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From fat to filter: the effect of adipose tissue-derived signals on kidney function

Nature Reviews Nephrology volume 21, pages 417–434 (2025)Cite this article

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Abstract

Obesity is associated with severe consequences for the renal system, including chronic kidney disease, kidney failure and increased mortality. Obesity has both direct and indirect effects on kidney health through several mechanisms, including activation of the renin–angiotensin system, mechanical compression, inflammation, fibrosis, increased filtration barrier permeability and renal nerve activity. The expansion of adipose tissue through hypertrophy and hyperplasia can induce haemodynamic changes that promote glomerular hyperfiltration to compensate for the greater metabolic demands of the increased body weight. Adipose expansion is also associated with the release of adipokines and pro-inflammatory cytokines, hyperinsulinaemia and insulin resistance, which exert direct and indirect effects on kidney function via various mechanisms. Increased uptake of fatty acids by the kidney leads to alterations in lipid metabolism and lipotoxicity, also contributing to the pro-inflammatory and pro-fibrotic environment. The role of the adipose tissue–brain–kidney axis in the obesity-associated decline in renal function is sustained by studies showing that stimulation of adipose tissue sensory neurons by locally released factors increases renal sympathetic nerve activity. Conversely, pre-existent kidney disease can contribute to adipose dysfunction through the accumulation of uraemic toxins and hormonal changes. These findings highlight the importance of crosstalk between adipose tissue and the kidneys and provide insights into the mechanisms underlying the associations between obesity and kidney disease.

Key points

  • The mechanisms by which adipose tissue exerts pathogenic effects on the kidney structure and function are multifactorial and include mechanical compression, haemodynamic effects, alterations in fatty acid metabolism, lipotoxicity, oxidative stress, inflammation and altered adipokine release.

  • In the context of obesity and metabolic disease, sensory neurons that innervate adipose tissue are stimulated by numerous locally released factors, sending signals to brain areas that increase the sympathetic outflow to the kidneys.

  • Elevated levels of uraemic toxins in patients with chronic kidney disease (CKD) promote adipose tissue loss and the ectopic accumulation of lipids, which in turn may contribute to worsening kidney function.

  • The exploration of therapeutic targets to down-modulate activity of the adipose afferent reflex could be a potential approach to reducing obesity-associated CKD.

  • Improved understanding of the pathological interactions between adipose tissue and the kidneys in the context of obesity and CKD will aid the identification of new renoprotective targets; drug-based, surgical and lifestyle interventions are under investigation.

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Fig. 1: Progression of kidney disease in the context of obesity.
Fig. 2: Adipose tissue-derived factors that compromise the health and function of the kidney.
Fig. 3: Anatomical and functional effects of obesity on the glomerulus.
Fig. 4: Consequences of obesity for the proximal tubule and collecting ducts.
Fig. 5: Overactivation of the adipose–brain–blood pressure axis during obesity.

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Acknowledgements

The authors’ work was supported by National Institutes of Health grants (R01-HL-142969 and R01-HL-1647 to A.S.L.).

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  1. These authors contributed equally: Nermin Ahmed, Carolina Dalmasso.

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  1. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA

    Nermin Ahmed, Carolina Dalmasso, Meghan B. Turner, Gertrude Arthur, Cole Cincinelli & Analia S. Loria

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Ahmed, N., Dalmasso, C., Turner, M.B. et al. From fat to filter: the effect of adipose tissue-derived signals on kidney function. Nat Rev Nephrol 21, 417–434 (2025). https://doi.org/10.1038/s41581-025-00950-5

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