Adiposity and cancer risk: New mechanistic insights from epidemiology

Nature Reviews Cancer

Volumn 15, Issue 8, 2015, Pages 484-498

  Renehan, Andrew G ^a   Zwahlen, Marcel ^b   Egger, Matthias ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

^b UNIVERSITY OF BERN   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTOKINE; SEX HORMONE; TUMOR MARKER;

BODY FAT DISTRIBUTION; BODY MASS; CANCER RISK; CARCINOGENESIS; DISEASE ASSOCIATION; EPIDEMIOLOGICAL DATA; EPIDEMIOLOGY; GENETIC ASSOCIATION; HUMAN; HYPOTHESIS; INFLAMMATION; INSULIN RESISTANCE; MENDELIAN RANDOMIZATION ANALYSIS; META ANALYSIS (TOPIC); MICROBIOME; MOLECULAR EPIDEMIOLOGY; MOLECULAR PATHOLOGY; NEOPLASM; NONHUMAN; OBESITY; PHENOTYPE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK ASSESSMENT; RISK FACTOR; STRUCTURAL EQUATION MODELING; SYSTEMIC DISEASE; WEIGHT GAIN; WEIGHT REDUCTION; ANIMAL; COMPLICATION; INCIDENCE; METABOLISM; NEOPLASMS; PATHOLOGY;

ADIPOSITY; ANIMALS; BODY MASS INDEX; HUMANS; INCIDENCE; INFLAMMATION; NEOPLASMS; OBESITY; RISK FACTORS;

EID: 84937842901     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3967     Document Type: Review

References (167)

1. Renehan, A., Tyson, M., Egger, M., Heller, R. F. &Zwahlen, M. Body mass index and incidence of cancer: a systematic review and meta-Analysis of prospective observational studies. Lancet 371, 569-578 (2008)
2. World Cancer Research Fund and American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective (AICR, 2007)
3. Renehan, A. G. Bariatric surgery, weight reduction and cancer prevention. Lancet Oncol. 10, 640-641 (2009)
4. Arnold, M. et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 36-46 (2014)
5. Calle, E. E. &Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579-591 (2004)
6. Sperrin, M., Marshall, A. D., Higgins, V., Buchan, I. E. &Renehan, A. G. Slowing down of adult body mass index trend increases in England: a latent class analysis of cross-sectional surveys (1992-2010). Int. J. Obes. 38, 818-824 (2014)
7. Aune, D. et al. Body mass index, abdominal fatness and pancreatic cancer risk: a systematic review and non-linear dose-response meta-Analysis of prospective studies. Ann. Oncol. 23, 843-852 (2012)
8. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and body size: individual participant meta-Analysis including 25, 157 women with ovarian cancer from 47 epidemiological studies. PLoS Med. 9, e1001200 (2012)
9. World Cancer Research Fund and American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Ovarian Cancer (AICR, 2014)
10. Larsson, S. C. &Wolk, A. Body mass index and risk of non-Hodgkin's and Hodgkin's lymphoma: a meta-Analysis of prospective studies. Eur. J. Cancer 47, 2422-2430 (2011)
11. Koebnick, C. et al. Body mass index, physical activity, and bladder cancer in a large prospective study. Cancer Epidemiol. Biomarkers Prev. 17, 1214-1221 (2008)
12. Moore, S. C. et al. Height, body mass index, and physical activity in relation to glioma risk. Cancer Res. 69, 8349-8355 (2009)
13. Lerro, C. C., McGlynn, K. A. &Cook, M. B. A systematic review and meta-Analysis of the relationship between body size and testicular cancer. Br. J. Cancer 103, 1467-1474 (2010)
14. Bhaskaran, K. et al. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet 384, 755-765 (2014
15. Freedland, S. J., Giovannucci, E. &Platz, E. A. Are findings from studies of obesity and prostate cancer really in conflict? Cancer Causes Control 17, 5-9 (2006)
16. Discacciati, A., Orsini, N. &Wolk, A. Body mass index and incidence of localized and advanced prostate cancer-A dose-response meta-Analysis of prospective studies. Ann. Oncol. 23, 1665-1671 (2012)
17. World Cancer Research Fund and American Institute for Cancer Research. Continuous Update Project Report: Diet, Nutrition, Physical Activity, and Prostate Cancer (AICR, 2014)
18. Coe, P. O., O'Reilly, D. A. &Renehan, A. G. Excess adiposity and gastrointestinal cancer. Br. J. Surg. 101, 1518-1531 (2014)
19. Keum, N. et al. Adult weight gain and adiposity-related cancers: a dose-response meta-Analysis of prospective observational studies. J. Natl Cancer Inst. 107, dju428 (2015)
20. Smith, L. et al. Body mass index and risk of lung cancer among never, former, and current smokers. J. Natl Cancer Inst. 104, 778-789 (2012)
21. Steffen, A. et al. Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol. Biomarkers Prev. 18, 2079-2089 (2009)
22. Gaudet, M. M. et al. Prospective studies of body mass index with head and neck cancer incidence and mortality. Cancer Epidemiol. Biomarkers Prev. 21, 497-503 (2012)
23. Etemadi, A. et al. A prospective cohort study of body size and risk of head and neck cancers in the NIH-AARP diet and health study. Cancer Epidemiol. Biomarkers Prev. 23, 2422-2429 (2014)
24. Akbartabartoori, M., Lean, M. E. &Hankey, C. R. Relationships between cigarette smoking, body size and body shape. Int. J. Obes. 29, 236-243 (2005)
25. Renehan, A. G., Leitzmann, M. F. &Zwahlen, M. Re: body mass index and risk of lung cancer among never, former, and current smokers. J. Natl Cancer Inst. 104, 1680-1681 (2012)
26. Renehan, A. G. in Handbook of Obesity (eds Bray, G. &Bouchard, C.) 561-572 (Informa Healthcare, 2014)
27. Crosbie, E. J., Zwahlen, M., Kitchener, H. C., Egger, M. &Renehan, A. G. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-Analysis. Cancer Epidemiol. Biomarkers Prev. 19, 3119-3130 (2010)
28. World Cancer Research Fund and American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Breast Cancer (AICR, 2010)
29. Eliassen, A. H. et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J. Natl Cancer Inst. 98, 1406-1415 (2006)
30. Kaaks, R. et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J. Natl Cancer Inst. 97, 755-765 (2005)
31. Renehan, A. G. Obesity and cancer in Asia-Pacific populations. Lancet Oncol. 11, 704-705 (2010)
32. Huang, Z. et al. Dual effects of weight and weight gain on breast cancer risk. J. Am. Med. Associ. 278, 1407-1411 (1997)
33. Kaaks, R. et al. Breast-cancer incidence in relation to height, weight and body-fat distribution in the Dutch 'DOM' cohort. Int. J. Cancer 76, 647-651 (1998)
34. Lahmann, P. H. et al. Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int. J. Cancer 111, 762-771 (2004)
35. Sperrin, M., Marshall, A. D., Higgins, V., Renehan, A. G. &Buchan, I. E. Body mass index relates weight to height differently in women and older adults: serial cross-sectional surveys in England (1992-2011). J. Public Health (Oxf.) fdv067 (2015)
36. Green, J. et al. Height and cancer incidence in the Million Women Study: prospective cohort, and meta-Analysis of prospective studies of height and total cancer risk. Lancet Oncol. 12, 785-794 (2011)
37. Renehan, A. G. Height and cancer: consistent links, but mechanisms unclear. Lancet Oncol. 12, 716-717 (2011)
38. Suzuki, R., Orsini, N., Saji, S., Key, T. J. &Wolk, A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status-A meta-Analysis. Int. J. Cancer 124, 698-712 (2009)
39. Ahn, J. et al. Adiposity, adult weight change, and postmenopausal breast cancer risk. Arch. Intern. Med. 167, 2091-2102 (2007)
40. Canchola, A. J. et al. Body size and the risk of postmenopausal breast cancer subtypes in the California Teachers Study cohort. Cancer Causes Control 23, 473-485 (2012)
41. Harris, H. R., Willett, W. C., Terry, K. L. &Michels, K. B. Body fat distribution and risk of premenopausal breast cancer in the Nurses' Health Study II. J. Natl Cancer Inst. 103, 273-278 (2011)
42. Ritte, R. et al. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res. 14, R76 (2012)
43. Setiawan, V. W. et al. Breast cancer risk factors defined by estrogen and progesterone receptor status: the multiethnic cohort study. Am. J. Epidemiol. 169, 1251-1259 (2009)
44. Phipps, A. I. et al. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 454-463 (2011)
45. Yang, X. R. et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J. Natl Cancer Inst. 103, 250-263 (2011)
46. Feigelson, H. S. et al. Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women. Cancer 107, 12-21 (2006)
47. Palmer, J. R., Adams-Campbell, L. L., Boggs, D. A., Wise, L. A. &Rosenberg, L. A prospective study of body size and breast cancer in black women. Cancer Epidemiol. Biomarkers Prev. 16, 1795-1802 (2007)
48. Potter, J. D. et al. Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women's Health Study: how many kinds of breast cancer are there? Cancer Epidemiol. Biomarkers Prev. 4, 319-326 (1995)
49. Suzuki, R., Rylander-Rudqvist, T., Ye, W., Saji, S. &Wolk, A. Body weight and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women: a prospective cohort study. Int. J. Cancer 119, 1683-1689 (2006)
50. Allred, D. C., Brown, P. &Medina, D. The origins of estrogen receptor-positive and estrogen receptor-negative human breast cancer. Breast Cancer Res. 6, 240-245 (2004)
51. Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798-802 (2010)
52. Bokhman, J. V. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 15, 10-17 (1983)
53. Setiawan, V. W. et al. Type I and II endometrial cancers: have they different risk factors? J. Clin. Oncol. 31, 2607-2618 (2013)
54. Olsen, C. M. et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr. Relat. Cancer 20, 251-262 (2013)
55. Campbell, P. T. et al. Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status. J. Natl Cancer Inst. 102, 391-400 (2010)
56. Satia, J. A. et al. Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study. Cancer Epidemiol. Biomarkers Prev. 14, 429-436 (2005)
57. Slattery, M. L. et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J. Natl Cancer Inst. 92, 1831-1836 (2000)
58. Hughes, L. A. et al. Body size and risk for colorectal cancers showing BRAF mutations or microsatellite instability: a pooled analysis. Int. J. Epidemiol. 41, 1060-1072 (2012)
59. Kuchiba, A. et al. Body mass index and risk of colorectal cancer according to fatty acid synthase expression in the nurses' health study. J. Natl Cancer Inst. 104, 415-420 (2012)
60. Morikawa, T. et al. Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with-catenin (CTNNB1) status. Cancer Res. 73, 1600-1610 (2013)
61. Khandekar, M. J., Cohen, P. &Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886-895 (2011)
62. Roberts, D. L., Dive, C. &Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301-316 (2010)
63. van Kruijsdijk, R. C., van der Wall, E. &Visseren, F. L. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol. Biomarkers Prev. 18, 2569-2578 (2009)
64. Renehan, A. G. in Clinical Endocrine Oncology (eds Hay, I. D. &Wass, J. A. H.) 32-40 (Oxford Univ. Press, 2008)
65. Travis, R. C. &Key, T. J. Oestrogen exposure and breast cancer risk. Breast Cancer Res. 5, 239-247 (2003)
66. Key, T. J. et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J. Natl Cancer Inst. 95, 1218-1226 (2003)
67. Kaaks, R. et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr. Relat. Cancer. 12, 1071-1082 (2005)
68. Derby, C. A., Zilber, S., Brambilla, D., Morales, K. H. &McKinlay, J. B. Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin. Endocrinol. 65, 125-131 (2006)
69. Kaaks, R., Lukanova, A. &Kurzer, M. S. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol. Biomarkers Prev. 11, 1531-1543 (2002)
70. Giovannucci, E. &Michaud, D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132, 2208-2225 (2007)
71. Thompson, I. M. et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 349, 215-224 (2003)
72. Platz, E. A. et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol. Biomarkers Prev. 14, 1262-1269 (2005)
73. Severi, G. et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 86-91 (2006)
74. Vona-Davis, L. &Rose, D. P. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr. Relat. Cancer 14, 189-206 (2007)
75. Dirat, B., Bochet, L., Escourrou, G., Valet, P. &Muller, C. Unraveling the obesity and breast cancer links: a role for cancer-Associated adipocytes? Endocr. Dev. 19, 45-52 (2010)
76. Muller, C. Tumour-surrounding adipocytes are active players in breast cancer progression. Ann. Endocrinol. 74, 108-110 (2013)
77. Chlebowski, R. T. et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N. Engl. J. Med. 350, 991-1004 (2004)
78. McKeown-Eyssen, G. Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol. Biomarkers Prev. 3, 687-695 (1994)
79. Giovannucci, E. Insulin and colon cancer. Cancer Causes Control 6, 164-179 (1995)
80. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159-169 (2012)
81. Renehan, A. G. et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363, 1346-1353 (2004)
82. Clayton, P. E., Banerjee, I., Murray, P. G. &Renehan, A. G. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat. Rev. Endocrinol. 7, 11-24 (2011
83. Xiang, A. H., Watanabe, R. M. &Buchanan, T. A. HOMA and Matsuda indices of insulin sensitivity: poor correlation with minimal model-based estimates of insulin sensitivity in longitudinal settings. Diabetologia 57, 334-338 (2014)
84. Zhou, X. H. et al. Diabetes, prediabetes and cancer mortality. Diabetologia 53, 1867-1876 (2010)
85. LeRoith, D. Can endogenous hyperinsulinaemia explain the increased risk of cancer development and mortality in type 2 diabetes: evidence from mouse models. Diabetes Metab. Res. Rev. 26, 599-601 (2010)
86. Badrick, E. &Renehan, A. G. Diabetes and cancer: 5 years into the recent controversy. Eur. J. Cancer 50, 2119-2125 (2014)
87. Bordeleau, L. et al. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 37, 1360-1366 (2014)
88. Renehan, A. G., Frystyk, J. &Flyvbjerg, A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol. Metab. 17, 328-336 (2006)
89. Tsilidis, K. K., Papatheodorou, S. I., Evangelou, E. &Ioannidis, J. P. Evaluation of excess statistical significance in meta-Analyses of 98 biomarker associations with cancer risk. J. Natl Cancer Inst. 104, 1867-1878 (2012)
90. Harvie, M. et al. Increase in serum total IGF-I and maintenance of free IGF-I levels following intentional weight loss in pre-menopausal women at increased risk of breast cancer. Open Obes. J. [online] www. researchgate.net/publication/234101282 (2010)
91. Fischer-Posovszky, P., Wabitsch, M. &Hochberg, Z. Endocrinology of adipose tissue-An update. Horm. Metab. Res. 39, 314-321 (2007)
92. Schaffler, A., Scholmerich, J. &Buechler, C. Mechanisms of disease: adipokines and breast cancer-endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat. Clin. Pract. Endocrinol. Metab. 3, 345-354 (2007)
93. Bray, G. A. The underlying basis for obesity: relationship to cancer. J. Nutr. 132, 3451S-3455S (2002)
94. Rose, D. P., Komninou, D. &Stephenson, G. D. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev. 5, 153-165 (2004)
95. Vansaun, M. N. Molecular pathways: adiponectin and leptin signaling in cancer. Clin. Cancer Res. 19, 1926-1932 (2013)
96. Renehan, A. G., Roberts, D. L. &Dive, C. Obesity and cancer: pathophysiological and biological mechanisms. Arch. Physiol. Biochem. 114, 71-83 (2008)
97. Gialamas, S. P. et al. Circulating leptin levels and risk of colorectal cancer and adenoma: a case-control study and meta-Analysis. Cancer Causes Control 24, 2129-2141 (2013)
98. Fasshauer, M., Klein, J., Neumann, S., Eszlinger, M. &Paschke, R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 290, 1084-1089 (2002)
99. Cnop, M. et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46, 459-469 (2003)
100. Dalamaga, M., Diakopoulos, K. N. &Mantzoros, C. S. The role of adiponectin in cancer: a review of current evidence. Endocr. Rev. 33, 547-594 (2012)
101. Hotamisligil, G. S. &Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat. Rev. Immunol. 8, 923-934 (2008)
102. Osborn, O. &Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363-374 (2012)
103. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808 (2003)
104. Erlinger, T. P., Platz, E. A., Rifai, N. &Helzlsouer, K. J. C-reactive protein and the risk of incident colorectal cancer. JAMA 291, 585-590 (2004)
105. Tsilidis, K. K. et al. C-reactive protein and colorectal cancer risk: a systematic review of prospective studies. Int. J. Cancer 123, 1133-1140 (2008)
106. Chan, A. T., Ogino, S., Giovannucci, E. L. &Fuchs, C. S. Inflammatory markers are associated with risk of colorectal cancer and chemopreventive response to anti-inflammatory drugs. Gastroenterology 140, 799-808 (2011)
107. Aleksandrova, K. et al. Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am. J. Epidemiol. 172, 407-418 (2010)
108. Song, M. et al. A prospective study of plasma inflammatory markers and risk of colorectal cancer in men. Br. J. Cancer 108, 1891-1898 (2013)
109. Dieudonne, M. N. et al. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem. Biophys. Res. Commun. 345, 271-279 (2006)
110. Hursting, S. D., Nunez, N. P., Varticovski, L. &Vinson, C. The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res. 67, 2391-2393 (2007)
111. Brenner, D. R. et al. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiol. Biomarkers Prev. 23, 1729-1751 (2014)
112. Byers, T. &Sedjo, R. L. Does intentional weight loss reduce cancer risk? Diabetes Obes. Metab. 13, 1063-1072 (2011)
113. Mason, C. et al. Effects of dietary weight loss and exercise on insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in postmenopausal women: a randomized controlled trial. Cancer Epidemiol. Biomarkers Prev. 22, 1457-1463 (2013)
114. Balagopal, P. B. et al. Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth: a scientific statement from the American Heart Association. Circulation 123, 2749-2769 (2011)
115. Canoy, D. et al. Body fat distribution and risk of coronary heart disease in men and women in the European Prospective Investigation Into Cancer and Nutrition in Norfolk cohort: a population-based prospective study. Circulation 116, 2933-2943 (2007)
116. Stefan, N., Haring, H. U., Hu, F. B. &Schulze, M. B. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 1, 152-162 (2013)
117. Moore, L. L., Chadid, S., Singer, M. R., Kreger, B. E. &Denis, G. V. Metabolic health reduces risk of obesity-related cancer in framingham study adults. Cancer Epidemiol. Biomarkers Prev. 23, 2057-2065 (2014)
118. Britton, K. A. &Fox, C. S. Ectopic fat depots and cardiovascular disease. Circulation 124, e837-841 (2011)
119. Cornier, M. A. et al. Assessing adiposity: a scientific statement from the American Heart Association. Circulation 124, 1996-2019 (2011)
120. Ouchi, N., Parker, J. L., Lugus, J. J. &Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85-97 (2011)
121. Fabbrini, E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl Acad. Sci. USA 106, 15430-15435 (2009)
122. Kahn, B. B. &Flier, J. S. Obesity and insulin resistance. J. Clin. Invest. 106, 473-481 (2000)
123. Aleksandrova, K., Nimptsch, K. &Pischon, T. Obesity and colorectal cancer. Front. Biosci. (Elite Ed.) 5, 61-77 (2013)
124. Moore, L. L. et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int. J. Obes. Relat. Metab. Disord. 28, 559-567 (2004)
125. Pischon, T. et al. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J. Natl Cancer Inst. 98, 920-931 (2006)
126. Folsom, A. R. et al. Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study. Arch. Intern. Med. 160, 2117-2128 (2000)
127. Keimling, M. et al. Comparison of associations of body mass index, abdominal adiposity, and risk of colorectal cancer in a large prospective cohort study. Cancer Epidemiol. Biomarkers Prev. 22, 1383-1394 (2013)
128. Oxentenko, A. S. et al. Body size and incident colorectal cancer: a prospective study of older women. Cancer Prev. Res. 3, 1608-1620 (2010)
129. Gaudet, M. M. et al. Waist circumference, body mass index, and postmenopausal breast cancer incidence in the Cancer Prevention Study-II Nutrition Cohort. Cancer Causes Control 25, 737-745 (2014)
130. Huang, Z. et al. Waist circumference, waist:hip ratio, and risk of breast cancer in the Nurses' Health Study. Am. J. Epidemiol. 150, 1316-1324 (1999)
131. World Cancer Research Fund and American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Pancreatic Cancer. (AICR, 2012)
132. World Cancer Research Fund and American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Endometrial Cancer. (AICR, 2013)
133. 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)
134. Fox, C. S. et al. Periaortic fat deposition is associated with peripheral arterial disease: the Framingham heart study. Circ. Cardiovasc. Imag. 3, 515-519 (2010)
135. Schautz, B., Later, W., Heller, M., Muller, M. J. &Bosy-Westphal, A. Associations between breast adipose tissue, body fat distribution and cardiometabolic risk in women: cross-sectional data and weight-loss intervention. Eur. J. Clin. Nutr. 65, 784-790 (2011)
136. Martinez-Outschoorn, U. E., Sotgia, F. &Lisanti, M. P. Caveolae and signalling in cancer. Nat. Rev. Cancer 15, 225-237 (2015)
137. 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)
138. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 15324-15329 (2011)
139. Stefan, N., Kantartzis, K. &Haring, H. U. Causes and metabolic consequences of fatty liver. Endocr. Rev. 29, 939-960 (2008)
140. Tacke, F., Luedde, T. &Trautwein, C. Inflammatory pathways in liver homeostasis and liver injury. Clin. Rev. Allergy Immunol. 36, 4-12 (2009)
141. 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)
142. Wang, Y., Ausman, L. M., Greenberg, A. S., Russell, R. M. &Wang, X. D. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int. J. Cancer 124, 540-546 (2009)
143. Michelotti, G. A., Machado, M. V. &Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656-665 (2013)
144. Hart, C. L., Morrison, D. S., Batty, G. D., Mitchell, R. J. &Davey Smith, G. Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ 340, c1240 (2010)
145. Sijens, P. E., Edens, M. A., Bakker, S. J. &Stolk, R. P. MRI-determined fat content of human liver, pancreas and kidney. World J. Gastroenterol. 16, 1993-1998 (2010)
146. Lashinger, L. M. et al. Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. Cancer Prev. Res. 4, 1030-1040 (2011
147. Hori, M. et al. Association of pancreatic Fatty infiltration with pancreatic ductal adenocarcinoma. Clin. Transl. Gastroenterol. 5, e53 (2014)
148. Bertolini, F., Petit, J. Y. &Kolonin, M. G. Stem cells from adipose tissue and breast cancer: hype, risks and hope. Br. J. Cancer 112, 419-423 (2015)
149. Tremaroli, V. &Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242-249 (2012)
150. Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508-512 (2014)
151. Ohtani, N. Microbiome and cancer. Semin. Immunopathol. 37, 65-72 (2015)
152. Thanassoulis, G. et al. Prevalence, distribution, and risk factor correlates of high pericardial and intrathoracic fat depots in the Framingham heart study. Circ. Cardiovasc. Imag. 3, 559-566 (2010)
153. Hernan, M. A., Hernandez-Diaz, S. &Robins, J. M. A structural approach to selection bias. Epidemiology 15, 615-625 (2004)
154. Hernan, M. A. &Robins, J. M. Instruments for causal inference: an epidemiologist's dream? Epidemiology 17, 360-372 (2006)
155. Smith, G. D. &Ebrahim, S. Mendelian randomization: prospects, potentials, and limitations. Int. J. Epidemiol. 33, 30-42 (2004)
156. Smith, G. D., Timpson, N. &Ebrahim, S. Strengthening causal inference in cardiovascular epidemiology through Mendelian randomization. Ann. Med. 40, 524-541 (2008)
157. Kilpelainen, T. O. et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat. Genet. 43, 753-760 (2011)
158. Speliotes, E. K. et al. Association analyses of 249, 796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937-948 (2010)
159. Tao, M. H. et al. Polymorphisms in the CYP19A1 (aromatase) gene and endometrial cancer risk in Chinese women. Cancer Epidemiol. Biomarkers Prev. 16, 943-949 (2007)
160. Wen, W. et al. The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk. Cancer 112, 2409-2416 (2008)
161. Lurie, G. et al. The obesity-Associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PLoS ONE 6, e16756 (2011)
162. Lewis, S. J. et al. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS ONE 5, e13485 (2010)
163. Tenesa, A. et al. Common genetic variants at the MC4R locus are associated with obesity, but not with dietary energy intake or colorectal cancer in the Scottish population. Int. J. Obes. 33, 284-288 (2009)
164. Sainz, J. et al. GWAS-identified common variants for obesity are not associated with the risk of developing colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 23, 1125-1128 (2014)
165. Bellamy, S. L., Lin, J. Y. &Ten Have, T. R. An introduction to causal modeling in clinical trials. Clin. Trials 4, 58-73 (2007)
166. Dossus, L. et al. Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC Cohort-A factor analysis. Am. J. Epidemiol. 177, 787-799 (2013)
167. Nead, K. T. et al. Evidence of a causal association between insulinemia and endometrial cancer: a Mendelian randomization analysis. J. Natl Cancer Inst. 107, djv178 (2015