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FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.
Qi Q, Kilpeläinen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, Sonestedt E, Chu AY, Renström F, Lin X, Ängquist LH, Huang J, Liu Z, Li Y, Asif Ali M, Xu M, Ahluwalia TS, Boer JM, Chen P, Daimon M, Eriksson J, Perola M, Friedlander Y, Gao YT, Heppe DH, Holloway JW, Houston DK, Kanoni S, Kim YM, Laaksonen MA, Jääskeläinen T, Lee NR, Lehtimäki T, Lemaitre RN, Lu W, Luben RN, Manichaikul A, Männistö S, Marques-Vidal P, Monda KL, Ngwa JS, Perusse L, van Rooij FJ, Xiang YB, Wen W, Wojczynski MK, Zhu J, Borecki IB, Bouchard C, Cai Q, Cooper C, Dedoussis GV, Deloukas P, Ferrucci L, Forouhi NG, Hansen T, Christiansen L, Hofman A, Johansson I, Jørgensen T, Karasawa S, Khaw KT, Kim MK, Kristiansson K, Li H, Lin X, Liu Y, Lohman KK, Long J, Mikkilä V, Mozaffarian D, North K, Pedersen O, Raitakari O, Rissanen H, Tuomilehto J, van der Schouw YT, Uitterlinden AG, Zillikens MC, Franco OH, Shyong Tai E, Ou Shu X, Siscovick DS, Toft U, Verschuren WM, Vollenweider P, Wareham NJ, Witteman JC, Zheng W, Ridker PM, Kang JH, Liang L, Jensen MK, Curhan GC, Pasquale LR, Hunter DJ, Mohlke KL, Uusitupa M, Cupples LA, Rankinen T, Orho-Melander M, Wang T, Chasman DI, Franks PW, Sørensen TI, Hu FB, Loos RJ, Nettleton JA, Qi L
(2014) Hum Mol Genet 23: 6961-72
MeSH Terms: Adult, African Americans, Aged, Alleles, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Asian Continental Ancestry Group, Body Mass Index, Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Female, Gene Frequency, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins
Show Abstract · Added April 3, 2018
FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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MeSH Terms
Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding.
Coate KC, Kraft G, Moore MC, Smith MS, Ramnanan C, Irimia JM, Roach PJ, Farmer B, Neal DW, Williams P, Cherrington AD
(2014) Am J Physiol Endocrinol Metab 307: E151-60
MeSH Terms: Animals, Blood Glucose, Diet, High-Fat, Dietary Carbohydrates, Dietary Fats, Dogs, Fructose, Glucokinase, Glucose, Glycerol, Lactic Acid, Liver, Male, Triglycerides
Show Abstract · Added June 2, 2014
In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.
Copyright © 2014 the American Physiological Society.
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14 MeSH Terms
Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth.
Wang D, Fu L, Ning W, Guo L, Sun X, Dey SK, Chaturvedi R, Wilson KT, DuBois RN
(2014) Proc Natl Acad Sci U S A 111: 7084-9
MeSH Terms: Adenoma, Animals, Cell Communication, Cell Line, Tumor, Colitis, Colorectal Neoplasms, Cyclooxygenase 2, Dextran Sulfate, Dietary Fats, Dinoprostone, Epithelial Cells, Humans, Macrophages, Male, Mice, Mice, Knockout, Monocytes, Receptors, Cytoplasmic and Nuclear
Show Abstract · Added May 27, 2014
Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.
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18 MeSH Terms
Influence of dietary fat type on benzo(a)pyrene [B(a)P] biotransformation in a B(a)P-induced mouse model of colon cancer.
Diggs DL, Myers JN, Banks LD, Niaz MS, Hood DB, Roberts LJ, Ramesh A
(2013) J Nutr Biochem 24: 2051-63
MeSH Terms: Animals, Aryl Hydrocarbon Hydroxylases, Benzo(a)pyrene, Biotransformation, Carcinogens, Chromatography, Thin Layer, Colon, Colonic Neoplasms, Cytochrome P-450 CYP1B1, DNA Adducts, Dietary Fats, Disease Models, Animal, Liver, Male, Mice
Show Abstract · Added March 7, 2014
In the US alone, around 60,000 lives/year are lost due to colon cancer. Diet and environment have been implicated in the development of sporadic colon tumors. The objective of this study was to determine how dietary fat potentiates the development of colon tumors through altered B(a)P biotransformation, using the Adenomatous polyposis coli with Multiple intestinal neoplasia mouse model. Benzo(a)pyrene was administered to mice through tricaprylin, and unsaturated (USF; peanut oil) and saturated (SF; coconut oil) fats at doses of 50 and 100 μg/kg via oral gavage over a 60-day period. Blood, colon, and liver were collected at the end of exposure period. The expression of B(a)P biotransformation enzymes [cytochrome P450 (CYP)1A1, CYP1B1 and glutathione-S-transferase] in liver and colon were assayed at the level of protein, mRNA and activities. Plasma and tissue samples were analyzed by reverse phase high-performance liquid chromatography for B(a)P metabolites. Additionally, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the (32)P-postlabeling method using a thin-layer chromatography system. Benzo(a)pyrene exposure through dietary fat altered its metabolic fate in a dose-dependent manner, with 100 μg/kg dose group registering an elevated expression of B(a)P biotransformation enzymes, and greater concentration of B(a)P metabolites, compared to the 50 μg/kg dose group (P<.05). This effect was more pronounced for SF group compared to USF group (P<.05). These findings establish that SF causes sustained induction of B(a)P biotransformation enzymes and extensive metabolism of this toxicant. As a consequence, B(a)P metabolites were generated to a greater extent in colon and liver, whose concentrations also registered a dose-dependent increase. These metabolites were found to bind with DNA and form B(a)P-DNA adducts, which may have contributed to colon tumors in a subchronic exposure regimen.
© 2013.
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15 MeSH Terms
Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis.
Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK
(2013) J Clin Invest 123: 5061-70
MeSH Terms: Animals, Appetite Depressants, Body Weight, Dietary Fats, Dietary Sucrose, Drug Resistance, Energy Metabolism, Feeding Behavior, Female, Glucagon, Glucose, Homeostasis, Hyperglycemia, Hyperinsulinism, Hyperphagia, Insulin, Insulin Resistance, Insulin Secretion, Male, Mice, Mice, Knockout, Neurons, Obesity, Pro-Opiomelanocortin, Receptor, Serotonin, 5-HT2C, Recombinant Fusion Proteins, Serotonin, Serotonin Receptor Agonists
Show Abstract · Added July 21, 2014
Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.
1 Communities
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28 MeSH Terms
Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice.
Inoue M, Jiang Y, Barnes RH, Tokunaga M, Martinez-Santibañez G, Geletka L, Lumeng CN, Buchner DA, Chun TH
(2013) Endocrinology 154: 4548-59
MeSH Terms: 3T3-L1 Cells, Adipose Tissue, White, Animals, Dietary Fats, Dose-Response Relationship, Drug, Epididymis, Fibrosis, Gene Expression Regulation, Glucose Clamp Technique, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Muscular Diseases, Obesity, Thrombospondin 1, Transcriptome
Show Abstract · Added July 21, 2014
Thrombospondin 1 (THBS1 or TSP-1) is a circulating glycoprotein highly expressed in hypertrophic visceral adipose tissues of humans and mice. High-fat diet (HFD) feeding induces the robust increase of circulating THBS1 in the early stages of HFD challenge. The loss of Thbs1 protects male mice from diet-induced weight gain and adipocyte hypertrophy. Hyperinsulinemic euglycemic clamp study has demonstrated that Thbs1-null mice are protected from HFD-induced insulin resistance. Tissue-specific glucose uptake study has revealed that the insulin-sensitive phenotype of Thbs1-null mice is mostly mediated by skeletal muscles. Further assessments of the muscle phenotype using RNA sequencing, quantitative PCR, and histological studies have demonstrated that Thbs1-null skeletal muscles are protected from the HFD-dependent induction of Col3a1 and Col6a1, coupled with a new collagen deposition. At the same time, the Thbs1-null mice display a better circadian rhythm and higher amplitude of energy expenditure with a browning phenotype in sc adipose tissues. These results suggest that THBS1, which circulates in response to a HFD, may induce insulin resistance and fibrotic tissue damage in skeletal muscles as well as the de-browning of sc adipose tissues in the early stages of a HFD challenge. Our study may shed new light on the pathogenic role played by a circulating extracellular matrix protein in the cross talk between adipose tissues and skeletal muscles during obesity progression.
1 Communities
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19 MeSH Terms
Obesity alters adipose tissue macrophage iron content and tissue iron distribution.
Orr JS, Kennedy A, Anderson-Baucum EK, Webb CD, Fordahl SC, Erikson KM, Zhang Y, Etzerodt A, Moestrup SK, Hasty AH
(2014) Diabetes 63: 421-32
MeSH Terms: Adipose Tissue, Animals, Dietary Fats, Gene Expression Regulation, Iron, Macrophages, Male, Mice, Obesity, Tissue Distribution
Show Abstract · Added January 10, 2014
Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.
1 Communities
2 Members
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10 MeSH Terms
Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue.
Camell C, Smith CW
(2013) PLoS One 8: e75147
MeSH Terms: Adipose Tissue, Animals, Cell Proliferation, Dietary Fats, Unsaturated, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Intercellular Adhesion Molecule-1, Macrophages, Male, Mesentery, Mice, Mice, Inbred C57BL, Oleic Acid, Real-Time Polymerase Chain Reaction
Show Abstract · Added July 21, 2014
Several studies have implicated fatty-acids as inflammatory regulators, suggesting that there may be a direct role for common dietary fatty-acids in regulating innate immune cells. In humans, a single high-fat meal increases systemic cytokines and leukocytes. In mice, short term high-fat feeding increases adipose tissue (AT) leukocytes and alters the inflammatory profile of AT macrophages. We have seen that short term high fat feeding to C57BL/6J male mice increases palmitic and oleic acid within AT depots, but oleic acid increase is highest in the mesenteric AT (MAT). In vitro, oleic acid increases M2 macrophage markers (CD206, MGL1, and ARG1) in a murine macrophage cell line, while addition of palmitic acid is able to inhibit that increase. Three day supplementation of a chow diet, with oleic acid, induced an increase in M2 macrophage markers in the MAT, but not in the epididymal AT. We tested whether increases in M2 macrophages occur during short term ad lib feeding of a high fat diet, containing oleic acid. Experiments revealed two distinct populations of macrophages were altered by a three day high milk-fat diet. One population, phenotypically intermediate for F4/80, showed diet-induced increases in CD206, an anti-inflammatory marker characteristic of M2 macrophages intrinsic to the AT. Evidence for a second population, phenotypically F4/80(HI)CD11b(HI) macrophages, showed increased association with the MAT following short term feeding that is dependent on the adhesion molecule, ICAM-1. Collectively, we have shown that short term feeding of a high-fat diet changes two population of macrophages, and that dietary oleic acid is responsible for increases in M2 macrophage polarization.
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14 MeSH Terms
Parenteral nutrition intravenous fat emulsions product shortage considerations.
A.S.P.E.N. Intravenous Fat Emulsion National Shortage Task Force, Vanek VW, Allen P, Harvey Banchik LP, Bistrian B, Collier S, Driscoll DF, Gura K, Houston DR, Miles J, Mirtallo J, Mogensen KM, Seidner D
(2013) Nutr Clin Pract 28: 528-9
MeSH Terms: Adult, Child, Deficiency Diseases, Dietary Fats, Fat Emulsions, Intravenous, Fatty Acids, Essential, Humans, Infant, Newborn, Parenteral Nutrition, Parenteral Nutrition Solutions, Parenteral Nutrition, Total, Practice Guidelines as Topic
Added September 30, 2015
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12 MeSH Terms
Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver.
Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J
(2013) J Am Heart Assoc 2: e000093
MeSH Terms: Active Transport, Cell Nucleus, Animals, Atherosclerosis, Cell Nucleus, Cell-Penetrating Peptides, Cholesterol, Dietary Fats, Disease Models, Animal, Fatty Liver, Female, Hypercholesterolemia, Liver, Mice, Mice, Transgenic, NF-kappa B, Peptides, Sterol Regulatory Element Binding Proteins, Transcription Factors, Triglycerides
Show Abstract · Added February 11, 2014
BACKGROUND - Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide.
METHODS AND RESULTS - A cell-penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low-density lipoprotein receptor-deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline-treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM-treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress-responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element-binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM-modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia.
CONCLUSIONS - Two-pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.
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19 MeSH Terms