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Rheumatic diseases and metabolism: where centre and periphery meet

Nature Reviews Rheumatology volume 20, pages 783–794 (2024)Cite this article

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Abstract

Over the past few decades, the connection between metabolism and various inflammatory and rheumatic diseases has been an area of active investigation. Nonetheless, the precise mechanisms underlying these relationships remain a topic of ongoing debate, owing in part to conflicting data. This discrepancy can be attributed to the predominant focus on peripheral mechanisms in research into the metabolic consequences of rheumatic diseases. However, a wealth of evidence supports the notion that the central nervous system, specifically the hypothalamus, has an important influence on metabolic homeostasis. Notably, links have been established between crucial hypothalamic mechanisms responsible for regulating energy balance (including food intake, thermogenesis, and glucose and lipid metabolism), such as AMP-activated protein kinase, and the pathophysiology of rheumatoid arthritis. This Review aims to comprehensively examine the current understanding of central metabolic control in rheumatic diseases and explore potential therapeutic options that target this pathophysiological mechanism.

Key points

  • A clear correlation exists between metabolism and rheumatic diseases; however, the molecular details of the association remain unclear.

  • Several areas of the central nervous system, such as the hypothalamus, have a major role in the regulation of energy metabolism.

  • Hypothalamic neuropeptides have been shown to be involved in the pathophysiology of rheumatic diseases.

  • Current evidence demonstrates that hypothalamic AMP-activated protein kinase has a role in the pathophysiology of rheumatic disease, by acting at both the metabolic and the inflammatory levels.

  • Overall, this evidence provides new mechanistic insights into the pathophysiology of rheumatic diseases, which might offer new alternatives to their clinical management and the treatment of associated comorbidities.

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Fig. 1: Rheumatic diseases affect whole-body metabolism.
Fig. 2: Hypothalamic and autonomic regulation of energy metabolism in rheumatic diseases.
Fig. 3: Targeting AMPK as a strategy to globally treat rheumatic diseases.

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Acknowledgements

The authors’ work is supported by funding from Ministerio de Ciencia e Innovación of Spain co-funded by the European Regional Development Fund (FEDER) of the European Union (ML: PID2021-128145NB-I00 and PDC2022-133958-I00); Instituto de Salud Carlos III, European Union, European Commission and FEDER (OG: PI20/00902, PI23/00289 and RICORS Programme RD21/0002/0025); Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN; OG: GPC IN607B2022/03); Sociedad Española de Columna Vertebral (GEER; OG: Becas Investigación GEER 2020 and 2023); and Fundación Asociación Española Contra el Cancer (AECC; ML: PRYGN234908LOPE). O.G. is member of Action CA21110 (Building an Open European Network on Osteoarthritis Research), funded by the European Union under the European Cooperation in Science and Technology Programme (COST).

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Authors and Affiliations

  1. NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain

    Miguel López

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, Spain

    Miguel López

  3. Servizo Galego de Saude (SERGAS)-Instituto de Investigación Sanitaria de Santiago (IDIS), the Neuroendocrine Interactions in Rheumatology and Inflammatory Disease (NEIRID) Lab, Santiago University Clinical Hospital, Santiago de Compostela, Spain

    Oreste Gualillo

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The authors contributed equally to all aspects of the article.

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Correspondence to Miguel López or Oreste Gualillo.

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M.L. declares that he holds an International Patent Application entitled “Populations of small extracellular vesicles for use in the treatment of obesity”, PCT/EP2022/071463. O.G. declares no competing interests.

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López, M., Gualillo, O. Rheumatic diseases and metabolism: where centre and periphery meet. Nat Rev Rheumatol 20, 783–794 (2024). https://doi.org/10.1038/s41584-024-01178-6

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