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Dysfunctional adipose tissue–lymphatic crosstalk in obesity

Nature Reviews Endocrinology (2026)Cite this article

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Abstract

The lymphatic vasculature is recognized for its roles in immunity, lipid transport and fluid homeostasis, but has been ignored, until recently, for its involvement in adipose tissue metabolism, obesity and associated comorbidities. States of overnutrition, such as in obesity, are associated with impairment of lymphatic function, leading to localized lymphoedema, adipogenesis and insulin resistance. Conversely, compromised lymphatic vasculature integrity can induce adiposity and accelerate insulin resistance. Through the use of advanced ‘omics’ and bioinformatic technologies coupled with functional experiments in cells, mice and humans, we now know that the lymphatic system is more than just a transport conduit and is intimately involved in tissue and organ homeostasis, including in adipose tissue. In this Review, we summarize the interconnected causes of obesity and lymphatic dysfunction with a particular focus on delineating the underappreciated yet fundamental crosstalk between the lymphatic network and white and brown adipose tissues. We also synthesize information on lymph-directed therapeutic strategies that have the potential to transform outcomes in obesity.

Key points

  • The extent of lymphatic vascularization is different between brown and white adipose tissue and depots.

  • Obesity-remodelled adipose tissue secretes factors that induce lymphatic dysfunction.

  • Lymphatic dysfunction initiates and accelerates adiposity, inflammation and systemic insulin resistance.

  • Restoring lymphatic function supports the resolution of obesity and its associated comorbidities.

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Fig. 1: Obesity-induced changes in subcutaneous and visceral adipose tissue.
Fig. 2: Effects of adipose tissue-secreted factors on lymphatics and effects of lymphatic dysfunction on adipose tissue in obesity.
Fig. 3: Therapeutic options in targeting lymphatics to resolve obesity and related morbidities.

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Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia

    William De Nardo, Andrea Y. Chan, Christopher J. H. Porter, Enyuan Cao & Natalie L. Trevaskis

  2. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia

    Natalie L. Trevaskis

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W.D.N., A.Y.C. and E.C. researched data for the article. W.D.N. and N.L.T. wrote the article. All authors contributed to the discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Natalie L. Trevaskis.

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Competing interests

C.J.H.P., N.L.T. and E.C. are inventors of the lymph-directing glyceride prodrug technology (PCT/AU2020/050997) including celecoxib prodrugs for the treatment of metabolic disease (PCT/US 17/753,936), that has been patented and licensed via a commercial agreement with Seaport Therapeutics. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Jorge A. Castorena-Gonzalez, Joseph Rutkowski and Evan Rosen for their contribution to the peer review of this work.

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De Nardo, W., Chan, A.Y., Porter, C.J.H. et al. Dysfunctional adipose tissue–lymphatic crosstalk in obesity. Nat Rev Endocrinol (2026). https://doi.org/10.1038/s41574-026-01243-y

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