OBESITY-INDUCED ENDOTHELIAL FENESTRATION AND CAPILLARY LEAKAGE CONTRIBUTE TO INCREASED PAIN SENSATION

Area of Science:

• Neuroscience
• Endocrinology
• Vascular Biology

Background:

• Peripheral pain is regulated by sensory nerve and tissue cell interactions.
• Obesity-associated small fiber neuropathy involves hypersensitive skin sensory nerves.
• Obesity-induced vascular abnormalities' impact on sensory dysfunction is unclear.

Purpose of the Study:

• To investigate the link between obesity, vascular changes, and sensory nerve hypersensitivity.
• To elucidate the molecular mechanisms driving obesity-related pain.
• To identify potential therapeutic targets for obesity-associated neuropathy.

Main Methods:

• Utilized a diet-induced obesity mouse model.
• Examined skin capillary structure and permeability.
• Investigated insulin signaling pathways in epidermal keratinocytes.
• Assessed nerve growth factor (NGF) production and sensory nerve TRPV1 expression.
• Evaluated the effect of modulating capillary permeability on pain hypersensitivity.

Main Results:

• Obesity led to fenestrated skin capillaries, enabling insulin diffusion into the epidermis.
• Insulin signaling, involving FOXO1, increased NGF production by keratinocytes.
• Elevated NGF enhanced TRPV1 in sensory nerves, causing hypersensitivity.
• Reducing capillary permeability decreased NGF and pain hypersensitivity.

Conclusions:

• Peripheral nerve-associated capillary permeability is a novel therapeutic target in obesity-associated sensory dysfunction.
• Insulin-induced NGF production via epidermal signaling contributes to pain in obesity.
• Modulating vascular permeability offers a potential strategy for managing neuropathic pain in obesity.