Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment

Tumor Biology

Volumn 37, Issue 11, 2016, Pages 14363-14380

  Teoh, Seong Lin ^a   Das, Srijit ^a  

^a UNIVERSITI KEBANGSAAN MALAYSIA MEDICAL CENTER   (Malaysia)

Author keywords

Aetiology; Cancer; Drugs; Genes; miRNA; Molecular biology; Obesity

Indexed keywords

ADIPOCYTOKINE; AGOUTI RELATED PROTEIN; BRAIN DERIVED NEUROTROPHIC FACTOR; C REACTIVE PROTEIN; FENRETINIDE; INSULIN; INSULIN INDUCED GENE 2 PROTEIN; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN 4 RECEPTOR; MESSENGER RNA; METFORMIN; MICRORNA; MICRORNA 143; MITOGEN ACTIVATED PROTEIN KINASE 7; NEUROPEPTIDE Y; PROOPIOMELANOCORTIN; PROTEIN BCL 2; REGULATOR PROTEIN; SEX HORMONE; TETRAHYDROLIPSTATIN; UNCLASSIFIED DRUG; AGRP PROTEIN, HUMAN; BRAIN-DERIVED NEUROTROPHIC FACTOR, HUMAN; INSIG2 PROTEIN, HUMAN; MEMBRANE PROTEIN; MIRN143 MICRORNA, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE; SIGNAL PEPTIDE;

APOPTOSIS; BREAST CANCER; BREAST CARCINOMA; CANCER RISK; CARCINOGENESIS; CELL CYCLE ARREST; CHRONIC INFLAMMATION; DIET INDUCED OBESITY; EARLY CANCER DIAGNOSIS; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; ENERGY BALANCE; FAT MASS AND OBESITY ASSOCIATED GENE; GENE; GENETIC SUSCEPTIBILITY; HUMAN; HYPERINSULINEMIA; HYPERLEPTINEMIA; HYPOXIA; KIDNEY CANCER; LIVER CANCER; LOCOMOTION; MACROPHAGE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ONCOGENE K RAS; PREVALENCE; PRIORITY JOURNAL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STROMA CELL; THYROID CANCER; TRIPLE NEGATIVE BREAST CANCER; TUMOR GROWTH; UTERUS CANCER; WEIGHT GAIN; ANIMAL; BIOSYNTHESIS; FEMALE; GENETICS; MALE; METABOLISM; MOUSE; NEOPLASM; PATHOLOGY;

ADIPOKINES; AGOUTI-RELATED PROTEIN; ANIMALS; BRAIN-DERIVED NEUROTROPHIC FACTOR; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FEMALE; GONADAL STEROID HORMONES; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LEPTIN; MALE; MEMBRANE PROTEINS; MICE; MICRORNAS; NEOPLASMS; NEUROPEPTIDE Y; OBESITY; PRO-OPIOMELANOCORTIN; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTORS, LEPTIN;

EID: 84987679838     PISSN: 10104283     EISSN: 14230380     Source Type: Journal    
DOI: 10.1007/s13277-016-5357-7     Document Type: Review

References (240)

1. WHO. Obesity: Preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000; 894:1–253.
2. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579–91.
3. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363(9403):157–63.
4. Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002;3(9):565–74.
5. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes. 2008;32(9):1431–7.
6. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307(5):491–7.
7. Berghofer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN. Obesity prevalence from a European perspective: a systematic review. BMC Public Health. 2008;8:200.
8. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, 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. 2014;384(9945):766–81.
9. Filozof C, Gonzalez C, Sereday M, Mazza C, Braguinsky J. Obesity prevalence and trends in Latin-American countries. Obes Rev. 2001;2(2):99–106.
10. Aekplakorn W, Inthawong R, Kessomboon P, Sangthong R, Chariyalertsak S, Putwatana P, et al. Prevalence and trends of obesity and association with socioeconomic status in Thai adults: National Health Examination Surveys, 1991–2009. J Obes. 2014;2014:410259.
11. Wang Y, Mi J, Shan XY, Wang QJ, Ge KYI. China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China. Int J Obes. 2007;31(1):177–88.
12. Pradeepa R, Anjana RM, Joshi SR, Bhansali A, Deepa M, Joshi PP, et al. Prevalence of generalized & abdominal obesity in urban & rural India—The ICMR-INDIAB study (phase-I) [ICMR-NDIAB-3]. Indian J Med Res. 2015;142(2):139–50.
13. Trayhurn P. The biology of obesity. Proc Nutr Soc. 2005;64(1):31–8.
14. Hill JO, Wyatt HR, Peters JC. Energy balance and obesity. Circulation. 2012;126(1):126–32.
15. Wright SM, Aronne LJ. Causes of obesity. Abdom Imaging. 2012;37(5):730–2.
16. Vassallo J. Pathogenesis of obesity. J Malta College Pharmacy Practice. 2007;12:19–22.
17. Hinney A, Vogel CI, Hebebrand J. From monogenic to polygenic obesity: recent advances. Eur Child Adolesc Psychiatry. 2010;19(3):297–310.
18. Choquet H, Meyre D. Genetics of obesity: what have we learned? Curr Genomics. 2011;12(3):169–79.
19. Loos RJ. Genetic determinants of common obesity and their value in prediction. Best Pract Res Clin Endocrinol Metab. 2012;26(2):211–26.
20. Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med. 1999;130(8):671–80.
21. Levenson AE, Haas ME, Miao J, Brown RJ, de Ferranti SD, Muniyappa R, et al. Effect of leptin replacement on PCSK9 in ob/ob mice and female lipodystrophic patients. Endocrinology. 2016. doi:10.1210/en.2015-1624:en20151624.
22. Hannema SE, Wit JM, Houdijk ME, van Haeringen A, Bik EC, Verkerk AJ, et al. Novel leptin receptor mutations identified in two girls with severe obesity are associated with increased bone mineral density. Horm Res Paediatr. 2016. doi:10.1159/000444055.
23. Catli G, Anik A, Tuhan HU, Kume T, Bober E, Abaci A. The relation of leptin and soluble leptin receptor levels with metabolic and clinical parameters in obese and healthy children. Peptides. 2014;56:72–6.
24. Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol. 2011;2011:197636.
25. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903–8.
26. Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 2015;372(1):48–54.
27. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes. 1996;45(11):1455–62.
28. Sainz N, Barrenetxe J, Moreno-Aliaga MJ, Martinez JA. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 2015;64(1):35–46.
29. Lin S, Storlien LH, Huang XF. Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. Brain Res. 2000;875(1–2):89–95.
30. reg and the prospects for vaccination against H. pylori infection. Front Immunol. 2012;3:316.
31. Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Goke M, et al. Expression of leptin and leptin receptor isoforms in the human stomach. Gut. 2000;47(4):481–6.
32. Burguera B, Couce ME, Long J, Lamsam J, Laakso K, Jensen MD, et al. The long form of the leptin receptor (OB-Rb) is widely expressed in the human brain. Neuroendocrinol. 2000;71(3):187–95.
33. Ceddia RB. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes. 2005;29(10):1175–83.
34. Bernotiene E, Palmer G, Gabay C. The role of leptin in innate and adaptive immune responses. Arthritis Res Ther 2006; 8(5):217.
35. Maamra M, Bidlingmaier M, Postel-Vinay MC, Wu Z, Strasburger CJ, Ross RJ. Generation of human soluble leptin receptor by proteolytic cleavage of membrane-anchored receptors. Endocrinol. 2001;142(10):4389–93.
36. Hileman SM, Pierroz DD, Masuzaki H, Bjorbaek C, El-Haschimi K, Banks WA, et al. Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinol. 2002;143(3):775–83.
37. Bouret SG, Bates SH, Chen S, Myers Jr MG, Simerly RB. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J Neurosci. 2012;32(4):1244–52.
38. Vong L, Ye C, Yang Z, Choi B, Chua Jr S, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron. 2011;71(1):142–54.
39. Korner J, Savontaus E, Chua Jr SC, Leibel RL, Wardlaw SL. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J Neuroendocrinol. 2001;13(11):959–66.
40. Phan J, Lipin RK. A lipodystrophy and obesity gene. Cell Metab. 2005;1(1):73–83.
41. Huang XF, Han M, South T, Storlien L. Altered levels of POMC, AgRP and MC4-R mRNA expression in the hypothalamus and other parts of the limbic system of mice prone or resistant to chronic high-energy diet-induced obesity. Brain Res. 2003;992(1):9–19.
42. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. 1999;5(9):1066–70.
43. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes. 2006;55(9):2549–53.
44. Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab. 2003;88(10):4633–40.
45. Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology. 1998;139(10):4428–31.
46. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL. Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet. 1997;17(3):273–4.
47. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278(5335):135–8.
48. Wu Q, Whiddon BB, Palmiter RD. Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc Natl Acad Sci U S A. 2012;109(8):3155–60.
49. Hoggard N, Johnstone AM, Faber P, Gibney ER, Elia M, Lobley G, et al. Plasma concentrations of a-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance perturbation. Clin Endocrinol. 2004;61(1):31–9.
50. Makimura H, Mizuno TM, Mastaitis JW, Agami R, Mobbs CV. Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci. 2002;3:18.
51. Tsaousidou E, Paeger L, Belgardt BF, Pal M, Wunderlich CM, Bronneke H, et al. Distinct roles for JNK and IKK activation in agouti-related peptide neurons in the development of obesity and insulin resistance. Cell Rep. 2014;9(4):1495–506.
52. Siljee JE, Unmehopa UA, Kalsbeek A, Swaab DF, Fliers E, Alkemade A. Melanocortin 4 receptor distribution in the human hypothalamus. Eur J Endocrinol. 2013;168(3):361–9.
53. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95.
54. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20(2):111–2.
55. Dubern B, Clement K, Pelloux V, Froguel P, Girardet JP, Guy-Grand B, et al. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and a-melanocyte-stimulating hormone genes in severely obese children. J Pediatr. 2001;139(2):204–9.
56. Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62(2):490–7.
57. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40(6):768–75.
58. Cauchi S, Stutzmann F, Cavalcanti-Proenca C, Durand E, Pouta A, Hartikainen AL, et al. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med. 2009;87(5):537–46.
59. Zobel DP, Andreasen CH, Grarup N, Eiberg H, Sorensen TI, Sandbaek A, et al. Variants near MC4R are associated with obesity and influence obesity-related quantitative traits in a population of middle-aged people: studies of 14,940 Danes. Diabetes. 2009;58(3):757–64.
60. Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S, et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet. 2004;74(3):572–81.
61. Young EH, Wareham NJ, Farooqi S, Hinney A, Hebebrand J, Scherag A, et al. The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes. 2007;31(9):1437–41.
62. Caruso C, Carniglia L, Durand D, Gonzalez PV, Scimonelli TN, Lasaga M. Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase a pathway. Mol Cell Endocrinol. 2012;348(1):47–54.
63. An JJ, Liao GY, Kinney CE, Sahibzada N, Xu B. Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab. 2015;22(1):175–88.
64. El-Gharbawy AH, Adler-Wailes DC, Mirch MC, Theim KR, Ranzenhofer L, Tanofsky-Kraff M, et al. Serum brain-derived neurotrophic factor concentrations in lean and overweight children and adolescents. J Clin Endocrinol Metab. 2006;91(9):3548–52.
65. Araya AV, Orellana X, Espinoza J. Evaluation of the effect of caloric restriction on serum BDNF in overweight and obese subjects: preliminary evidences. Endocrine. 2008;33(3):300–4.
66. Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM, et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes. 2006;55(12):3366–71.
67. Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359(9):918–27.
68. Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, et al. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex. 2013;49(10):2700–10.
69. Shinawi M, Sahoo T, Maranda B, Skinner SA, Skinner C, Chinault C, et al. 11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity. Am J Med Genet A. 2011;155A(6):1272–80.
70. Zegers D, Hendrickx R, Verrijken A, Van Hoorenbeeck K, Van Camp JK, de Craemer V, et al. Screening for genetic variants in BDNF that contribute to childhood obesity. Pediatr Obes. 2014;9(1):36–42.
71. Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K, et al. Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2005;132B(1):96–9.
72. Mou Z, Hyde TM, Lipska BK, Martinowich K, Wei P, Ong CJ, et al. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus. Cell Rep. 2015;13(6):1073–80.
73. Beckers S, Peeters A, Zegers D, Mertens I, Van Gaal L, Van Hul W. Association of the BDNF Val66Met variation with obesity in women. Mol Genet Metab. 2008;95(1–2):110–2.
74. Ma XY, Qiu WQ, Smith CE, Parnell LD, Jiang ZY, Ordovas JM et al. Association between BDNF rs6265 and obesity in the Boston Puerto Rican Health study. J Obes 2012; 2012:102942.
75. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3(7):e115.
76. Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007;39(6):724–6.
77. Fredriksson R, Hagglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, et al. The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology. 2008;149(5):2062–71.
78. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316(5826):889–94.
79. Jonsson A, Renstrom F, Lyssenko V, Brito EC, Isomaa B, Berglund G, et al. Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15, 925 Swedish and 2, 511 Finnish adults. Diabetologia. 2009;52(7):1334–8.
80. Hubacek JA, Bohuslavova R, Kuthanova L, Kubinova R, Peasey A, Pikhart H, et al. The FTO gene and obesity in a large eastern European population sample: the HAPIEE study. Obesity. 2008;16(12):2764–6.
81. Prakash J, Srivastava N, Awasthi S, Agarwal CG, Natu SM, Rajpal N, et al. Association of FTO rs17817449 SNP with obesity and associated physiological parameters in a north Indian population. Ann Hum Biol. 2011;38(6):760–3.
82. Harbron J, van der Merwe L, Zaahl MG, Kotze MJ, Senekal M. Fat mass and obesity-associated (FTO) gene polymorphisms are associated with physical activity, food intake, eating behaviors, psychological health, and modeled change in body mass index in overweight/obese Caucasian adults. Nutrients. 2014;6(8):3130–52.
83. Vcelak J, Lukasova P, Vankova M, Vejrazkova D, Kvasnickova H, Vrbikova J, et al. FTO gene is associated not only with obesity-related quantitative traits but also with higher OGTT stimulated glycaemia and leptin level. Diabetologia. 2008;51(Suppl 1):S326.
84. Benedict C, Axelsson T, Soderberg S, Larsson A, Ingelsson E, Lind L, et al. Fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults. Diabetes. 2014;63(11):3955–9.
85. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458(7240):894–8.
86. Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, et al. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol. 2008;294(4):R1185–96.
87. Church C, Lee S, Bagg EA, McTaggart JS, Deacon R, Gerken T, et al. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet. 2009;5(8):e1000599.
88. Takaishi K, Duplomb L, Wang MY, Li J, Unger RH. Hepatic insig-1 or -2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats. Proc Natl Acad Sci U S A. 2004;101(18):7106–11.
89. Yabe D, Brown MS, Goldstein JL. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A. 2002;99(20):12753–8.
90. Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312(5771):279–83.
91. Hotta K, Nakamura M, Nakata Y, Matsuo T, Kamohara S, Kotani K, et al. INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese. J Hum Genet. 2008;53(9):857–62.
92. Andreasen CH, Mogensen MS, Borch-Johnsen K, Sandbaek A, Lauritzen T, Sorensen TI, et al. Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18,014 Danes. PLoS One. 2008;3(8):e2872.
93. Hall DH, Rahman T, Avery PJ, Keavney B. INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families. BMC Med Genet. 2006;7:83.
94. Boes E, Kollerits B, Heid IM, Hunt SC, Pichler M, Paulweber B, et al. INSIG2 polymorphism is neither associated with BMI nor with phenotypes of lipoprotein metabolism. Obesity. 2008;16(4):827–33.
95. Wang HJ, Zhang H, Zhang SW, Pan YP, Ma J. Association of the common genetic variant upstream of INSIG2 gene with obesity related phenotypes in Chinese children and adolescents. Biomed Environ Sci. 2008;21(6):528–36.
96. Malzahn D, Muller-Nurasyid M, Heid IM, Wichmann HE, the KORA Study Group, Bickeboller H. Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R. Eur J Hum Genet. 2014;22(10):1217–24.
97. Ng MC, Tam CH, WY S, JS H, AW C, HM L, et al. Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese. J Clin Endocrinol Metab. 2010;95(5):2418–25.
98. Poveda A, Ibanez ME, Rebato E. Common variants in BDNF, FAIM2, FTO, MC4R, NEGR1, and SH2B1 show association with obesity-related variables in Spanish Roma population. Am J Hum Biol. 2014;26(5):660–9.
99. Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S, Garg S, et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet. 2013;45(5):513–7.
100. Pillai RS. Micro RNA function: multiple mechanisms for a tiny RNA? RNA. 2005;11(12):1753–61.
101. Schickel R, Boyerinas B, Park SM, Peter ME. Micro RNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008;27(45):5959–74.
102. Xie H, Lim B, Lodish HF. Micro RNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes. 2009;58(5):1050–7.
103. Takanabe R, Ono K, Abe Y, Takaya T, Horie T, Wada H, et al. Up-regulated expression of micro RNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. Biochem Biophys Res Commun. 2008;376(4):728–32.
104. Chartoumpekis DV, Zaravinos A, Ziros PG, Iskrenova RP, Psyrogiannis AI, Kyriazopoulou VE, et al. Differential expression of micro RNAs in adipose tissue after long-term high-fat diet-induced obesity in mice. PLoS One. 2012;7(4):e34872.
105. Kloting N, Berthold S, Kovacs P, Schon MR, Fasshauer M, Ruschke K, et al. Micro RNA expression in human omental and subcutaneous adipose tissue. PLoS One. 2009;4(3):e4699.
106. Ortega FJ, Mercader JM, Catalan V, Moreno-Navarrete JM, Pueyo N, Sabater M, et al. Targeting the circulating micro RNA signature of obesity. Clin Chem. 2013;59(5):781–92.
107. Pescador N, Perez-Barba M, Ibarra JM, Corbaton A, Martinez-Larrad MT, Serrano-Rios M. Serum circulating micro RNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS One. 2013;8(10):e77251.
108. Lin Q, Gao Z, Alarcon RM, Ye J, Yun Z. A role of miR-27 in the regulation of adipogenesis. FEBS J. 2009;276(8):2348–58.
109. Rhee SY, Park SW, Kim DJ, Woo J. Gender disparity in the secular trends for obesity prevalence in Korea: analyses based on the KNHANES 1998–2009. Korean J Intern Med. 2013;28(1):29–34.
110. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11(12):886–95.
111. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev. 2009;18(10):2569–78.
112. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.
113. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95(5):2111–9.
114. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745–51.
115. Dubois V, Jarde T, Delort L, Billard H, Bernard-Gallon D, Berger E, et al. Leptin induces a proliferative response in breast cancer cells but not in normal breast cells. Nutr Cancer. 2014;66(4):645–55.
116. Yuan Y, Zhang J, Cai L, Ding C, Wang X, Chen H, et al. Leptin induces cell proliferation and reduces cell apoptosis by activating c-myc in cervical cancer. Oncol Rep. 2013;29(6):2291–6.
117. Chen C, Chang YC, Lan MS, Breslin M. Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways. Int J Oncol. 2013;42(3):1113–39.
118. Yan D, Avtanski D, Saxena NK, Sharma D. Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires beta-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways. J Biol Chem. 2012;287(11):8598–612.
119. Nepal S, Kim MJ, Hong JT, Kim SH, Sohn DH, Lee SH, et al. Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: involvement of p53/FoxO3A axis. Oncotarget. 2015;6(9):7166–81.
120. Catalano S, Leggio A, Barone I, De Marco R, Gelsomino L, Campana A, et al. A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo. J Cell Mol Med. 2015;19(5):1122–32.
121. Weaver JU, Holly JM, Kopelman PG, Noonan K, Giadom CG, White N, et al. Decreased sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP-1) in extreme obesity. Clin Endocrinol. 1990;33(3):415–22.
122. Perseghin G, Calori G, Lattuada G, Ragogna F, Dugnani E, Garancini MP, et al. Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol. 2012;49(6):421–8.
123. Sciacca L, Cassarino MF, Genua M, Vigneri P, Giovanna Pennisi M, Malandrino P, et al. Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression. J Cell Physiol. 2014;229(11):1817–21.
124. Hursting SD. Obesity and cancer: mechanistic insights from transdisciplinary studies. Mol Cancer Res. 2016;14(1_Suppl):IA25.
125. Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett. 2012;326(2):191–8.
126. Ferguson RD, Gallagher EJ, Cohen D, Tobin-Hess A, Alikhani N, Novosyadlyy R, et al. Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer. Endocr Relat. Cancer. 2013;20(3):391–401.
127. Liu S, Zhang Q, Chen C, Ge D, Qu Y, Chen R et al. Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor. Oncotarget 2016; doi:10.18632/oncotarget.7296.
128. Ande SR, Nguyen KH, Padilla-Meier GP, Nyomba BL, Mishra S. Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity-linked tumor development in insulin resistance-dependent manner. Oncogene. 2016. doi:10.1038/onc.2015.501.
129. Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, Chierici R, et al. Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. J Clin Endocrinol Metab. 1995;80(2):654–8.
130. Simo R, Saez-Lopez C, Lecube A, Hernandez C, Fort JM, Selva DM. Adiponectin upregulates SHBG production: molecular mechanisms and potential implications. Endocrinology. 2014;155(8):2820–30.
131. Hormones E, Group BCC, Key TJ, Appleby PN, Reeves GK, Travis RC, et al. Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol. 2013;14(10):1009–19.
132. Lin JH, Zhang SM, Rexrode KM, Manson JE, Chan AT, Wu K, et al. Association between sex hormones and colorectal cancer risk in men and women. Clin Gastroenterol Hepatol. 2013;11(4):419–24.
133. Yue W, Yager JD, Wang JP, Jupe ER, Santen RJ. Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids. 2013;78(2):161–70.
134. Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S, et al. Estrogenic regulation of S6 K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene. 2012;31(49):5073–80.
135. Liao XH, DL L, Wang N, Liu LY, Wang Y, Li YQ, et al. Estrogen receptor a mediates proliferation of breast cancer MCF-7 cells via a p21/PCNA/E2F1-dependent pathway. FEBS J. 2014;281(3):927–42.
136. Zhang Z, Zhou D, Lai Y, Liu Y, Tao X, Wang Q, et al. Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett. 2012;319(1):89–97.
137. Lin CY, Chen PC, Kuo HK, Lin LY, Lin JW, Hwang JJ. Effects of obesity, physical activity, and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance in the National Health and Nutrition Survey 1999–2002. Nutr Metab Cardiovasc Dis. 2010;20(10):713–9.
138. Rethorst CD, Bernstein I, Trivedi MH. Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009–2010 National Health and Nutrition Examination Survey NHANES. J Clin Psychiatry. 2014;75(12):e1428–32.
139. Sola E, Jover A, Lopez-Ruiz A, Jarabo M, Vaya A, Morillas C, et al. Parameters of inflammation in morbid obesity: lack of effect of moderate weight loss. Obes Surg. 2009;19(5):571–6.
140. Zheng C, Yang Q, Cao J, Xie N, Liu K, Shou P, et al. Local proliferation initiates macrophage accumulation in adipose tissue during obesity. Cell Death Dis. 2016;7:e2167.
141. DY O, Morinaga H, Talukdar S, Bae EJ, Olefsky JM. Increased macrophage migration into adipose tissue in obese mice. Diabetes. 2012;61(2):346–54.
142. Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, Seewaldt V, et al. Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res. 2013;73(19):6080–93.
143. Incio J, Tam J, Rahbari NN, Suboj P, McManus DT, Chin SM, et al. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-15-1839.
144. Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med. 2014;20(4):377–84.
145. Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science. 2013;339(6116):218–22.
146. Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res. 2013;19(22):6074–83.
147. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, AW Jr F. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.
148. Alhaj SA, Aljawadi A, Ramalingam L, Moustaid-Moussa N. Obesity-breast cancer interactions: effects of adipocytes on breast cancer cells and preventive effects of omega 3 fatty acids. FASEB J. 2016;30(1 Suppl):691.
149. Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008;49(7):1562–8.
150. 2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2012;2(4):356–65.
151. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56(4):901–11.
152. Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in C57BL/6 J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes. 2008;32(3):451–63.
153. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118–28.
154. Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose tissue hypoxia, inflammation, and fibrosis in obese insulin-sensitive and obese insulin-resistant subjects. J Clin Endocrinol Metab. 2016;101(4):1422–8.
155. Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, et al. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1a-dependent and HIF-1a-independent manner in obese mice. Diabetologia. 2013;56(6):1403–12.
156. Zhang Y, Daquinag A, Traktuev DO, Amaya-Manzanares F, Simmons PJ, March KL, et al. White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res. 2009;69(12):5259–66.
157. Klopp AH, Zhang Y, Solley T, Amaya-Manzanares F, Marini F, Andreeff M, et al. Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin Cancer Res. 2012;18(3):771–82.
158. Zhang Y, Daquinag AC, Amaya-Manzanares F, Sirin O, Tseng C, Kolonin MG. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res. 2012;72(20):5198–208.
159. Rowan BG, Gimble JM, Sheng M, Anbalagan M, Jones RK, Frazier TP et al. Human adipose tissue-derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts. PLoS One 2014; 9(2):e89595.
160. Ali AS, Ali S, Ahmad A, Bao B, Philip PA, Sarkar FH. Expression of microRNAs: potential molecular link between obesity, diabetes and cancer. Obes Rev. 2011;12(12):1050–62.
161. Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72(5–6):397–402.
162. Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene. 2009;28(10):1385–92.
163. Clape C, Fritz V, Henriquet C, Apparailly F, Fernandez PL, Iborra F, et al. miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice. PLoS One. 2009;4(10):e7542.
164. Liu L, Yu X, Guo X, Tian Z, Su M, Long Y, et al. miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep. 2012;5(3):753–60.
165. Meerson A, Traurig M, Ossowski V, Fleming JM, Mullins M, Baier LJ. Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia. 2013;56(9):1971–9.
166. Sun T, Wang X, He HH, Sweeney CJ, Liu SX, Brown M, et al. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene. 2014;33(21):2790–800.
167. Kawaguchi T, Komatsu S, Ichikawa D, Morimura R, Tsujiura M, Konishi H, et al. Clinical impact of circulating miR-221 in plasma of patients with pancreatic cancer. Br J Cancer. 2013;108(2):361–9.
168. Di Martino MT, Gulla A, Cantafio ME, Lionetti M, Leone E, Amodio N, et al. In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma. Oncotarget. 2013;4(2):242–55.
169. Roscigno G, Quintavalle C, Donnarumma E, Puoti I, Diaz-Lagares A, Iaboni M, et al. MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b. Oncotarget. 2016;7(1):580–92.
170. Hwang MS, Yu N, Stinson SY, Yue P, Newman RJ, Allan BB, et al. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS One. 2013;8(6):e66502.
171. + levels and SIRT1 activity by directly targeting NAMPT. Aging Cell. 2013;12(6):1062–72.
172. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2015;125(3):1362.
173. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, et al. TGF-b-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22(3):291–303.
174. Li L, Yuan L, Luo J, Gao J, Guo J, Xie X. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin Exp Med. 2013;13(2):109–17.
175. Morimoto LM, White E, Chen Z, Chlebowski RT, Hays J, Kuller L, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13(8):741–51.
176. Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23(38):6365–78.
177. Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun. 2006;345(1):271–9.
178. Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev. 2004;5(3):153–65.
179. Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab. 1993;77(6):1622–8.
180. Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst. 2002;94(22):1704–11.
181. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6.
182. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-a expression. Diabetes. 2003;52(7):1779–85.
183. Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, OY F, et al. Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett. 2006;237(1):109–14.
184. Tan A, Dang Y, Chen G, Mo Z. Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications. Int J Clin Exp Pathol. 2015;8(10):13405–10.
185. da Cunha PA, de LK CB, AF S, Kubelka C, MC R, BL F, et al. Interaction between obesity-related genes, FTO and MC4R, associated to an increase of breast cancer risk. Mol Biol Rep. 2013;40(12):6657–64.
186. Ko EM, Walter P, Clark L, Jackson A, Franasiak J, Bolac C, et al. The complex triad of obesity, diabetes and race in type I and II endometrial cancers: prevalence and prognostic significance. Gynecol Oncol. 2014;133(1):28–32.
187. Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer Sweden. Cancer Causes Control. 2000;11(2):185–92.
188. Secord AA, Hasselblad V, Von Gruenigen VE, Gehrig PA, Modesitt SC, Bae-Jump V, et al. Body mass index and mortality in endometrial cancer: a systematic review and meta-analysis. Gynecol Oncol. 2016;140(1):184–90.
189. Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Levitt J, et al. Obesity and age at diagnosis of endometrial cancer. Obstet Gynecol. 2014;124(2 Pt 1):300–6.
190. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomark Prev. 2002;11(12):1531–43.
191. Lurie G, Gaudet MM, Spurdle AB, Carney ME, Wilkens LR, Yang HP, et al. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PLoS One. 2011;6(2):e16756.
192. Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31(20):2607–18.
193. Macleod LC, Hotaling JM, Wright JL, Davenport MT, Gore JL, Harper J, et al. Risk factors for renal cell carcinoma in the VITAL study. J Urol. 2013;190(5):1657–61.
194. Chow WH, Gridley G, JF Jr F, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med. 2000;343(18):1305–11.
195. Sanfilippo KM, McTigue KM, Fidler CJ, Neaton JD, Chang Y, Fried LF, et al. Hypertension and obesity and the risk of kidney cancer in 2 large cohorts of US men and women. Hypertension. 2014;63(5):934–41.
196. Kanasaki K, Kitada M, Kanasaki M, Koya D. The biological consequence of obesity on the kidney. Nephrol Dial Transplant. 2013;28(Suppl 4):iv1–7.
197. Keaney Jr JF, Larson MG, Vasan RS, Wilson PW, Lipinska I, Corey D, et al. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham study. Arterioscler Thromb Vasc Biol. 2003;23(3):434–9.
198. Hakimi AA, Furberg H, Zabor EC, Jacobsen A, Schultz N, Ciriello G, et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J Natl Cancer Inst. 2013;105(24):1862–70.
199. Han JM, Kim TY, Jeon MJ, Yim JH, Kim WG, Song DE, et al. Obesity is a risk factor for thyroid cancer in a large, ultrasonographically screened population. Eur J Endocrinol. 2013;168(6):879–86.
200. Engeland A, Tretli S, Akslen LA, Bjorge T. Body size and thyroid cancer in two million Norwegian men and women. Br J Cancer. 2006;95(3):366–70.
201. Zhao ZG, Guo XG, Ba CX, Wang W, Yang YY, Wang J, et al. Overweight, obesity and thyroid cancer risk: a meta-analysis of cohort studies. J Int Med Res. 2012;40(6):2041–50.
202. Paes JE, Hua K, Nagy R, Kloos RT, Jarjoura D, Ringel MD. The relationship between body mass index and thyroid cancer pathology features and outcomes: a clinicopathological cohort study. J Clin Endocrinol Metab. 2010;95(9):4244–50.
203. Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97(7):1005–8.
204. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 2006;35(3):204–14.
205. Park EJ, Lee JH, GY Y, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208.
206. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101.
207. Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA. 2001;286(8):921–9.
208. Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. cohort. Cancer Epidemiol Biomark Prev. 2005;14(2):459–66.
209. Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomark Prev. 1995;4(2):85–92.
210. Veugelers PJ, Porter GA, Guernsey DL, Casson AG. Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma. Dis Esophagus. 2006;19(5):321–8.
211. Moghaddam AA, Woodward M, Huxley R. Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomark Prev. 2007;16(12):2533–47.
212. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122(5):327–34.
213. Terry PD, Miller AB, Rohan TE. Obesity and colorectal cancer risk in women. Gut. 2002;51(2):191–4.
214. Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer. 2007;96(9):1457–61.
215. Gong Z, Neuhouser ML, Goodman PJ, Albanes D, Chi C, Hsing AW, et al. Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer Epidemiol Biomark Prev. 2006;15(10):1977–83.
216. Lewis SJ, Murad A, Chen L, Davey Smith G, Donovan J, Palmer T, et al. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS One. 2010;5(10):e13485.
217. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res. 2006;12(5):1447–53.
218. Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles JM, et al. Leptin expression in colorectal and breast cancer patients. Int J Mol Med. 2000;5(4):421–6.
219. Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 2004; 10(13):4325–4331.
220. Saglam K, Aydur E, Yilmaz M, Goktas S. Leptin influences cellular differentiation and progression in prostate cancer. J Urol. 2003;169(4):1308–11.
221. Stattin P, Soderberg S, Hallmans G, Bylund A, Kaaks R, Stenman UH, et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J Clin Endocrinol Metab. 2001;86(3):1341–5.
222. Petridou E, Belechri M, Dessypris N, Koukoulomatis P, Diakomanolis E, Spanos E, et al. Leptin and body mass index in relation to endometrial cancer risk. Ann Nutr Metab. 2002;46(3–4):147–51.
223. Somasundar P, AK Y, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res. 2003;113(1):50–5.
224. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279(47):48487–90.
225. Hak AE, Stehouwer CD, Bots ML, Polderman KH, Schalkwijk CG, Westendorp IC, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;19(8):1986–91.
226. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282(22):2131–5.
227. Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation. 2002;105(5):564–9.
228. McLaughlin T, Abbasi F, Lamendola C, Liang L, Reaven G, Schaaf P, et al. Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation. 2002;106(23):2908–12.
229. Khaodhiar L, Ling PR, Blackburn GL, Bistrian BR. Serum levels of interleukin-6 and C-reactive protein correlate with body mass index across the broad range of obesity. J Parenter Enter Nutr. 2004;28(6):410–5.
230. Volkova E, Willis JA, Wells JE, Robinson BA, Dachs GU, Currie MJ. Association of angiopoietin-2, C-reactive protein and markers of obesity and insulin resistance with survival outcome in colorectal cancer. Br J Cancer. 2011;104(1):51–9.
231. Simone V, D’Avenia M, Argentiero A, Felici C, Rizzo FM, De Pergola G, et al. Obesity and breast cancer: molecular interconnections and potential clinical applications. Oncologist. 2016. doi:10.1634/theoncologist.2015-0351.
232. Miranda VC, Barroso-Sousa R, Glasberg J, Riechelmann RP. Exploring the role of metformin in anticancer treatments: a systematic review. Drugs Today. 2014;50(9):623–40.
233. Noto H, Goto A, Tsujimoto T, Osame K, Noda M. Latest insights into the risk of cancer in diabetes. J Diabetes Investig. 2013;4(3):225–32.
234. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–302.
235. Pavone ME, Malpani SS, Dyson M, Kim JJ, Bulun SE. Fenretinide: a potential treatment for endometriosis. Reprod Sci. 2016. doi:10.1177/1933719116632920.
236. Busada JT, Niedenberger BA, Velte EK, Keiper BD, Geyer CB. Mammalian target of rapamycin complex 1 (mTORC1) is required for mouse spermatogonial differentiation in vivo. Dev Biol 2015; 407(1):90–102.
237. McIlroy GD, Tammireddy SR, Maskrey BH, Grant L, Doherty MK, Watson DG, et al. Fenretinide mediated retinoic acid receptor signalling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function and nutrient stress signalling in adipocytes and adipose tissue. Biochem Pharmacol. 2016;100:86–97.
238. Kant S, Kumar A, Singh SM. Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma: implication of reconstituted tumor microenvironment and multidrug resistance phenotype. Biochim Biophys Acta. 2014;1840(1):294–302.
239. Hill TK, Davis AL, Wheeler FB, Kelkar SS, Freund EC, Lowther WT, et al. Development of a self-assembled nanoparticle formulation of orlistat, Nano-ORL, with increased cytotoxicity against human tumor cell lines. Mol Pharm. 2016;13(3):720–8.
240. Bhargava-Shah A, Foygel K, Devulapally R, Paulmurugan R. Orlistat and antisense-miRNA-loaded PLGA-PEG nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine. 2016;11(3):235–47.