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Equine veterinary journal2026; doi: 10.1002/evj.70195

Protective effects of adiponectin receptor agonists against equine lamellar endoplasmic reticulum stress.

Abstract: Lamellar endoplasmic reticulum (ER) stress occurs in hyperinsulinemia-associated and sepsis-related laminitis. Adiponectin is associated with reduced laminitis risk and inhibits ER stress in other species. Objective: To induce ER stress in ex vivo equine lamellar cells using pharmacological agents. To determine whether co-treatment with adiponectin receptor agonists (ARAs) reduces ER stress. Methods: In vitro. Methods: Lamellar cells from n = 4-5 horses were treated with tunicamycin or thapsigargin (10-1000 nM) for 2-24 h. ER-stressed cells were co-treated with full-length adiponectin (FLA; 30-3000 ng/mL), globular adiponectin (gA; 30-3000 ng/mL), AdipoRon (2-50 μM), or AICAR (1 mM) for 24 h. Expression of binding immunological protein (BIP) and spliced X-box binding protein (sXBP1; two ER stress markers), ribosomal protein 6 (RPS6), and interleukin-6 and -8 was determined using qRT-PCR and western blotting. Results: BIP expression increased in a concentration- and time-dependent manner and was highest after 24 h treatment with 1000 nM tunicamycin (mRNA: mean [95% CI] log fold-change [FC] = 4.8 [3.7-5.9]; p < 0.001; protein: logFC = 3.3 [2.7-4.0]; p < 0.001). XBP1 splicing increased from 6% [4-8] (control) to a maximum of 89% [86-93] (p < 0.001). Thapsigargin induced similar responses. Interleukin-6 (2 h; maximum logFC = 3.1 [0.7-5.6]; p = 0.03) and interleukin-8 (24 h; maximum logFC = 5.4 [2.6-8.2]; p = 0.04) increased with both stressors. ER stress-induced BIP protein expression was decreased by AICAR (logFC = -2.0 [-5.1 to -1.1], p = 0.04) and AdipoRon (maximum logFC = -1.8 [-2.1 to -1.5]; p = 0.001; tunicamycin), and by FLA (logFC = -1.3 [-1.8 to -0.7]; p = 0.002), and gA (logFC = -1.2 [-1.9 to -0.5]; p = 0.004; thapsigargin). Tunicamycin-induced XBP1 splicing decreased with FLA and AdipoRon (maximum change = -11%; p = 0.01), and with all ARAs after thapsigargin treatment (maximum change = -46%; p < 0.001). Total RPS6 expression was decreased by gA, AdipoRon, and AICAR (maximum logFC = -0.9; p < 0.001; tunicamycin). AdipoRon reduced RPS6 phosphorylation (logFC = -1.4 [-3.6 to -0.7]; p = 0.02; tunicamycin). Conclusions: Mixed lamellar cell population, small sample size. Conclusions: ARAs reduced ER stress marker expression in ex vivo equine lamellar cells, suggesting potential for laminitis treatment and prevention.
© 2026 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.
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Publication Date: 2026-05-20 PubMed ID: 42161434DOI: 10.1002/evj.70195Google Scholar: Lookup
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Summary

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Protective effects of adiponectin receptor agonists against equine lamellar endoplasmic reticulum stress

Overview of the Study

  • This study investigated how endoplasmic reticulum (ER) stress occurs in equine lamellar cells, which is relevant to laminitis, a painful hoof disease in horses.
  • Researchers tested if activating adiponectin receptors with specific agonists can reduce ER stress markers, suggesting a potential therapeutic strategy for laminitis.

Background

  • Laminitis: A hoof disease in horses often linked to hyperinsulinemia (high insulin levels) and sepsis.
  • ER stress: A cellular condition where the ER has trouble folding proteins properly, which contributes to disease processes.
  • Adiponectin: A hormone known to be protective against laminitis and can inhibit ER stress in species other than horses.

Study Objectives

  • To induce ER stress in isolated equine lamellar cells using pharmacological agents.
  • To determine whether adiponectin receptor agonists (ARAs) can reduce ER stress in these cells.

Methods

  • Sample: Lamellar cells isolated from 4-5 horses.
  • ER stress induction: Cells were treated with
    • Tunicamycin (10-1000 nM), a compound that disrupts protein folding causing ER stress.
    • Thapsigargin (10-1000 nM), which disturbs calcium balance triggering ER stress.
  • Treatment durations ranged from 2 to 24 hours.
  • Co-treatments: ER-stressed cells were treated for 24 hours with adiponectin receptor agonists:
    • Full-length adiponectin (FLA) at 30-3000 ng/mL
    • Globular adiponectin (gA) at 30-3000 ng/mL
    • AdipoRon (synthetic adiponectin receptor agonist) at 2-50 μM
    • AICAR (AMPK activator) at 1 mM
  • Outcome measures: Expression of ER stress markers and inflammatory cytokines were measured:
    • BIP (Binding immunoglobulin protein), an ER stress marker
    • sXBP1 (Spliced X-box binding protein 1), another ER stress marker reflecting ER stress response activation
    • RPS6 (Ribosomal protein S6), related to protein synthesis regulation
    • Interleukin-6 and Interleukin-8, markers of inflammation
  • Techniques used: quantitative RT-PCR and western blotting

Key Results

  • ER Stress Induction:
    • BIP expression increased with dose and duration of tunicamycin/thapsigargin treatment; highest after 24h with 1000 nM tunicamycin.
    • XBP1 splicing increased significantly, indicating ER stress activation (from 6% in controls to up to 89%).
    • Interleukin-6 and Interleukin-8 mRNA levels increased, confirming an inflammatory response accompanying ER stress.
  • Effects of Adiponectin Receptor Agonists (ARAs) on ER Stress:
    • AICAR and AdipoRon significantly reduced BIP protein expression induced by tunicamycin.
    • Full-length adiponectin and globular adiponectin reduced BIP expression induced by thapsigargin.
    • FLA and AdipoRon decreased tunicamycin-induced sXBP1 splicing; all ARAs reduced sXBP1 splicing after thapsigargin treatment.
    • Globular adiponectin, AdipoRon, and AICAR decreased total RPS6 expression after tunicamycin treatment.
    • AdipoRon also reduced phosphorylation of RPS6, an indicator of reduced protein synthesis activity linked to stress.

Conclusions and Implications

  • Adiponectin receptor agonists effectively reduced markers of ER stress in cultured equine lamellar cells.
  • This suggests a potential therapeutic role for ARAs in treating or preventing laminitis by targeting ER stress pathways.
  • Limitations include using a mixed population of lamellar cells and a small sample size from 4-5 horses, so further research is needed.
  • The findings support targeting cellular stress responses as a strategy to reduce laminitis risk and could pave the way for novel treatments.

Cite This Article

APA
Barnabé MA, Elliott J, Menzies-Gow NJ, Bailey SR, Bamford NJ, Chang YM, Gage MC. (2026). Protective effects of adiponectin receptor agonists against equine lamellar endoplasmic reticulum stress. Equine Vet J. https://doi.org/10.1002/evj.70195

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English

Researcher Affiliations

Barnabé, Marine A
  • Department of Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.
Elliott, Jonathan
  • Department of Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.
Menzies-Gow, Nicola J
  • Department of Clinical Sciences and Services, Royal Veterinary College, Hertfordshire, UK.
Bailey, Simon R
  • Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia.
Bamford, Nicholas J
  • Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia.
Chang, Yu-Mei
  • Department of Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.
Gage, Matthew C
  • Department of Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.

Grant Funding

  • Horserace Betting Levy Board

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