Adipose-driven complement-lipid reprogramming controls nociceptive vulnerability in obesity-associated osteoarthritis

Area of Science:

• Immunometabolism
• Neuroscience
• Osteoarthritis Pathophysiology

Background:

• Obesity exacerbates osteoarthritis (OA) pain beyond joint damage.
• A need exists for non-opioid pain treatments targeting systemic factors.

Purpose of the Study:

• Investigate the role of adipose-derived complement factor D (FD) in obesity-associated OA pain.
• Identify systemic mechanisms linking obesity, inflammation, and pain in OA.
• Explore novel therapeutic targets for OA pain beyond the joint.

Main Methods:

• Multi-omics analysis (serum, lipids) in obese mice with surgically induced OA.
• Genetic and adipose reconstitution models for complement factor D (FD).
• Human metabolomics data analysis (IDEA weight-loss trial) and dorsal root ganglion (DRG) neuron functional studies.

Main Results:

• Adipose-derived FD regulates systemic immunometabolic state; FD deficiency worsens pain, while restoring FD normalizes pain and inflammation without altering joint structure.
• Conserved shifts in linoleic and arachidonic acid-derived lipids correlate with pain phenotypes in mice and pain improvement in humans.
• Lipid cocktails modulate human DRG neuron excitability and TRPV1 sensitivity; DRG transcriptomics reveal diet and FD-dependent complement and neuronal excitability pathway activation.

Conclusions:

• An adipose-complement-lipid axis systemically regulates nociceptive vulnerability, independent of joint damage.
• This axis provides a mechanistic basis for pain-structure discordance in obesity-associated OA.
• Identified extra-articular targets offer potential for translational, non-opioid OA pain therapies.