James, W. P. T. & McPherson, K. The costs of overweight. Lancet Public Health 2, e203–e204 (2017).
Malik, V. S., Willett, W. C. & Hu, F. B. Global obesity: trends, risk factors and policy implications. Nat. Rev. Endocrinol. 9, 13–27 (2013).
NCD Risk Factor Collaboration. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387, 1377–1396 (2016).
Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).
Hales, C. M., Fryar, C. D., Carroll, M. D., Freedman, D. S. & Ogden, C. L. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007–2008 to 2015–2016. JAMA 319, 1723–1725 (2018).
Cawley, J. & Meyerhoefer, C. The medical care costs of obesity: an instrumental variables approach. J. Health Econ. 31, 219–230 (2012).
Lauby-Secretan, B. et al. Body fatness and cancer — viewpoint of the IARC Working Group. N. Engl. J. Med. 375, 794–798 (2016).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Ligibel, J. A. et al. American Society of Clinical Oncology position statement on obesity and cancer. J. Clin. Oncol. 32, 3568–3574 (2014).
Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591 (2004).
Tao, W. & Lagergren, J. Clinical management of obese patients with cancer. Nat. Rev. Clin. Oncol. 10, 519–533 (2013).
Rosenquist, K. J. et al. Fat quality and incident cardiovascular disease, all-cause mortality, and cancer mortality. J. Clin. Endocrinol. Metab. 100, 227–234 (2015).
Iyengar, N. M. et al. Systemic correlates of white adipose tissue inflammation in early-stage breast cancer. Clin. Cancer Res. 22, 2283–2289 (2016).
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
Wajchenberg, B. L. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21, 697–738 (2000).
Neeland, I. J. et al. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity 21, E439–E447 (2013).
McLaughlin, T., Lamendola, C., Liu, A. & Abbasi, F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J. Clin. Endocrinol. Metab. 96, E1756–E1760 (2011).
Fox, C. S. et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116, 39–48 (2007).
Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer — mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).
Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).
Font-Burgada, J., Sun, B. & Karin, M. Obesity and cancer: the oil that feeds the flame. Cell Metab. 23, 48–62 (2016).
Lengyel, E., Makowski, L., DiGiovanni, J. & Kolonin, M. G. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4, 374–384 (2018).
Olson, O. C., Quail, D. F. & Joyce, J. A. Obesity and the tumor microenvironment. Science 358, 1130–1131 (2017).
Borrud, L. G. et al. Body composition data for individuals 8 years of age and older: U.S. population, 1999–2004. Vital Health Stat. 250, 1–87 (2010).
Flegal, K. M. et al. Comparisons of percentage body fat, body mass index, waist circumference, and waist-stature ratio in adults. Am. J. Clin. Nutr. 89, 500–508 (2009).
Brestoff, J. R. & Artis, D. Immune regulation of metabolic homeostasis in health and disease. Cell 161, 146–160 (2015).
Howe, L. R., Subbaramaiah, K., Hudis, C. A. & Dannenberg, A. J. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin. Cancer Res. 19, 6074–6083 (2013).
Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).
Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).
Reilly, S. M. & Saltiel, A. R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643 (2017).
Kanneganti, T. D. & Dixit, V. D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).
Giordano, A. et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J. Lipid Res. 54, 2423–2436 (2013).
Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).
Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).
Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).
Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
Youm, Y. H. et al. The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep. 1, 56–68 (2012).
Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
Nagareddy, P. R. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821–835 (2014).
Amano, S. U. et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19, 162–171 (2014).
Braune, J. et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198, 2927–2934 (2017).
Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).
Haka, A. S. et al. Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation. J. Lipid Res. 57, 980–992 (2016).
Kolb, R. et al. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat. Commun. 7, 13007 (2016).
Arkan, M. C. et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191–198 (2005).
Solinas, G. et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. 6, 386–397 (2007).
Iyengar, N. M. et al. Metabolic obesity, adipose inflammation and elevated breast aromatase in women with normal body mass index. Cancer Prev. Res. 10, 235–243 (2017).
Koru-Sengul, T. et al. Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians. Breast Cancer Res. Treat. 158, 113–126 (2016).
Carter, J. M. et al. Macrophagic “crown-like structures” are associated with an increased risk of breast cancer in benign breast disease. Cancer Prev. Res. 11, 113–119 (2018).
Diaz-Cruz, E. S., Sugimoto, Y., Gallicano, G. I., Brueggemeier, R. W. & Furth, P. A. Comparison of increased aromatase versus ERalpha in the generation of mammary hyperplasia and cancer. Cancer Res. 71, 5477–5487 (2011).
Gucalp, A. et al. Periprostatic adipose inflammation is associated with high-grade prostate cancer. Prostate Cancer Prostatic Dis. 20, 418–423 (2017).
Iyengar, N. M. et al. White adipose tissue inflammation and cancer-specific survival in patients with squamous cell carcinoma of the oral tongue. Cancer 122, 3794–3802 (2016).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).
Nguyen, M. T. et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via toll-like receptors 2 and 4 and JNK-dependent pathways. J. Biol. Chem. 282, 35279–35292 (2007).
Shaul, M. E., Bennett, G., Strissel, K. J., Greenberg, A. S. & Obin, M. S. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet–induced obesity in mice. Diabetes 59, 1171–1181 (2010).
Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).
Hill, D. A. et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc. Natl Acad. Sci. USA 115, E5096–E5105 (2018).
Tkach, M. & Thery, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).
Xu, X. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 18, 816–830 (2013).
Kratz, M. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 20, 614–625 (2014).
Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).
Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).
Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).
Liu, J. et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15, 940–945 (2009).
Olson, O. C. & Joyce, J. A. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat. Rev. Cancer 15, 712–729 (2015).
Xia, S. et al. Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J. Biol. Chem. 286, 23591–23599 (2011).
Clements, V. K. et al. Frontline science: high fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells. J. Leukoc. Biol. 103, 395–407 (2018).
Macdougall, C. E. et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab. 27, 588–601 (2018).
Yang, H. et al. Obesity accelerates thymic aging. Blood 114, 3803–3812 (2009).
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).
Canter, R. J. et al. Obesity results in higher PD-1-mediated T cell suppression but greater T cell effector functions following blockade. J. Clin. Oncol. 36, S65 (2018).
McQuade, J. L. et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 19, 310–322 (2018).
Winer, D. A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
Cipolletta, D. et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).
Kolodin, D. et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 21, 543–557 (2015).
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).
O’Sullivan, T. E. et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45, 428–441 (2016).
Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
Sung, H. K. et al. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab. 17, 61–72 (2013).
Lee, Y. S. et al. Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity. Cell 157, 1339–1352 (2014).
Arendt, L. M. et al. Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res. 73, 6080–6093 (2013).
Shah, D. et al. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury. Sci. Rep. 5, 11362 (2015).
Wang, L. et al. Enhancement of endothelial permeability by free fatty acid through lysosomal cathepsin B-mediated Nlrp3 inflammasome activation. Oncotarget 7, 73229–73241 (2016).
Incio, J. et al. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci. Transl Med. 10, eaag0945 (2018).
Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417–427 (2011).
Tammela, T. & Alitalo, K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 140, 460–476 (2010).
Greene, A. K., Grant, F. D. & Slavin, S. A. Lower-extremity lymphedema and elevated body-mass index. N. Engl. J. Med. 366, 2136–2137 (2012).
McLaughlin, S. A. et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J. Clin. Oncol. 26, 5213–5219 (2008).
Wong, B. W. et al. The role of fatty acid beta-oxidation in lymphangiogenesis. Nature 542, 49–54 (2017).
Stacker, S. A. et al. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 14, 159–172 (2014).
Harvey, N. L. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat. Genet. 37, 1072–1081 (2005).
Escobedo, N. et al. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice. JCI Insight 1, e85096 (2016).
Lund, A. W. Rethinking lymphatic vessels and antitumor immunity. Trends Cancer 2, 548–551 (2016).
Hespe, G. E. et al. Exercise training improves obesity-related lymphatic dysfunction. J. Physiol. 594, 4267–4282 (2016).
Nitti, M. D. et al. Obesity-induced lymphatic dysfunction is reversible with weight loss. J. Physiol. 594, 7073–7087 (2016).
Escobedo, N. & Oliver, G. The lymphatic vasculature: its role in adipose metabolism and obesity. Cell Metab. 26, 598–609 (2017).
Cao, Y. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab. 18, 478–489 (2013).
Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).
Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).
Tanaka, M. et al. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat. Commun. 5, 4982 (2014).
Seo, B. R. et al. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci. Transl Med. 7, 301ra130 (2015).
Iyengar, P. et al. Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J. Clin. Invest. 115, 1163–1176 (2005).
Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).
Halberg, N. et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009).
Incio, J. et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 6, 852–869 (2016).
Zhang, Z. & Scherer, P. E. Adipose tissue: the dysfunctional adipocyte - a cancer cell’s best friend. Nat. Rev. Endocrinol. 14, 132–134 (2018).
Zhang, M. et al. Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov. 8, 1006–1025 (2018).
Laurent, V. et al. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat. Commun. 7, 10230 (2016).
Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).
Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946 (2001).
Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).
Zhang, T. et al. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat. Commun. 7, 11674 (2016).
Zhang, Y. et al. White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res. 69, 5259–5266 (2009).
Zhang, Y. et al. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res. 72, 5198–5208 (2012).
Klopp, A. H. et al. Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin. Cancer Res. 18, 771–782 (2012).
Song, Y. H. et al. Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol. 60–61, 190–205 (2017).
Strong, A. L. et al. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res. 17, 112 (2015).
Daquinag, A. C. et al. Targeted proapoptotic peptides depleting adipose stromal cells inhibit tumor growth. Mol. Ther. 24, 34–40 (2016).
Stern, J. H., Rutkowski, J. M. & Scherer, P. E. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 23, 770–784 (2016).
Quail, D. F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974–987 (2017).
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
Li, R. et al. Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression. Cell Metab. 19, 702–711 (2014).
Ericksen, R. E. et al. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. Gut 63, 385–394 (2014).
Nelson, E. R. et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342, 1094–1098 (2013).
Wu, Q. et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 5, 637–645 (2013).
Baek, A. E. et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat. Commun. 8, 864 (2017).
Voisin, M. et al. Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor. Proc. Natl Acad. Sci. USA 114, E9346–E9355 (2017).
Behan, J. W. et al. Adipocytes impair leukemia treatment in mice. Cancer Res. 69, 7867–7874 (2009).
Sheng, X. et al. Adipocytes sequester and metabolize the chemotherapeutic daunorubicin. Mol. Cancer Res. 15, 1704–1713 (2017).
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
Olson, O. C., Kim, H., Quail, D. F., Foley, E. A. & Joyce, J. A. Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep. 19, 101–113 (2017).
Zarrinpar, A., Chaix, A., Yooseph, S. & Panda, S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 20, 1006–1017 (2014).
Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).
Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).
Costa, M. J. et al. Circadian rhythm gene period 3 is an inhibitor of the adipocyte cell fate. J. Biol. Chem. 286, 9063–9070 (2011).
Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).
Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).
Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).
Miyazawa, M. et al. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice. Cancer Prev. Res. 11, 215–226 (2017).
Klil-Drori, A. J., Azoulay, L. & Pollak, M. N. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat. Rev. Clin. Oncol. 14, 85–99 (2017).
Ghorpade, D. S. et al. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555, 673–677 (2018).
Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).
Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).
Cypess, A. M. et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).
Bhardwaj, P. et al. Estrogen protects against obesity-induced mammary gland inflammation in mice. Cancer Prev. Res. 8, 751–759 (2015).
Cancello, R. et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54, 2277–2286 (2005).
Adams, T. D. et al. Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357, 753–761 (2007).
Sjostrom, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).
Schauer, D. P. et al. Bariatric surgery and the risk of cancer in a large multisite cohort. Ann. Surg. https://doi.org/10.1097/SLA.0000000000002525 (2017).
Ligibel, J. A. et al. Randomized phase III trial evaluating the role of weight loss in adjuvant treatment of overweight and obese women with early breast cancer (Alliance A011401): study design. NPJ Breast Cancer 3, 37 (2017).
Clement, K. et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 18, 1657–1669 (2004).
Aleman, J. O. et al. Effects of rapid weight loss on systemic and adipose tissue inflammation and metabolism in obese postmenopausal women. J. Endocr. Soc. 1, 625–637 (2017).
Wernstedt Asterholm, I. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103–118 (2014).
Bhardwaj, P. et al. Caloric restriction reverses obesity-induced mammary gland inflammation in mice. Cancer Prev. Res. 6, 282–289 (2013).
Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).
Esposito, K. et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292, 1440–1446 (2004).
Esposito, K. et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289, 1799–1804 (2003).
Toledo, E. et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern. Med. 175, 1752–1760 (2015).
Samaha, F. F. et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N. Engl. J. Med. 348, 2074–2081 (2003).
Foster, G. D. et al. A randomized trial of a low-carbohydrate diet for obesity. N. Engl. J. Med. 348, 2082–2090 (2003).
Shai, I. et al. Weight loss with a low-carbohydrate, mediterranean, or low-fat diet. N. Engl. J. Med. 359, 229–241 (2008).
Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M. & Jones, L. W. Exercise-dependent regulation of the tumour microenvironment. Nat. Rev. Cancer 17, 620–632 (2017).
Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816–825 (2016).
Dieli-Conwright, C. M. et al. Effects of aerobic and resistance exercise on metabolic syndrome, sarcopenic obesity, and circulating biomarkers in overweight or obese survivors of breast cancer: a randomized controlled trial. J. Clin. Oncol. 36, 875–883 (2018).
Playdon, M. C. et al. Weight gain after breast cancer diagnosis and all-cause mortality: systematic review and meta-analysis. J. Natl Cancer Inst. 107, djv275 (2015).
Demark-Wahnefried, W. et al. Weight management and physical activity throughout the cancer care continuum. CA Cancer J. Clin. 68, 64–89 (2018).
Iyengar, N. M. et al. Body fat and risk of breast cancer in postmenopausal women with normal body mass index. JAMA Oncol. (in the press).
Mirsoian, A. et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 211, 2373–2383 (2014).
Gupta, S. Obesity: the fat advantage. Nature 537, S100–S102 (2016).
Denis, G. V. & Obin, M. S. ‘Metabolically healthy obesity’: origins and implications. Mol. Aspects Med. 34, 59–70 (2013).
Stefan, N., Schick, F. & Haring, H. U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 26, 292–300 (2017).
Rubin, R. Postmenopausal women with a “normal” BMI might be overweight or even obese. JAMA 319, 1185–1187 (2018).
WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363, 157–163 (2004).
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
Lee, J. M. et al. Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. J. Exp. Med. 215, 627–644 (2018).
Masamoto, Y. et al. Adiponectin enhances antibacterial activity of hematopoietic cells by suppressing bone marrow inflammation. Immunity 44, 1422–1433 (2016).
Liu, A. et al. Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4. Nat. Commun. 9, 708 (2018).
Trottier, M. D., Naaz, A., Li, Y. & Fraker, P. J. Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice. Proc. Natl Acad. Sci. USA 109, 7622–7629 (2012).
Lu, Z. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat. Med. 23, 79–90 (2017).
Yun, J. P. et al. Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models. Cancer Prev. Res. 3, 1259–1264 (2010).
Shafat, M. S. et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood 129, 1320–1332 (2017).
Poynter, J. N. et al. Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes. Cancer Epidemiol. 40, 134–140 (2016).
Butturini, A. M. et al. Obesity and outcome in pediatric acute lymphoblastic leukemia. J. Clin. Oncol. 25, 2063–2069 (2007).
Rossi, E. L. et al. Obesity-associated alterations in inflammation, epigenetics, and mammary tumor growth persist in formerly obese mice. Cancer Prev. Res. 9, 339–348 (2016).
Greenstein, A. S. et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661–1670 (2009).
Rosen, C. J. & Bouxsein, M. L. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2, 35–43 (2006).
Estruch, R. et al. Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 378, e34 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01697566 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01101438 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02065687 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02040376 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01655719 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00780234 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01838317 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00099021 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00427999 (2016).
Irwin, M. L. et al. Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol. Biomarkers Prev. 18, 306–313 (2009).
Fairey, A. S. et al. Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol. Biomarkers Prev. 12, 721–727 (2003).
Spencer, M. et al. Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity. PLOS ONE 9, e102190 (2014).