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The role of obesity and adipose tissue dysfunction in osteoarthritis pain

Nature Reviews Rheumatology volume 20, pages 565–584 (2024)Cite this article

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Abstract

Obesity has a pivotal and multifaceted role in pain associated with osteoarthritis (OA), extending beyond the mechanistic influence of BMI. It exerts its effects both directly and indirectly through various modifiable risk factors associated with OA-related pain. Adipose tissue dysfunction is highly involved in OA-related pain through local and systemic inflammation, immune dysfunction, and the production of pro-inflammatory cytokines and adipokines. Adipose tissue dysfunction is intricately connected with metabolic syndrome, which independently exerts specific effects on OA-related pain, distinct from its association with BMI. The interplay among obesity, adipose tissue dysfunction and metabolic syndrome influences OA-related pain through diverse pain mechanisms, including nociceptive pain, peripheral sensitization and central sensitization. These complex interactions contribute to the heightened pain experience observed in individuals with OA and obesity. In addition, pain management strategies are less efficient in individuals with obesity. Importantly, therapeutic interventions targeting obesity and metabolic syndrome hold promise in managing OA-related pain. A deeper understanding of the intricate relationship between obesity, metabolic syndrome and OA-related pain is crucial and could have important implications for improving pain management and developing innovative therapeutic options in OA.

Key points

  • Obesity serves as an important risk factor for pain in osteoarthritis (OA) and is associated with all modifiable risk factors related to OA-related pain.

  • Adipose tissue dysfunction has a specific role in OA-related pain independently of BMI.

  • Serum and synovial fluid levels of leptin are closely associated with OA-related pain after adjustment for BMI, whereas the role of adiponectin in OA pain is controversial.

  • Metabolic syndrome is associated with OA-related pain independently of BMI.

  • Obesity modulates nociceptive, neuropathic-like and nociplastic pain through neuromodulators and both peripheral and central sensitization.

  • Therapeutics used in the treatment of obesity and metabolic syndrome could also hold promise for the management of OA-related pain, particularly GLP1R agonists.

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Fig. 1: Relationship between obesity and osteoarthritis-related pain risk factors.
Fig. 2: Adipose tissue expansion in obesity and metabolite production.
Fig. 3: Interplay between obesity, adipose tissue dysfunction, metabolic syndrome and osteoarthritis-related pain.
Fig. 4: Adipose tissue dysfunction and osteoarthritis-related pain phenotypes.

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Acknowledgements

The authors thank C. Williams for editorial feedback on the manuscript.

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Authors and Affiliations

  1. Department of Rheumatology, Sorbonne University, AP-HP Saint-Antoine hospital, Paris, France

    Marie Binvignat, Jérémie Sellam & Francis Berenbaum

  2. Sorbonne University, INSERM UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France

    Marie Binvignat, Jérémie Sellam & Francis Berenbaum

  3. Sorbonne University, INSERM UMRS_959, I3 Lab Immunology Immunopathology Immunotherapy, Paris, France

    Marie Binvignat

  4. Boston University School of Medicine, Department of Medicine, Section of Rheumatology, Boston, MA, USA

    David T. Felson

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Contributions

M.B. and J.S. contributed equally to researching data for the article and writing the article. All authors made a substantial contribution to discussion of the content and to review/editing the manuscript before submission.

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Correspondence to Jérémie Sellam.

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Competing interests

M.B. declares that she has received grant support from the French Society of Rheumatology, the Osteoarthritis Foundation and Pfizer ADVANCE 2020 program, and a doctoral fellowship from Sorbonne University. J.S. declares that he has received personal fees from MSD, Pfizer, Abbvie, Fresenius Kabi, BMS, Roche, Chugai, Sandoz, Lilly, Novartis, Galapagos, AstraZeneca, UCB and Janssen, and research grants from Pfizer, MSD, Schwa Medico and BMS. F.B. declares that he has received institutional grants from TRB Chemedica and Pfizer; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bone Therapeutics, Cellprothera, Galapagos, Gilead, Grunenthal, GSK, Eli Lilly, MerckSerono, MSD, Nordic Bioscience, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov and 4P Pharma; has received honoraria for lectures from Expanscience, Pfizer, Viatris; has received payment for expert testimony from Pfizer and Eli Lilly; has received travel support from Nordic Pharma, Pfizer, Eli Lilly and Novartis; and owns stock in and is CEO of 4Moving Biotech, a company developing intraarticular liraglutide for knee osteoarthritis. D.T.F. declares no competing interests.

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Nature Reviews Rheumatology thanks Changhai Ding and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Adipokines

Also known as adipocytokines. Cell-signalling proteins produced by adipose tissue and adipocytes with diverse effects on metabolism, energy storage and inflammation.

Central sensitization

Increased excitability of neurons within the central nervous system, causing normal sensory inputs to generate abnormal responses; can be triggered by persistent activity in nociceptors and results in an amplified perception of pain, often leading to a hypersensitive and exaggerated response to stimuli.

Lipokines

Fatty acids or lipid-controlling hormones that can modulate lipid metabolism.

Metainflammation

Also known as metaflammation. Low-grade inflammation associated with obesity, insulin resistance and metabolic diseases.

Mismatch disease

A health condition that develops when inherited traits are inadequately or imperfectly adapted to rapid changes in modern environmental conditions.

Neuropathic-like pain

Pain associated with nerve damage, injury or dysfunction of the peripheral or central nervous system.

Nociceptive pain

Pain resulting from tissue damage or inflammation that involves an excess of nociception, which refers to the perception of noxious stimuli.

Nociplastic pain

Pain related to a disturbance in the pain pathways, without clear evidence of tissue or nerve damage; involves peripheral sensitization, central sensitization and an impairment in the descending inhibitory controls.

Peripheral sensitization

Lowering of the pain threshold and an increased responsiveness of sensory nerve fibres at their peripheral endings and within dorsal root ganglia, leading to heightened sensitivity to pain.

Sarcopenic obesity

The combination of obesity and low muscle mass; its definition varies across studies, but commonly involves the association of the lowest two quintiles of skeletal muscular mass with the highest two quintiles of fat mass.

Subcutaneous adipose tissue

Adipose tissue localized beneath the skin; contributes to insulation, energy storage and endocrine functions.

Visceral adipose tissue

Adipose tissue localized within the abdominal cavity around internal organs; linked to metabolic syndrome and systemic inflammation.

White adipose tissue

The predominant subtype of adipose tissue, constituting approximately 80% of adipose tissue in adults; important for energy regulation and lipid storage through the production of triacylglycerol.

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Binvignat, M., Sellam, J., Berenbaum, F. et al. The role of obesity and adipose tissue dysfunction in osteoarthritis pain. Nat Rev Rheumatol 20, 565–584 (2024). https://doi.org/10.1038/s41584-024-01143-3

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