Deleted in Breast Cancer 1 Limits Adipose Tissue Fat Accumulation and Plays a Key Role in the Development of Metabolic Syndrome Phenotype

Diabetes - Tập 64 Số 1 - Trang 12-22 - 2015
Carlos Escande1,2,3, Verónica Nin1,3, Tamar Pirtskhalava3, Claudia C.S. Chini1,3, Tamar Tchkonia3, James L. Kirkland3, Eduardo N. Chini1,3
1Department of Anesthesiology, Mayo Clinic, Rochester, MN
2Institut Pasteur Montevideo, Montevideo, Uruguay
3Kogod Aging Center, Mayo Clinic, Rochester, MN

Tóm tắt

Obesity is often regarded as the primary cause of metabolic syndrome. However, many lines of evidence suggest that obesity may develop as a protective mechanism against tissue damage during caloric surplus and that it is only when the maximum fat accumulation capacity is reached and fatty acid spillover occurs into to peripheral tissues that metabolic diseases develop. In this regard, identifying the molecular mechanisms that modulate adipocyte fat accumulation and fatty acid spillover is imperative. Here we identify the deleted in breast cancer 1 (DBC1) protein as a key regulator of fat storage capacity of adipocytes. We found that knockout (KO) of DBC1 facilitated fat cell differentiation and lipid accumulation and increased fat storage capacity of adipocytes in vitro and in vivo. This effect resulted in a “healthy obesity” phenotype. DBC1 KO mice fed a high-fat diet, although obese, remained insulin sensitive, had lower free fatty acid in plasma, were protected against atherosclerosis and liver steatosis, and lived longer. We propose that DBC1 is part of the molecular machinery that regulates fat storage capacity in adipocytes and participates in the “turn-off” switch that limits adipocyte fat accumulation and leads to fat spillover into peripheral tissues, leading to the deleterious effects of caloric surplus.

Từ khóa


Tài liệu tham khảo

Flegal, 2007, Cause-specific excess deaths associated with underweight, overweight, and obesity, JAMA, 298, 2028, 10.1001/jama.298.17.2028

National Institutes of Health, 2004, Strategic Plan for NIH Obesity Research

Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell, 9, 667, 10.1111/j.1474-9726.2010.00608.x

Unger, 2010, Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity, Trends Endocrinol Metab, 21, 345, 10.1016/j.tem.2010.01.009

Wang, 2008, Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome, Proc Natl Acad Sci U S A, 105, 6139, 10.1073/pnas.0801981105

Listenberger, 2003, Triglyceride accumulation protects against fatty acid-induced lipotoxicity, Proc Natl Acad Sci U S A, 100, 3077, 10.1073/pnas.0630588100

Almandoz, 2013, Spillover of Fatty acids during dietary fat storage in type 2 diabetes: relationship to body fat depots and effects of weight loss, Diabetes, 62, 1897, 10.2337/db12-1407

Asterholm, 2007, Mouse models of lipodystrophy key reagents for the understanding of the metabolic syndrome, Drug Discov Today Dis Models, 4, 17, 10.1016/j.ddmod.2007.10.003

Savage, 2009, Mouse models of inherited lipodystrophy, Dis Model Mech, 2, 554, 10.1242/dmm.002907

Kim, 2007, Obesity-associated improvements in metabolic profile through expansion of adipose tissue, J Clin Invest, 117, 2621, 10.1172/JCI31021

Franckhauser, 2002, Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance, Diabetes, 51, 624, 10.2337/diabetes.51.3.624

Wildman, 2009, Healthy obesity, Curr Opin Clin Nutr Metab Care, 12, 438, 10.1097/MCO.0b013e32832c6db7

Naukkarinen, 2014, Characterising metabolically healthy obesity in weight-discordant monozygotic twins, Diabetologia, 57, 167, 10.1007/s00125-013-3066-y

Kim, 2008, DBC1 is a negative regulator of SIRT1, Nature, 451, 583, 10.1038/nature06500

Escande, 2010, Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice, J Clin Invest, 120, 545, 10.1172/JCI39319

Zhao, 2008, Negative regulation of the deacetylase SIRT1 by DBC1, Nature, 451, 587, 10.1038/nature06515

Chini, 2010, HDAC3 is negatively regulated by the nuclear protein DBC1, J Biol Chem, 285, 40830, 10.1074/jbc.M110.153270

Chini, 2013, DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα, Biochem J, 451, 453, 10.1042/BJ20121085

Trauernicht, 2007, Modulation of estrogen receptor alpha protein level and survival function by DBC-1, Mol Endocrinol, 21, 1526, 10.1210/me.2007-0064

Koyama, 2010, Repression of estrogen receptor beta function by putative tumor suppressor DBC1, Biochem Biophys Res Commun, 392, 357, 10.1016/j.bbrc.2010.01.025

Hiraike, 2010, Identification of DBC1 as a transcriptional repressor for BRCA1, Br J Cancer, 102, 1061, 10.1038/sj.bjc.6605577

Li, 2009, Inhibition of SUV39H1 methyltransferase activity by DBC1, J Biol Chem, 284, 10361, 10.1074/jbc.M900956200

Park, 2013, Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-kappaB, Apoptosis, 18, 649, 10.1007/s10495-013-0847-1

Vaughan, 1962, The production and release of glycerol by adipose tissue incubated in vitro, J Biol Chem, 237, 3354, 10.1016/S0021-9258(19)70821-7

Chalkiadaki, 2012, High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction, Cell Metab, 16, 180, 10.1016/j.cmet.2012.07.003

Donkor, 2008, Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men, J Clin Endocrinol Metab, 93, 233, 10.1210/jc.2007-1535

Ohman, 2008, Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice, Circulation, 117, 798, 10.1161/CIRCULATIONAHA.107.717595

Öhman, 2011, Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice, Atherosclerosis, 219, 33, 10.1016/j.atherosclerosis.2011.07.012

Chiba, 2003, VLDL induces adipocyte differentiation in ApoE-dependent manner, Arterioscler Thromb Vasc Biol, 23, 1423, 10.1161/01.ATV.0000085040.58340.36

Nin, 2014, Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis, J Biol Chem, 289, 5518, 10.1074/jbc.M113.512913

Stancu, 2012, Dual role of lipoproteins in endothelial cell dysfunction in atherosclerosis, Cell Tissue Res, 349, 433, 10.1007/s00441-012-1437-1

Lu, 2013, Palmitate induces apoptosis in mouse aortic endothelial cells and endothelial dysfunction in mice fed high-calorie and high-cholesterol diets, Life Sci, 92, 1165, 10.1016/j.lfs.2013.05.002

Appleton, 2013, Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study, Diabetes Care, 36, 2388, 10.2337/dc12-1971

Escande, Deleted in Breast Cancer 1 regulates cellular senescence during obesity, Aging Cell

Bordone, 2007, SIRT1 transgenic mice show phenotypes resembling calorie restriction, Aging Cell, 6, 759, 10.1111/j.1474-9726.2007.00335.x

Pfluger, 2008, Sirt1 protects against high-fat diet-induced metabolic damage, Proc Natl Acad Sci U S A, 105, 9793, 10.1073/pnas.0802917105

Caron, 2014, The SIRT1 deacetylase protects mice against the symptoms of metabolic syndrome, FASEB J, 10.1096/fj.13-243568

Hallakou, 1997, Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat, Diabetes, 46, 1393, 10.2337/diabetes.46.9.1393

Miyazaki, 2001, Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients, Diabetologia, 44, 2210, 10.1007/s001250100031

Qiang, 2012, Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ, Cell, 150, 620, 10.1016/j.cell.2012.06.027

Thông tin
Thông tin xuất bản

Diabetes

Tập 64 Số 1

12-22

Thông tin tác giả