{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:54:46Z","timestamp":1787032486313,"version":"build-2736575974"},"posted":{"date-parts":[[2026,3,21]]},"group-title":"Physiology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["DP2AG093209, R00AR078949, AG046927, AR072999, AR074992, P50 CA094056, R01NS111929, F32NS134563, K01AR079045"],"award-info":[{"award-number":["DP2AG093209, R00AR078949, AG046927, AR072999, AR074992, P50 CA094056, R01NS111929, F32NS134563, K01AR079045"]}]},{"name":"NIH","award":["SCIR_025458, U19NS130608, SCR_025458"],"award-info":[{"award-number":["SCIR_025458, U19NS130608, SCR_025458"]}]},{"name":"NIH","award":["P30 AR073752, P30 CA091842"],"award-info":[{"award-number":["P30 AR073752, P30 CA091842"]}]},{"name":"NIH","award":["P30 AR079206"],"award-info":[{"award-number":["P30 AR079206"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Obesity amplifies osteoarthritis (OA) pain disproportionately to joint damage, creating a major unmet clinical need for non-opioid interventions that act beyond the joint. Using OA as a translational model, we integrated serum multi-omics in obese mice with surgically induced OA and genetic and adipose-reconstitution models of complement factor D (FD). In humans, we analyzed longitudinal metabolomics data from the IDEA weight-loss trial and conducted functional studies in dorsal root ganglion (DRG) neurons. Adipose-derived FD emerged as a regulator of systemic immunometabolic state: FD deficiency in obese mice worsened pain sensitivity whereas restoring circulating FD normalized pain and inflammatory markers without altering joint structure. Cross-species lipid profiling identified conserved shifts in linoleic acid versus arachidonic acid-derived lipids that were associated with pain phenotypes in mice and with pain improvement in humans. Defined lipid cocktails modulated excitability and TRPV1 sensitivity in human DRG neurons, and transcriptomics of knee-innervating DRGs revealed diet and FD-dependent activation of complement and neuronal excitability pathways. Together, these findings define an adipose-complement-lipid axis that regulates nociceptive vulnerability independent of joint damage and identify extra-articular targets for translational, non-opioid OA pain therapies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>We identify an adipose-complement-lipid axis that systemically regulates sensory neuron sensitization, providing a mechanistic basis for pain-structure discordance in obesity-associated osteoarthritis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.19.712962","type":"posted-content","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T04:35:14Z","timestamp":1774154114000},"source":"Crossref","is-referenced-by-count":1,"title":["Adipose-driven complement-lipid reprogramming controls nociceptive vulnerability in obesity-associated osteoarthritis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9330-6903","authenticated-orcid":false,"given":"Hope D.","family":"Welhaven","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4098-9090","authenticated-orcid":false,"given":"Joseph B.","family":"Lesnak","sequence":"additional","affiliation":[{"name":"Center for Advanced Pain Studies, Department of Neuroscience, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin L.","family":"Lenz","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA"},{"name":"Shriners Hospitals for Children, St. Louis, MO, 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