology; Internal Medicine
Record Identifier: 9985183136902771

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