Long-term effect of early postnatal overnutrition on insulin resistance and serum fatty acid profiles in male rats

Lipids in Health and Disease

Wei Cai⁴  Zhong-Yi Yu³  Fei Liang²  Jian-Hua Sun²  Yi-Qun Jia¹  Jia Jia⁵  Fei Bei⁴ 

[1] Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China;Department of Neonatology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China;School of Public Health, Physiotherapy & Sports Science, University College Dublin, Belfield, Dublin 4, Ireland;Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China;Shanghai Center for Bioformation Technology, 1278 Keyuan Road, Shanghai 201203, China

关键词: Fatty acid;    Glucose transporter 4;    Insulin receptor substrate 1;    Insulin resistance;    Early overnutrition;   

Others  :  1233282
DOI  :  10.1186/s12944-015-0094-2

 received in 2015-04-20, accepted in 2015-08-14,  发布年份 2015

【 摘 要 】

Background

Increasing evidence suggests that overnutrition during the early postnatal period, a critical window of development, increases the risk of adult-onset obesity and insulin resistance. In this study, we investigated the impact of overnutrition during the suckling period on body weight, serum biochemistry and serum fatty acid metabolomics in male rats.

Methods

Rats raised in small litters (SL, 3 pups/dam) and normal litters (NL, 10 pups/dam) were used to model early postnatal overnutrition and control, respectively. Serum glucose, triglyceride, high-density lipoprotein-cholesterol, free fatty acid, insulin and leptin concentrations were assayed using standard biochemical techniques. Serum fatty acids were identified and quantified using a gas chromatography–mass spectrometry-based metabolomic approach. mRNA and protein levels of key components of the insulin receptor signaling pathway were measured in epididymal fat and gastrocnemius muscle by quantitative PCR and western blotting.

Results

SL rats were 37.3 % and 15.1 % heavier than NL rats at weaning and 16-weeks-old, respectively. They had increased visceral fat mass, adult-onset insulin resistance and glucose intolerance as well as elevated serum levels of free fatty acids and triglycerides. All detectable fatty acids were elevated in the serum of SL pups at weaning compared to NL controls, and significant increases in the levels of four fatty acids (palmitic acid, palmitoleic acid, oleic acid and arachidonic acid) persisted into adulthood. Moreover, a significantly positive correlation was identified between an insulin resistance index (HOMA-IR) and concentrations of myristic, palmitic, palmitoleic and oleic acid in serum at postnatal 16 weeks. Early postnatal overnutrition also resulted in a significant downregulation of insulin receptor substrate-1 (Irs-1), protein kinase B (Akt2) and glucose transporter 4 (Glut4) at the protein level in epididymal fat of SL rats at 16 weeks, accompanied by decreased mRNA levels for Irs-1 and Glut4. In gastrocnemius muscle, Akt2 and Glut4 mRNA and Glut4 protein levels were significantly decreased in SL rats.

Conclusions

This study demonstrates that early postnatal overnutrition can have long-lasting effects on body weight and serum fatty acid profiles and can lead to impaired insulin signaling pathway in visceral white adipose tissue and skeletal muscle, which may play a major role in IR.

【 授权许可】

   
2015 Bei et al.

【 图 表 】

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【 参考文献 】

• [1]Xu Y, Wang L, He J, Bi Y, Li M, Wang T et al.. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310:948-59.
• [2]Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes. 1995; 44:369-74.
• [3]Toschke AM, Grote V, Koletzko B, von Kries R. Identifying children at high risk for overweight at school entry by weight gain during the first 2 years. Arch Pediatr Adolesc Med. 2004; 158:449-52.
• [4]Patel MS, Srinivasan M. Metabolic programming due to alterations in nutrition in the immediate postnatal period. J Nutr. 2010; 140:658-61.
• [5]Taveras EM, Rifas-Shiman SL, Sherry B, Oken E, Haines J, Kleinman K et al.. Crossing growth percentiles in infancy and risk of obesity in childhood. Arch Pediatr Adolesc Med. 2011; 165:993-8.
• [6]Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W et al.. Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res. 1999; 836:146-55.
• [7]Cunha AC, Pereira RO, Pereira MJ, Soares Vde M, Martins MR, Teixeira MT et al.. Long-term effects of overfeeding during lactation on insulin secretion--the role of GLUT-2. J Nutr Biochem. 2009; 20:435-42.
• [8]Conceicao EP, Franco JG, Oliveira E, Resende AC, Amaral TA, Peixoto-Silva N et al.. Oxidative stress programming in a rat model of postnatal early overnutrition--role of insulin resistance. J Nutr Biochem. 2013; 24:81-7.
• [9]Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414:799-806.
• [10]Rossetti L, Stenbit AE, Chen W, Hu M, Barzilai N, Katz EB et al.. Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene. J Clin Invest. 1997; 100:1831-9.
• [11]Li J, Houseknecht KL, Stenbit AE, Katz EB, Charron MJ. Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. FASEB J. 2000; 14:1117-25.
• [12]Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007; 5:237-52.
• [13]Hodge AM, English DR, O’Dea K, Sinclair AJ, Makrides M, Gibson RA et al.. Plasma phospholipid and dietary fatty acids as predictors of type 2 diabetes: interpreting the role of linoleic acid. Am J Clin Nutr. 2007; 86:189-97.
• [14]Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS et al.. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr. 2010; 92:1350-8.
• [15]Kusunoki M, Tsutsumi K, Nakayama M, Kurokawa T, Nakamura T, Ogawa H et al.. Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus. J Med Invest. 2007; 54:243-7.
• [16]Friedrich N. Metabolomics in diabetes research. J Endocrinol. 2012; 215:29-42.
• [17]Kotronen A, Velagapudi VR, Yetukuri L, Westerbacka J, Bergholm R, Ekroos K et al.. Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia. 2009; 52:684-90.
• [18]Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365:1415-28.
• [19]Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D et al.. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999; 48:1270-4.
• [20]Krebs M, Roden M. Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem. 2004; 11:901-8.
• [21]Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012; 15:635-45.
• [22]Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr. 2006; 84:1043-54.
• [23]Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B, Dewey KG. Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: the DARLING Study. Am J Clin Nutr. 1993; 58:152-61.
• [24]Stettler N, Zemel BS, Kumanyika S, Stallings VA. Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics. 2002; 109:194-9.
• [25]Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ. 2000; 320:967-71.
• [26]Plagemann A, Harder T, Schellong K, Schulz S, Stupin JH. Early postnatal life as a critical time window for determination of long-term metabolic health. Best Pract Res Clin Endocrinol Metab. 2012; 26:641-53.
• [27]Liu HW, Mahmood S, Srinivasan M, Smiraglia DJ, Patel MS. Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats. J Nutr Biochem. 2013; 24:1859-69.
• [28]Boullu-Ciocca S, Achard V, Tassistro V, Dutour A, Grino M. Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood. Diabetes. 2008; 57:669-77.
• [29]Fiorotto ML, Burrin DG, Perez M, Reeds PJ. Intake and use of milk nutrients by rat pups suckled in small, medium, or large litters. Am J Physiol. 1991; 260:R1104-13.
• [30]Hou M, Liu Y, Zhu L, Sun B, Guo M, Buren J et al.. Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats. PLoS ONE. 2011; 6: Article ID e25726
• [31]Conceicao EP, Trevenzoli IH, Oliveira E, Franco JG, Carlos AS, Nascimento-Saba CC et al.. Higher white adipocyte area and lower leptin production in adult rats overfed during lactation. Horm Metab Res. 2011; 43:513-6.
• [32]Glavas MM, Kirigiti MA, Xiao XQ, Enriori PJ, Fisher SK, Evans AE et al.. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology. 2010; 151:1598-610.
• [33]Rodrigues AL, de Moura EG, Passos MC, Trevenzoli IH, da Conceicao EP, Bonono IT et al.. Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats. J Nutr Biochem. 2011; 22:109-17.
• [34]Rodrigues AL, de Moura EG, Passos MC, Dutra SC, Lisboa PC. Postnatal early overnutrition changes the leptin signalling pathway in the hypothalamic-pituitary-thyroid axis of young and adult rats. J Physiol. 2009; 587:2647-61.
• [35]Dusserre E, Moulin P, Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta. 2000; 1500:88-96.
• [36]Habbout A, Li N, Rochette L, Vergely C. Postnatal Overfeeding in Rodents by Litter Size Reduction Induces Major Short- and Long-Term Pathophysiological Consequences. J Nutr. 2013; 143:553-62.
• [37]Plagemann A, Roepke K, Harder T, Brunn M, Harder A, Wittrock-Staar M et al.. Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding. J Perinat Med. 2010; 38:393-400.
• [38]Boullu-Ciocca S, Dutour A, Guillaume V, Achard V, Oliver C, Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. Diabetes. 2005; 54:197-203.
• [39]Davidowa H, Plagemann A. Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats. Neuroreport. 2007; 18:521-4.
• [40]Kappeler L, De Magalhaes FC, Leneuve P, Xu J, Brunel N, Chatziantoniou C et al.. Early postnatal nutrition determines somatotropic function in mice. Endocrinology. 2009; 150:314-23.
• [41]Shulman RG, Bloch G, Rothman DL. In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proc Natl Acad Sci U S A. 1995; 92:8535-42.
• [42]Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006; 444:847-53.
• [43]Rodrigues AL, De Souza EP, Da Silva SV, Rodrigues DS, Nascimento AB, Barja-Fidalgo C et al.. Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition. J Endocrinol. 2007; 195:485-94.
• [44]Liu Z, Lim CY, Su MY, Soh SL, Shui G, Wenk MR et al.. Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations. J Endocrinol. 2013; 219:131-43.
• [45]Carvalho E, Jansson PA, Nagaev I, Wenthzel AM, Smith U. Insulin resistance with low cellular IRS-1 expression is also associated with low GLUT4 expression and impaired insulin-stimulated glucose transport. FASEB J. 2001; 15:1101-3.
• [46]Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T et al.. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994; 372:182-6.
• [47]Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB et al.. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001; 292:1728-31.
• [48]Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E et al.. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001; 409:729-33.
• [49]Marin P, Rebuffe-Scrive M, Smith U, Bjorntorp P. Glucose uptake in human adipose tissue. Metabolism. 1987; 36:1154-60.
• [50]Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012; 13:227-32.
• [51]Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012; 148:852-71.
• [52]Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem. 2004; 279:36608-15.
• [53]Van Epps-Fung M, Williford J, Wells A, Hardy RW. Fatty acid-induced insulin resistance in adipocytes. Endocrinology. 1997; 138:4338-45.
• [54]Ishii M, Maeda A, Tani S, Akagawa M. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. Arch Biochem Biophys. 2015; 566:26-35.
• [55]Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3 T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys. 2003; 419:101-9.
• [56]Massao Hirabara S, de Oliveira Carvalho CR, Mendonca JR, Piltcher Haber E, Fernandes LC, Curi R. Palmitate acutely raises glycogen synthesis in rat soleus muscle by a mechanism that requires its metabolization (Randle cycle). FEBS Lett. 2003; 541:109-14.
• [57]Xu F, Tavintharan S, Sum CF, Woon K, Lim SC, Ong CN. Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics. J Clin Endocrinol Metab. 2013; 98:E1060-5.
• [58]Benoit SC, Kemp CJ, Elias CF, Abplanalp W, Herman JP, Migrenne S et al.. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest. 2009; 119:2577-89.
• [59]Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab. 2013; 24:76-84.
• [60]Yuzefovych L, Wilson G, Rachek L. Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab. 2010; 299:E1096-105.
• [61]Roberts LD, Koulman A, Griffin JL. Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2014; 2:65-75.
• [62]Poletto AC, Furuya DT, David-Silva A, Ebersbach-Silva P, Lellis Santos C, Correa-Giannella ML et al.. Oleic and linoleic fatty acids downregulate Slc2a4/GLUT4 expression via NFKB and SREBP1 in skeletal muscle cells. Mol Cell Endocrinol. 2015; 401:65-72.
• [63]Wu M, Wang X, Duan Q, Lu T. Arachidonic acid can significantly prevent early insulin resistance induced by a high-fat diet. Ann Nutr Metab. 2007; 51:270-6.
• [64]Williams ES, Baylin A, Campos H. Adipose tissue arachidonic acid and the metabolic syndrome in Costa Rican adults. Clin Nutr. 2007; 26:474-82.
• [65]Shen S, Sun Q, Liang Z, Cui X, Ren X, Chen H et al.. A prognostic model of triple-negative breast cancer based on miR-27b-3p and node status. PLoS ONE. 2014; 9:e100664.
• [66]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001; 25:402-8.