Abstract
In human health, there is interest in developing specific diets to reduce body weight. These studies are mainly focused on phenotypic changes induced in blood measurements, i.e., triglycerides, HDL, LDL, and insulin, and on physical changes, i.e., body weight and BMI. To evaluate the biological impact of diet interventions, it is very important to investigate the molecular mechanisms driving the diet-induced phenotypic changes in relevant tissues. However, studying these effects in humans is difficult due to ethical concerns in doing interventions and obtaining tissue samples and good animal models are therefore needed. Göttingen minipigs, a small size obesity prone pig breed, have previously been shown to be a useful translational animal model for metabolic studies. In this study, 16 Göttingen minipig males (2-month old) were submitted to 13 weeks of differential diets to investigate the initial stages of diet-induced metabolic changes. Half of them were fed a high-fat/cholesterol, low-carbohydrate (HFLC) diet, and the other half were fed a low- fat/cholesterol, high-carbohydrate (LFHC) diet. After 13 weeks, the HFLC group weighted less and had dyslipidemia compared to the LFHC group. Liver, pancreas, and adipose tissues were collected at slaughter. Gene expression profiling of 83 metabolism-relevant genes was performed using high-throughput qPCR. In total, 41 genes were deregulated in at least one of the five tissues analyzed, with liver being the most drastically affected tissue. The new knowledge gained in this study could potentially be of value for considering direct modulation of gene expression by nutrient content in the diet.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amuzie C, Swart JR, Rogers CS et al (2016) A translational model for diet-related atherosclerosis: effect of statins on hypercholesterolemia and atherosclerosis in a minipig. Toxicol Pathol 44(3):442–449. doi:10.1177/0192623315622304
Assessment SC on HT (2013) Dietary treatment of obesity: A systematic review. Swedish Council on Health Technology Assessment (SBU)
Auguet T, Terra X, Quintero Y et al (2013) Liver lipocalin 2 expression in severely obese women with non alcoholic fatty liver disease. Exp Clin Endocrinol Diabetes 121:119–124. doi:10.1055/s-0032-1331696
Brown M, Goldstein J (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232(4746):34–47
Chatrath H, Vuppalanchi R, Chalasani N (2012) Dyslipidemia in patients with nonalcoholic fatty liver disease. Semin Liver Dis 32:022–029. doi:10.1055/s-0032-1306423
Christoffersen BO, Grand N, Golozoubova V et al (2007) Gender-associated differences in metabolic syndrome-related parameters in Göttingen minipigs. Comp Med 57:493–504
Christoffersen B, Golozoubova V, Pacini G et al (2013) The young Göttingen minipig as a model of childhood and adolescent obesity: influence of diet and gender. Obesity 21:149–158. doi:10.1002/oby.20249
Cirera S (2013) Highly efficient method for isolation of total RNA from adipose tissue. BMC Res Notes 6:472. doi:10.1186/1756-0500-6-472
Cirera S, Jensen MS, Elbrond VS et al (2014) Expression studies of six human obesity-related genes in seven tissues from divergent pig breeds. Anim Genet 45:59–66. doi:10.1111/age.12082
Detjen KM, Brembeck FH, Welzel M et al (2000) Activation of protein kinase Calpha inhibits growth of pancreatic cancer cells via p21(cip)-mediated G(1) arrest. J Cell Sci 113(Pt 17):3025–3035
Eckel RH, Alberti KGMM, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 375:181–183. doi:10.1016/S0140-6736(05)66378-7
Fenech M, El_Sohemy A, Cahill L et al (2011) Nutrigenetics and nutrigenomics: viewpoints on the current status and applications in nutrition research and practice. J Nutrigenet Nutrigenom 4(2):69–89. doi:10.1159/000327772
Ferreira DF, Fiamoncini J, Prist IH et al (2015) Novel role of TLR4 in NAFLD development: modulation of metabolic enzymes expression. Biochim Biophys Acta 1851(10):1353–1359. doi:10.1016/j.bbalip.2015.07.002
Gallego-Escuredo JM, Gómez-Ambrosi J, Catalan V et al (2015) Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes 39:121–129. doi:10.1038/ijo.2014.76
Gomez-Ambrosi J, Catalán V, Diez-Caballero A et al (2003) Gene expression profile of omental adipose tissue in human obesity. FASEB J 18:215–217. doi:10.1096/fj.03-0591fje
Guillerm-Regost C, Louveau I, Sébert SP et al (2006) Cellular and biochemical features of skeletal muscle in obese yucatan minipigs. Obesity 14:1700–1707. doi:10.1038/oby.2006.195
Haagensen AMJ, Klein AB, Ettrup A et al (2013) Cognitive performance of Göttingen minipigs is affected by diet in a spatial hole-board discrimination test. PLoS ONE 8:e79429. doi:10.1371/journal.pone.0079429
Haagensen AMJ, Sørensen DB, Sandøe P et al (2014) High fat, low carbohydrate diet limit fear and aggression in Göttingen minipigs. PLoS ONE 9:e93821. doi:10.1371/journal.pone.0093821
Højland Ipsen D, Tveden-Nyborg P, Lykkesfeldt J (2016) Normal weight dyslipidemia: is it all about the liver? Obesity. doi:10.1002/oby.21443
Holvoet P (2008) Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Verh K Acad Geneeskd Belg 70(3):193–219
Jacobsen MJ, Mentzel CMJ, Olesen AS et al (2016) Altered methylation profile of lymphocytes is concordant with perturbation of lipids metabolism and inflammatory response in obesity. J Diabetes Res. doi:10.1155/2016/8539057
Johansson LE, Danielsson AP, Parikh H et al (2012) Differential gene expression in adipose tissue from obese human subjects during weight loss and weight maintenance. Am J Clin Nutr 96:196–207. doi:10.3945/ajcn.111.020578
Kavazarakis E, Moustaki M, Gourgiotis D et al (2001) Relation of serum leptin levels to lipid profile in healthy children. Metabolism 50:1091–1094
Kristensen T, Fredholm M, Cirera S (2015) Expression study of GLUT4 translocation-related genes in a porcine pre-diabetic model. Mamm Genome 26(11–12):650–657. doi:10.1007/s00335-015-9601-z
Lakshman R, Elks CE, Ong KK (2012) Childhood obesity. Circulation 126:1770–1779. doi:10.1161/CIRCULATIONAHA.111.047738
Lan H, Rabaglia ME, Stoehr JP et al (2003) Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility. Diabetes 52(3):688–700
Lattimer JM, Haub MD (2010) Effects of dietary fiber and its components on metabolic health. Nutrients 2(12):1266–1289. doi:10.3390/nu2121266
Li J, Yu X, Pan W, Unger RH (2002) Gene expression profile of rat adipose tissue at the onset of high-fat-diet obesity. Am J Physiol Endocrinol Metab 282(6):E1334–E1341
Lifshitz F (2008) Obesity in children. J Clin Res Pediatr Endocrinol 1:53–60. doi:10.4008/jcrpe.v1i2.35
Makris A, Foster GD (2011) Dietary approaches to the treatment of obesity. Psychiatr Clin North Am 34:813–827. doi:10.1016/j.psc.2011.08.004
Mentzel CMJC, Alkan F, Keinicke H et al (2016) Joint profiling of miRNAs and mRNAs reveals miRNA mediated gene regulation in the Göttingen minipig obesity model. PLoS ONE 11:e0167285. doi:10.1371/journal.pone.0167285
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765. doi:10.1146/annurev.immunol.19.1.683
Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V et al (2011) Role for PPAR in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J 25:2538–2550. doi:10.1096/fj.10-173716
Newberry EP, Xie Y, Kennedy SM, Luo J, Davidson NO (2006) Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. Hepatology 44(5):1191–1205
Padilla J, Jenkins NT, Lee S, et al (2013) Vascular transcriptional alterations produced by juvenile obesity in Ossabaw swine. Physiol Genom 45(11):434–446
Pyörälä K, Laakso M, Uusitupa M (1987) Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 3(2):463–524
Rødgaard T, Skovgaard K, Moesgaard SG et al (2014) Extensive changes in innate immune gene expression in obese Göttingen minipigs do not lead to changes in concentrations of circulating cytokines and acute phase proteins. Anim Genet 45:67–73. doi:10.1111/age.12090
Samms RJ, Cheng CC, Kharitonenkov A et al (2016) Overexpression of β-Klotho in adipose tissue sensitizes male mice to endogenous FGF21 and provides protection from diet-induced obesity. Endocrinology 157(4):1467–1480. doi:10.1210/en.2015-1722
Sébert SP, Lecannu G, Kozlowski F et al (2005) Childhood obesity and insulin resistance in a Yucatan mini-piglet model: putative roles of IGF-1 and muscle PPARs in adipose tissue activity and development. Int J Obes 29:324–333. doi:10.1038/sj.ijo.0802823
Smith EM, Zhang Y, Baye TM et al (2010) INSIG1 influences obesity-related hypertriglyceridemia in humans. J Lipid Res 51:701–708. doi:10.1194/jlr.M001404
Spurlock ME, Gabler NK (2008) The development of porcine models of obesity and the metabolic syndrome. J Nutr 138:397–402
Thévenod F (2008) Pathophysiology of diabetes mellitus type 2: roles of obesity, insulin resistance and β-cell dysfunction. Diabetes Cancer 19:1–18
Toedebusch RG, Roberts MD, Wells KD et al (2014) Unique transcriptomic signature of omental adipose tissue in Ossabaw swine: a model of childhood obesity. Physiol Genom 46(10):362–375
Tonne JM, Sakuma T, Deeds MC et al (2013) Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy. Dis Model Mech 6:1236–1245. doi:10.1242/dmm.012591
Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339
Trujillo ME, Sullivan S, Harten I et al (2004) Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 89:5577–5582. doi:10.1210/jc.2004-0603
Tveden-Nyborg P, Birck MM, Ipsen DH et al (2016) Diet-induced dyslipidemia leads to nonalcoholic fatty liver disease and oxidative stress in guinea pigs. Transl Res 168:146–160. doi:10.1016/j.trsl.2015.10.001
Videla LA, Pettinelli P (2012) Misregulation of PPAR functioning and its pathogenic consequences associated with nonalcoholic fatty liver disease in human obesity. PPAR Res 2012:14
Wang R, Wang X, Zhuang L (2016) Gene expression profiling reveals key genes and pathways related to the development of non-alcoholic fatty liver disease. Ann Hepatol 15(2):190–199. doi:10.5604/16652681.1193709
Wu D, Shen M, Chu N (2001) Relationship between plasma leptin levels and lipid profiles among school children in Taiwan: The Taipei Children Heart Study. Eur J Epidemiol 17:911–916. doi:10.1023/A:1016280427032
Yao L, Heuser-Baker J, Herlea-Pana O et al (2014). Deficiency in adipocyte chemokine receptor CXCR4 exacerbates obesity and compromises thermoregulatory responses of brown adipose tissue in a mouse model of diet-induced obesity. FASEB J 28(10):4534–4550. doi:10.1096/fj.14-249797
Ye P, Cheah IK, Halliwell B (2013) High fat diets and pathology in the guinea pig. Atherosclerosis or liver damage? Biochim Biophys Acta 1832:355–364. doi:10.1016/j.bbadis.2012.11.008
Yongming P, Zhaowei C, Yichao M et al (2015) Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet. Cardiovasc Diabetol 14:6. doi:10.1186/s12933-014-0165-0
Acknowledgements
We thank Mette Juul Jacobsen for counseling in gene selection, Minna Jakobsen for technical assistance in the qPCR on MxPro platform and Professor Peter Sandøe, principal investigator (PI) in the in vivo study for fundraising and co-supervision. This study was supported by a grant from the Danish Research Council for Independent Research (DFF 1335-00127).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mentzel, C.M.J., Cardoso, T.F., Lex, A.M.J. et al. Fat and carbohydrate content in the diet induces drastic changes in gene expression in young Göttingen minipigs. Mamm Genome 28, 166–175 (2017). https://doi.org/10.1007/s00335-017-9690-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-017-9690-y