1. Moreno, B. et al. Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine 47, 793–805 (2014).

2. Moreno, B., Crujeiras, A. B., Bellido, D., Sajoux, I. & Casanueva, F. F. Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine 54, 681–690 (2016).

3. Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

4. Goldberg, E. L. et al. Beta-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 18, 2077–2087 (2017).

5. Lu, Y. et al. Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-kappaB signaling pathways. Neurosci. Lett. 683, 13–18 (2018).

6. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

7. Ageing and Health Fact Sheet 404 (World Health Organization, 2015).

8. Kanneganti, T. D. & Dixit, V. D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).

9. Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

10. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

11. Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836–1845 (2010).

12. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614 (1997).

13. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

14. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

15. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).

16. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

17. Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).

18. Cahill, G. F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).

19. Simeone, T. A., Simeone, K. A. & Rho, J. M. Ketone bodies as anti-seizure agents. Neurochem. Res. 42, 2011–2018 (2017).

20. Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557 e548 (2017).

21. Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546 e535 (2017).

22. Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).

23. Youm, Y. H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013).

24. Puchalska, P. et al. Hepatocyte-macrophage acetoacetate shuttle protects against tissue fibrosis. Cell Metab. 29, 383–398 (2018).

25. Kennedy, A. R. et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol. Metab. 292, E1724–E1739 (2007).

26. Srivastava, S., Baxa, U., Niu, G., Chen, X. & Veech, R. L. A ketogenic diet increases brown adipose tissue mitochondrial proteins and UCP1 levels in mice. IUBMB Life 65, 58–66 (2013).

27. Kohlgruber, A. C. et al. Gammadelta T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. Nat. Immunol. 19, 464–474 (2018).

28. Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007).

29. Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).

30. Paget, C. et al. CD3bright signals on gammadelta T cells identify IL-17A-producing Vgamma6Vdelta1+ T cells. Immunol. Cell Biol. 93, 198–212 (2015).

31. Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Ann. Rev. Pathol. 5, 99–118 (2010).

32. Wiley, C. D. et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043–1050 (2017).

33. Costanzo, A. E. et al. Obesity impairs gammadelta T cell homeostasis and antiviral function in humans. PLoS ONE 10, e0120918 (2015).

34. Taylor, K. R., Mills, R. E., Costanzo, A. E. & Jameson, J. M. Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS ONE 5, e11422 (2010).

35. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

36. Edwards, C. et al. d-beta-hydroxybutyrate extends lifespan in C. elegans. Aging 6, 621–644 (2014).

37. Xie, Z. et al. Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

38. Garbow, J. R. et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G956–G967 (2011).

39. Ellenbroek, J. H. et al. Long-term ketogenic diet causes glucose intolerance and reduced beta- and alpha-cell mass but no weight loss in mice. Am. J. Physiol. Endocrinol. Metab. 306, E552–E558 (2014).

40. Rosenbaum, M. et al. Glucose and lipid homeostasis and inflammation in humans following an isocaloric ketogenic diet. Obesity 27, 971–981 (2019).

41. Sastre, J. et al. Aging of the liver: age-associated mitochondrial damage in intact hepatocytes. Hepatology 24, 1199–1205 (1996).

42. Wang, W. et al. A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab. 30, 174–189 e175 (2019).

43. Cheng, C. W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131 e1115 (2019).

44. Wencker, M. et al. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat. Immunol. 15, 80–87 (2014).

45. Guo, X. J. et al. Lung gammadelta T cells mediate protective responses during neonatal influenza infection that are associated with type 2 immunity. Immunity 49, 531–544 e536 (2018).

46. Nielsen, M. M., Witherden, D. A. & Havran, W. L. Gammadelta T cells in homeostasis and host defence of epithelial barrier tissues. Nat. Rev. Immunol. 17, 733–745 (2017).

47. Mehta, P., Nuotio-Antar, A. M. & Smith, C. W. Gammadelta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J. Leukoc. Biol. 97, 121–134 (2015).

48. Zuniga, L. A. et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J. Immunol. 185, 6947–6959 (2010).

49. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

50. Zhang, B. et al. Differential requirements of TCR signaling in homeostatic maintenance and function of dendritic epidermal T cells. J. Immunol. 195, 4282–4291 (2015).

51. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

52. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Meth. 9, 676–682 (2012).

53. Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Meth. 9, 671–675 (2012).

54. Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).

55. Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).

56. Wickham, H. ggplot2: Elegant Graphics for Data Analysis (Springer, 2016).

57. Mudge, J. M. & Harrow, J. Creating reference gene annotation for the mouse C57BL6/J genome assembly. Mamm. Genome 26, 366–378 (2015).

58. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

59. Karolchik, D. et al. The UCSC table browser data retrieval tool. Nucleic Acids Res. 32, D493–D496 (2004). (Database issue).

60. Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

61. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

62. Sergushichev, A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. Preprint at bioRxiv https://doi.org/10.1101/060012 (2016).

63. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).