TLQP-21

TLQP-21 was identified as a C3AR1 ligand using a receptor-orphan matching approach. C3AR1 is a complement receptor expressed on macrophages and microglia that, when activated by TLQP-21, triggers release of pro-inflammatory mediators including ATP and nitric oxide. Microglial C3AR1 activation in the spinal cord enhances mechanical hyperalgesia and contributes to the maintenance of chronic pain states following peripheral nerve injury.

TLQP-21 acts on adrenal chromaffin cells to stimulate epinephrine secretion and increase basal metabolic rate. In VGF knockout mice, which lack TLQP-21 among other VGF peptides, hyperphagia and obesity develop, and metabolic rate is reduced. TLQP-21 administration in obese mice increases energy expenditure and reduces body weight, consistent with a metabolic regulatory role.

Spinal TLQP-21 injection sensitizes dorsal horn neurons to mechanical stimuli through microglial C3AR1 activation and ATP release. C3AR1 knockout mice show reduced hyperalgesia after nerve injury, validating the TLQP-21/C3AR1 pathway in chronic pain maintenance. C3AR1 antagonism or TLQP-21 neutralization represents a non-opioid approach to neuropathic pain.

VGF-derived peptides including TLQP-21 regulate energy balance; VGF-null mice are obese with impaired thermogenesis. Peripheral TLQP-21 injection activates adrenal epinephrine secretion and increases brown adipose tissue thermogenesis. These findings position TLQP-21 as a potential anti-obesity target distinct from standard anorexigenic peptides.

VGF and TLQP-21 are significantly reduced in the CSF and brains of Alzheimer's disease patients, with reductions correlating with cognitive decline. VGF levels in CSF have been evaluated as an AD biomarker. The reduction in VGF-derived peptides may contribute to impaired neuroplasticity and synaptic maintenance in AD.