Obesity and Cancer: The Oil that Feeds the Flame

Cell Metabolism - Tập 23 - Trang 48-62 - 2016
Joan Font-Burgada1, Beicheng Sun2, Michael Karin1
1Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA
2Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China

Tài liệu tham khảo

Adams, 2013, Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease, Hepatology, 57, 590, 10.1002/hep.26184 Aghajan, 2012, Obesity, autophagy and the pathogenesis of liver and pancreatic cancers, J. Gastroenterol. Hepatol., 27, 10, 10.1111/j.1440-1746.2011.07008.x Aguirre, 2002, Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action, J. Biol. Chem., 277, 1531, 10.1074/jbc.M101521200 Amundadottir, 2009, Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer, Nat. Genet., 41, 986, 10.1038/ng.429 Antuna-Puente, 2008, Adipokines: the missing link between insulin resistance and obesity, Diabetes Metab., 34, 2, 10.1016/j.diabet.2007.09.004 Ascha, 2010, The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis, Hepatology, 51, 1972, 10.1002/hep.23527 Bajaj, 2014, Altered profile of human gut microbiome is associated with cirrhosis and its complications, J. Hepatol., 60, 940, 10.1016/j.jhep.2013.12.019 Bandaru, 2013, The impact of obesity on immune response to infection and vaccine: an insight into plausible mechanisms, Endocrinol. Metab. Syndr., 2, 113 Boraska, 2010, Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes, BMC Med. Genet., 11, 69, 10.1186/1471-2350-11-69 Bosch, 2005, Epidemiology of hepatocellular carcinoma, Clin. Liver Dis., 9, 191, 10.1016/j.cld.2004.12.009 Burska, 2015, Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis, PLoS ONE, 10, e0128889, 10.1371/journal.pone.0128889 Caesar, 2012, Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice, Gut, 61, 1701, 10.1136/gutjnl-2011-301689 Calle, 2004, Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms, Nat. Rev. Cancer, 4, 579, 10.1038/nrc1408 Calle, 2003, Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults, N. Engl. J. Med., 348, 1625, 10.1056/NEJMoa021423 Cani, 2007, Metabolic endotoxemia initiates obesity and insulin resistance, Diabetes, 56, 1761, 10.2337/db06-1491 Catrina, 2004, Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function, Diabetes, 53, 3226, 10.2337/diabetes.53.12.3226 Chalasani, 2010, Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease, Gastroenterology, 139, 1567, 10.1053/j.gastro.2010.07.057 Chassaing, 2015, Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 519, 92, 10.1038/nature14232 Cheung, 1998, An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha, Endocrinology, 139, 4928, 10.1210/endo.139.12.6336 Cho, 2012, The human microbiome: at the interface of health and disease, Nat. Rev. Genet., 13, 260, 10.1038/nrg3182 Clark, 2003, The prevalence and etiology of elevated aminotransferase levels in the United States, Am. J. Gastroenterol., 98, 960, 10.1111/j.1572-0241.2003.07486.x Conde, 2014, An update on leptin as immunomodulator, Expert Rev. Clin. Immunol., 10, 1165, 10.1586/1744666X.2014.942289 Considine, 1996, Serum immunoreactive-leptin concentrations in normal-weight and obese humans, N. Engl. J. Med., 334, 292, 10.1056/NEJM199602013340503 Cox, 2012, Silencing the killers: paracrine immune suppression in pancreatic cancer, Cancer Cell, 21, 715, 10.1016/j.ccr.2012.05.029 Crighton, 2006, DRAM, a p53-induced modulator of autophagy, is critical for apoptosis, Cell, 126, 121, 10.1016/j.cell.2006.05.034 Dalamaga, 2012, The role of adiponectin in cancer: a review of current evidence, Endocr. Rev., 33, 547, 10.1210/er.2011-1015 Dandona, 2004, Inflammation: the link between insulin resistance, obesity and diabetes, Trends Immunol., 25, 4, 10.1016/j.it.2003.10.013 Davila, 2012, The rising incidence of hepatocellular carcinoma in the United States: an update, Gastroenterology, 142, 10.1016/S0016-5085(12)63549-5 Day, 1998, Steatohepatitis: a tale of two “hits”?, Gastroenterology, 114, 842, 10.1016/S0016-5085(98)70599-2 Di Minno, 2012, Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-α blockers, J. Rheumatol., 39, 1042, 10.3899/jrheum.111391 Ehses, 2007, Increased number of islet-associated macrophages in type 2 diabetes, Diabetes, 56, 2356, 10.2337/db06-1650 El-Haschimi, 2000, Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity, J. Clin. Invest., 105, 1827, 10.1172/JCI9842 El-Serag, 2007, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis, Gastroenterology, 132, 2557, 10.1053/j.gastro.2007.04.061 Ellulu, 2014, Epidemiology of obesity in developing countries: challenges and prevention, Global Epidemic Obesity, 2, 10.7243/2052-5966-2-2 Endo, 2011, Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis, Gut, 60, 1363, 10.1136/gut.2010.235754 Evans, 2005, Metformin and reduced risk of cancer in diabetic patients, BMJ, 330, 1304, 10.1136/bmj.38415.708634.F7 Fabbrini, 2010, Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications, Hepatology, 51, 679, 10.1002/hep.23280 Fasshauer, 2015, Adipokines in health and disease, Trends Pharmacol. Sci., 36, 461, 10.1016/j.tips.2015.04.014 Feig, 2012, The pancreas cancer microenvironment, Clin. Cancer Res., 18, 4266, 10.1158/1078-0432.CCR-11-3114 Ferlay, 2015, Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012, Int. J. Cancer, 136, E359, 10.1002/ijc.29210 Feuerer, 2009, Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters, Nat. Med., 15, 930, 10.1038/nm.2002 Flossmann, 2007, Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies, Lancet, 369, 1603, 10.1016/S0140-6736(07)60747-8 Font-Burgada, 2015, Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer, Cell, 162, 766, 10.1016/j.cell.2015.07.026 Franchi, 2012, Sensing and reacting to microbes through the inflammasomes, Nat. Immunol., 13, 325, 10.1038/ni.2231 Frayling, 2007, A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity, Science, 316, 889, 10.1126/science.1141634 Fu, 2011, Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity, Nature, 473, 528, 10.1038/nature09968 Gallistl, 2001, Changes in serum interleukin-6 concentrations in obese children and adolescents during a weight reduction program, Int. J. Obes. Relat. Metab. Disord., 25, 1640, 10.1038/sj.ijo.0801808 Ganeshan, 2014, Metabolic regulation of immune responses, Annu. Rev. Immunol., 32, 609, 10.1146/annurev-immunol-032713-120236 Gialamas, 2011, Serum adiponectin levels and tissue expression of adiponectin receptors are associated with risk, stage, and grade of colorectal cancer, Metabolism, 60, 1530, 10.1016/j.metabol.2011.03.020 Goldfine, 2013, Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial, Ann. Intern. Med., 159, 1, 10.7326/0003-4819-159-1-201307020-00003 Grarup, 2014, Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond, Diabetologia, 57, 1528, 10.1007/s00125-014-3270-4 Grivennikov, 2010, Immunity, inflammation, and cancer, Cell, 140, 883, 10.1016/j.cell.2010.01.025 Grivennikov, 2012, Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth, Nature, 491, 254, 10.1038/nature11465 Gukovskaya, 2012, Autophagy and pancreatitis, Am. J. Physiol. Gastrointest. Liver Physiol., 303, G993, 10.1152/ajpgi.00122.2012 Gukovsky, 2015, Impaired autophagy triggers chronic pancreatitis: lessons from pancreas-specific atg5 knockout mice, Gastroenterology, 148, 501, 10.1053/j.gastro.2015.01.012 Han, 2015, The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1, Nature, 524, 243, 10.1038/nature14557 Haslam, 2005, Obesity, Lancet, 366, 1197, 10.1016/S0140-6736(05)67483-1 He, 2010, Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation, Cancer Cell, 17, 286, 10.1016/j.ccr.2009.12.048 He, 2013, Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling, Cell, 155, 384, 10.1016/j.cell.2013.09.031 Healy, 2015, Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine, J. Hepatol., 62, 599, 10.1016/j.jhep.2014.10.024 Hirosumi, 2002, A central role for JNK in obesity and insulin resistance, Nature, 420, 333, 10.1038/nature01137 Hirsch, 2009, Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission, Cancer Res., 69, 7507, 10.1158/0008-5472.CAN-09-2994 Holmberg, 2013, Hepatitis C in the United States, N. Engl. J. Med., 368, 1859, 10.1056/NEJMp1302973 Holzer, 2011, Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation, Cell, 147, 173, 10.1016/j.cell.2011.08.034 Hotamisligil, 1993, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science, 259, 87, 10.1126/science.7678183 Hruban, 2000, Genetic progression in the pancreatic ducts, Am. J. Pathol., 156, 1821, 10.1016/S0002-9440(10)65054-7 Hummasti, 2010, Endoplasmic reticulum stress and inflammation in obesity and diabetes, Circ. Res., 107, 579, 10.1161/CIRCRESAHA.110.225698 Inami, 2011, Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells, J. Cell Biol., 193, 275, 10.1083/jcb.201102031 Inokuchi-Shimizu, 2014, TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis, J. Clin. Invest., 124, 3566, 10.1172/JCI74068 Irvin, 2011, Genome-wide detection of allele specific copy number variation associated with insulin resistance in African Americans from the HyperGEN study, PLoS ONE, 6, e24052, 10.1371/journal.pone.0024052 Ishikawa, 2006, Subcutaneous fat modulates insulin sensitivity in mice by regulating TNF-alpha expression in visceral fat, Horm. Metab. Res., 38, 631, 10.1055/s-2006-954580 Karin, 2002, NF-kappaB at the crossroads of life and death, Nat. Immunol., 3, 221, 10.1038/ni0302-221 Kars, 2010, Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women, Diabetes, 59, 1899, 10.2337/db10-0308 Kawasaki, 2012, Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue, Sci. Rep., 2, 799, 10.1038/srep00799 Kim, 2009, Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis, Nature, 457, 102, 10.1038/nature07623 Kim, 2011, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1, Nat. Cell Biol., 13, 132, 10.1038/ncb2152 Klover, 2005, Interleukin-6 depletion selectively improves hepatic insulin action in obesity, Endocrinology, 146, 3417, 10.1210/en.2004-1468 Komatsu, 2005, Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice, J. Cell Biol., 169, 425, 10.1083/jcb.200412022 Komatsu, 2007, Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice, Cell, 131, 1149, 10.1016/j.cell.2007.10.035 Komatsu, 2010, The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1, Nat. Cell Biol., 12, 213, 10.1038/ncb2021 Kopp, 2012, Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell, 22, 737, 10.1016/j.ccr.2012.10.025 Lamas, 2002, Obesity and immunocompetence, Eur. J. Clin. Nutr., 56, S42, 10.1038/sj.ejcn.1601484 Lazo, 2013, Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994, Am. J. Epidemiol., 178, 38, 10.1093/aje/kws448 Lee, 2013, Sestrins orchestrate cellular metabolism to attenuate aging, Cell Metab., 18, 792, 10.1016/j.cmet.2013.08.018 Li, 2013, Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice, J. Clin. Invest., 123, 2231, 10.1172/JCI64498 Lim, 2014, The role of the IL-22/IL-22R1 axis in cancer, Cytokine Growth Factor Rev., 25, 257, 10.1016/j.cytogfr.2014.04.005 Lin, 2011, An overview of genetic polymorphisms and pancreatic cancer risk in molecular epidemiologic studies, J. Epidemiol., 21, 2, 10.2188/jea.JE20100090 Ling, 2012, KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma, Cancer Cell, 21, 105, 10.1016/j.ccr.2011.12.006 Liu, 2012, Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer, J. Nutr. Biochem., 23, 1207, 10.1016/j.jnutbio.2011.07.002 Liu, 2014, Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma, J. Hepatol., 61, 75, 10.1016/j.jhep.2014.02.030 Loos, 2008, Common variants near MC4R are associated with fat mass, weight and risk of obesity, Nat. Genet., 40, 768, 10.1038/ng.140 Louis, 2014, The gut microbiota, bacterial metabolites and colorectal cancer, Nat. Rev. Microbiol., 12, 661, 10.1038/nrmicro3344 Lüttges, 1999, Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution, Virchows Arch., 435, 461, 10.1007/s004280050428 Macia, 2006, Impairment of dendritic cell functionality and steady-state number in obese mice, J. Immunol., 177, 5997, 10.4049/jimmunol.177.9.5997 Maeda, 2005, IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis, Cell, 121, 977, 10.1016/j.cell.2005.04.014 Maniati, 2011, Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice, J. Clin. Invest., 121, 4685, 10.1172/JCI45797 Marchesini, 2001, Metformin in non-alcoholic steatohepatitis, Lancet, 358, 893, 10.1016/S0140-6736(01)06042-1 Mareninova, 2009, Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis, J. Clin. Invest., 119, 3340 Marí, 2006, Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis, Cell Metab., 4, 185, 10.1016/j.cmet.2006.07.006 McCullough, 2004, The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease, Clin. Liver Dis., 8, 521, 10.1016/j.cld.2004.04.004 McNelis, 2014, Macrophages, immunity, and metabolic disease, Immunity, 41, 36, 10.1016/j.immuni.2014.05.010 Meerzaman, 2014, Genome-wide transcriptional sequencing identifies novel mutations in metabolic genes in human hepatocellular carcinoma, Cancer Genomics Proteomics, 11, 1 Menon, 2012, Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice, Sci. Signal., 5, ra24, 10.1126/scisignal.2002739 Moon, 2013, Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice, Gut, 62, 561, 10.1136/gutjnl-2012-302092 Moscat, 2012, p62: a versatile multitasker takes on cancer, Trends Biochem. Sci., 37, 230, 10.1016/j.tibs.2012.02.008 Mutoh, 2011, Loss of adiponectin promotes intestinal carcinogenesis in Min and wild-type mice, Gastroenterology, 140, 2000, 10.1053/j.gastro.2011.02.019 Nakagawa, 2014, ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development, Cancer Cell, 26, 331, 10.1016/j.ccr.2014.07.001 Naugler, 2007, Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production, Science, 317, 121, 10.1126/science.1140485 Ng, 2014, 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, 10.1016/S0140-6736(14)60460-8 Nielsen, 2004, Splanchnic lipolysis in human obesity, J. Clin. Invest., 113, 1582, 10.1172/JCI21047 Ogden, 2014, Prevalence of childhood and adult obesity in the United States, 2011-2012, JAMA, 311, 806, 10.1001/jama.2014.732 Otake, 2010, Decreased levels of plasma adiponectin associated with increased risk of colorectal cancer, World J. Gastroenterol., 16, 1252, 10.3748/wjg.v16.i10.1252 Ozcan, 2006, Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes, Science, 313, 1137, 10.1126/science.1128294 Park, 2010, Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression, Cell, 140, 197, 10.1016/j.cell.2009.12.052 Pei, 2014, Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity, Hum. Mol. Genet., 23, 820, 10.1093/hmg/ddt464 Perera, 2015, Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism, Nature, 524, 361, 10.1038/nature14587 Petersen, 2010, A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33, Nat. Genet., 42, 224, 10.1038/ng.522 Petersen, 2010, Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease, N. Engl. J. Med., 362, 1082, 10.1056/NEJMoa0907295 Poullis, 2004, Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk, Cancer Epidemiol. Biomarkers Prev., 13, 279, 10.1158/1055-9965.EPI-03-0160 Qu, 2007, Autophagy gene-dependent clearance of apoptotic cells during embryonic development, Cell, 128, 931, 10.1016/j.cell.2006.12.044 Quinn, 2013, Repositioning metformin for cancer prevention and treatment, Trends Endocrinol. Metab., 24, 469, 10.1016/j.tem.2013.05.004 Rahib, 2014, Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States, Cancer Res., 74, 2913, 10.1158/0008-5472.CAN-14-0155 Reinehr, 2004, Adiponectin before and after weight loss in obese children, J. Clin. Endocrinol. Metab., 89, 3790, 10.1210/jc.2003-031925 Rhim, 2012, EMT and dissemination precede pancreatic tumor formation, Cell, 148, 349, 10.1016/j.cell.2011.11.025 Rocchini, 2002, Childhood obesity and a diabetes epidemic, N. Engl. J. Med., 346, 854, 10.1056/NEJM200203143461112 Roden, 1996, Mechanism of free fatty acid-induced insulin resistance in humans, J. Clin. Invest., 97, 2859, 10.1172/JCI118742 Romeo, 2008, Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease, Nat. Genet., 40, 1461, 10.1038/ng.257 Rosen, 2014, What we talk about when we talk about fat, Cell, 156, 20, 10.1016/j.cell.2013.12.012 Rothwell, 2011, Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials, Lancet, 377, 31, 10.1016/S0140-6736(10)62110-1 Saitoh, 2008, Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production, Nature, 456, 264, 10.1038/nature07383 Schneider, 2014, Liver autophagy: much more than just taking out the trash, Nat. Rev. Gastroenterol. Hepatol., 11, 187, 10.1038/nrgastro.2013.211 Schulz, 2014, High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity, Nature, 514, 508, 10.1038/nature13398 Schwabe, 2013, The microbiome and cancer, Nat. Rev. Cancer, 13, 800, 10.1038/nrc3610 Schwimmer, 2009, Heritability of nonalcoholic fatty liver disease, Gastroenterology, 136, 1585, 10.1053/j.gastro.2009.01.050 Seki, 2009, CCR1 and CCR5 promote hepatic fibrosis in mice, J. Clin. Invest., 119, 1858 Sheridan, 2012, Obesity is associated with impaired immune response to influenza vaccination in humans, Int. J. Obes., 36, 1072, 10.1038/ijo.2011.208 Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J. Clin. Invest., 116, 3015, 10.1172/JCI28898 Solinas, 2006, Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates, Proc. Natl. Acad. Sci. USA, 103, 16454, 10.1073/pnas.0607626103 Solinas, 2007, JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity, Cell Metab., 6, 386, 10.1016/j.cmet.2007.09.011 Solomon, 2011, Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis, JAMA, 305, 2525, 10.1001/jama.2011.878 Sookoian, 2011, Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease, Hepatology, 53, 1883, 10.1002/hep.24283 Speliotes, 2011, Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits, PLoS Genet., 7, e1001324, 10.1371/journal.pgen.1001324 Stanley, 2011, TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome, J. Clin. Endocrinol. Metab., 96, E146, 10.1210/jc.2010-1170 Sugiyama, 2009, Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway, Int. J. Oncol., 34, 339 Takamura, 2011, Autophagy-deficient mice develop multiple liver tumors, Genes Dev., 25, 795, 10.1101/gad.2016211 Tanaka, 2000, T lymphopenia in genetically obese-diabetic Wistar fatty rats: effects of body weight reduction on T cells, Metabolism, 49, 1261, 10.1053/meta.2000.9516 Tang, 2011, Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer, Cancer Epidemiol. Biomarkers Prev., 20, 779, 10.1158/1055-9965.EPI-10-0845 Taniguchi, 2014, IL-6 and related cytokines as the critical lynchpins between inflammation and cancer, Semin. Immunol., 26, 54, 10.1016/j.smim.2014.01.001 Teixeira, 2012, Potential mechanisms for the emerging link between obesity and increased intestinal permeability, Nutr. Res., 32, 637, 10.1016/j.nutres.2012.07.003 Tilg, 2011, Gut microbiome, obesity, and metabolic dysfunction, J. Clin. Invest., 121, 2126, 10.1172/JCI58109 Tremaroli, 2012, Functional interactions between the gut microbiota and host metabolism, Nature, 489, 242, 10.1038/nature11552 Tremaroli, 2015, Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation, Cell Metab., 22, 228, 10.1016/j.cmet.2015.07.009 Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest, Nature, 444, 1027, 10.1038/nature05414 Uddin, 2011, Role of leptin and its receptors in the pathogenesis of thyroid cancer, Int. J. Clin. Exp. Pathol., 4, 637 Umemura, 2014, Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition, Cell Metab., 20, 133, 10.1016/j.cmet.2014.05.001 Upadhyay, 2012, Lymphotoxin regulates commensal responses to enable diet-induced obesity, Nat. Immunol., 13, 947, 10.1038/ni.2403 Uusitupa, 2003, Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study, Diabetes, 52, 2532, 10.2337/diabetes.52.10.2532 Uysal, 1997, Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function, Nature, 389, 610, 10.1038/39335 Vincent, 2011, Pancreatic cancer, Lancet, 378, 607, 10.1016/S0140-6736(10)62307-0 Wang, 2014, Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes, Nature, 514, 237, 10.1038/nature13564 Warburg, 1956, On the origin of cancer cells, Science, 123, 309, 10.1126/science.123.3191.309 Waris, 2002, Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3, Biochem. Pharmacol., 64, 1425, 10.1016/S0006-2952(02)01300-X Watanabe, 2010, The genetics of insulin resistance: Where’s Waldo?, Curr. Diab. Rep., 10, 476, 10.1007/s11892-010-0143-1 Weisberg, 2003, Obesity is associated with macrophage accumulation in adipose tissue, J. Clin. Invest., 112, 1796, 10.1172/JCI200319246 Wen, 2012, Meta-analysis identifies common variants associated with body mass index in east Asians, Nat. Genet., 44, 307, 10.1038/ng.1087 White, 2010, Role of autophagy in suppression of inflammation and cancer, Curr. Opin. Cell Biol., 22, 212, 10.1016/j.ceb.2009.12.008 2004, Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies, Lancet, 363, 157, 10.1016/S0140-6736(03)15268-3 Willer, 2009, Six new loci associated with body mass index highlight a neuronal influence on body weight regulation, Nat. Genet., 41, 25, 10.1038/ng.287 Wiseman, 2008, The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective, Proc. Nutr. Soc., 67, 253, 10.1017/S002966510800712X Wolf, 2014, Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes, Cancer Cell, 26, 549, 10.1016/j.ccell.2014.09.003 Wu, 2012, Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations, Nat. Genet., 44, 62, 10.1038/ng.1020 Xu, 2003, Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance, J. Clin. Invest., 112, 1821, 10.1172/JCI200319451 Xu, 2013, Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation, Cell Metab., 18, 816, 10.1016/j.cmet.2013.11.001 Yamauchi, 2002, Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase, Nat. Med., 8, 1288, 10.1038/nm788 Yan, 2006, Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation, Cancer Res., 66, 11565, 10.1158/0008-5472.CAN-06-2540 Yang, 2008, Interleukin-6 stimulates lipolysis in porcine adipocytes, Endocrine, 33, 261, 10.1007/s12020-008-9085-7 Yang, 2010, Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance, Cell Metab., 11, 467, 10.1016/j.cmet.2010.04.005 Yang, 2015, METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction, Science, 349, 500, 10.1126/science.aaa0079 Yen, 2008, How to live long and prosper: autophagy, mitochondria, and aging, Physiology (Bethesda), 23, 248, 10.1152/physiol.00013.2008 Yoshimoto, 2013, Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome, Nature, 499, 97, 10.1038/nature12347 Zatloukal, 2002, p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases, Am. J. Pathol., 160, 255, 10.1016/S0002-9440(10)64369-6 Zhang, 2002, Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP, Diabetes, 51, 2929, 10.2337/diabetes.51.10.2929 Zhou, 2011, A role for mitochondria in NLRP3 inflammasome activation, Nature, 469, 221, 10.1038/nature09663