29: Neuregulin-4 From Brown Adipose Tissue Preserves Sensory Innervation in Diabetes

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Neuroimmunology, Assessment and Measurement of Pain/Nociception, Behavioral studies

Background and Aims: Diabetic peripheral neuropathy (DPN) particularly the distal symmetric painful form, is a common debilitating complication of diabetes that causes burning and shooting pain, numbness and disability. Current treatments are largely symptomatic, often ineffective and limited by side effects, underscoring the need for disease-modifying approaches that preserve peripheral nerve integrity. Neuregulin-4 (NRG4) is enriched in brown adipose tissue (BAT) and exerts trophic, anti-inflammatory actions. We hypothesis that BAT-derived NRG4 preserves intra-BAT afferents and dorsal root ganglion (DRG) neurons via ErbB4/PI3K/PIP₃ signaling, and whether loss of this trophic axis in diabetes drives sensory degeneration and pain.

Methods: Streptozotocin (STZ)-induced diabetic rodent models were used throughout. Interscapular BAT was surgically ablated to assess its contribution to neuropathic pain. BAT-derived NRG4 was selectively suppressed by local siRNA delivery, with or without rescue by recombinant NRG4 supplementation to determine its protective role. Behavioral nociceptive responses and metabolic parameters were quantified accordingly. DRG excitability, neuronal phenotype, and inflammation were assessed using electrophysiology, immunohistochemistry, molecular analyses, and c-Fos mapping. Downstream ErbB4–PI3K/PIP₃ signaling and peripheral nerve integrity were evaluated using biochemical assays and morphometric analyses.

Results: BAT removal in STZ-diabetic rodents reproducibly increased mechanical allodynia and thermal hyperalgesia and worsened fasting glycaemia. BAT-ablated animals exhibited elevated c-Fos in corresponding DRG segments and markedly reduced PGP9.5⁺ intra-BAT sensory fiber density. Proteomic and lipidomic profiling of pain-prone BAT revealed dysregulated PI3K-related pathways and diminished PIP₃ levels. Local NRG4 suppression intensified pain and decreased BAT NRG4 protein, whereas recombinant NRG4 supplementation reversed pain behaviors and restored protective signatures. Paradoxically, BAT-specific ErbB4 knockdown produced a protective phenotype with increased NRG4 expression/secretion and reduced p-STAT3, consistent with release of an ErbB4–STAT3 brake on NRG4 output.

Conclusions: Our pilot data support a novel neuro-metabolic model: BAT-derived NRG4 preserves sensory neuron structure and function via an ErbB4 to PI3K/PIP₃ trophic axis, and diabetes-associated BAT dysfunction disrupts this axis to promote axonal degeneration and DNP. These findings motivate circuit mapping, mechanistic dissection of NRG4 action in DRG, causality testing by loss/gain-of-function, and translational studies linking BAT activity and circulating NRG4 to human neuropathic pain — opening potential BAT-targeted or NRG4-based therapeutic strategies.

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Presenting Author: Liao Boya
Submitting Author: Boya Liao

Senior Author: Stanley Wong Sau Ching

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Fei Meng - The University of Hong Kong
• Stanley, Wong Sau Ching - The University of Hong Kong
• Yang Jinghan - The University of Hong Kong