Skip to main content
SpringerLink
Log in

Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

The global incidence of human obesity has more than doubled over the past three decades. An ovine model of obesity was developed to determine effects of maternal obesity and arginine supplementation on maternal, placental, and fetal parameters of growth, health, and well being. One-hundred-twenty days prior to embryo transfer, ewes were fed either ad libitum (n = 10) to induce obesity or 100% National Research Council-recommended nutrient requirements (n = 10) as controls. Embryos from superovulated ewes with normal body condition were transferred to the uterus of control-fed and obese ewes on day 5.5 post-estrus to generate genetically similar singleton pregnancies. Beginning on day 100 of gestation, obese ewes received intravenous administration of saline or l-arginine-HCl three times daily (81 mg arginine/kg body weight/day) to day 125, whereas control-fed ewes received saline. Fetal growth was assessed at necropsy on day 125. Maternal obesity increased (1) percentages of maternal and fetal carcass lipids and (2) concentrations of leptin, insulin, glucose, glutamate, leucine, lysine and threonine in maternal plasma while reducing (1) concentrations of progesterone, glycine and serine in maternal plasma and (2) amniotic and allantoic fluid volumes. Administration of l-arginine to obese ewes increased arginine and ornithine concentrations in maternal and fetal plasma, amniotic fluid volume, protein content in maternal carcass, and fetal brown adipose tissue (+60%), while reducing maternal lipid content and circulating leptin levels. Fetal or placental weight did not differ among treatments. Results indicate that arginine treatment beneficially reduces maternal adiposity and enhances fetal brown adipose tissue development in obese ewes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

BAT:

Brown adipose tissue

cGMP:

Cyclic guanosine monophosphate

DM:

Dry matter

NRC:

National Research Council

WAT:

White adipose tissue

References

  • Aagaard-Tillery KM, Grove K, Bishop J et al (2008) Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41:91–102

    Article  PubMed  CAS  Google Scholar 

  • Alarcon-Aguilar FJ, Almanza-Perez J, Blancas G et al (2008) Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice. Eur J Pharmacol 599:152–158

    Article  PubMed  CAS  Google Scholar 

  • Alexander G (1978) Quantitative development of adipose tissue in foetal sheep. Aust J Biol Sci 31:489–503

    PubMed  CAS  Google Scholar 

  • Appaji Rao N, Ambili M, Jala VR et al (2003) Structure-function relationship in serine hydroxymethyltransferase. Biochim Biophys Acta 1647:24–29

    Article  PubMed  CAS  Google Scholar 

  • Armitage JA, Lakasing L, Taylor PD et al (2005) Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy. J Physiol 565:171–184

    Article  PubMed  CAS  Google Scholar 

  • Asakura H (2004) Fetal and neonatal thermoregulation. J Nippon Med Sch 71:360–370

    Article  CAS  Google Scholar 

  • Bispham J, Gopalakrishnan GS, Dandrea J et al (2003) Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology 144:3575–3585

    Article  PubMed  CAS  Google Scholar 

  • Blachier F, Davila AM, Benamouzig R et al (2011) Channelling of arginine in NO and polyamine pathways in colonocytes and consequences. Front Biosci 16:1331–1343

    Article  PubMed  CAS  Google Scholar 

  • Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359

    Article  PubMed  CAS  Google Scholar 

  • Clarke L, Bryant MJ, Lomax MA et al (1997) Maternal manipulation of brown adipose tissue and liver development in the ovine fetus during late gestation. Br J Nutr 77:871–883

    Article  PubMed  CAS  Google Scholar 

  • Cox J, Williams S, Grove K et al (2009) A maternal high-fat diet is accompanied by alterations in the fetal primate metabolome. Am J Obstet Gynecol 201:e281–e289

    Article  Google Scholar 

  • Cypess AM, Lehman S, Williams G et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517

    Article  PubMed  CAS  Google Scholar 

  • Delavaud C, Bocquier F, Chilliard Y et al (2000) Plasma leptin determination in ruminants: effect of nutritional status and body fatness on plasma leptin concentration assessed by a specific RIA in sheep. J Endocrinol 165:519–526

    Article  PubMed  CAS  Google Scholar 

  • Dunn GA, Bale TL (2009) Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150:4999–5009

    Article  PubMed  CAS  Google Scholar 

  • Eklou-Lawson M, Bernard F, Neveux N et al (2009) Colonic luminal ammonia and portal blood l-glutamine and l-arginine concentrations: a possible link between colon mucosa and liver ureagenesis. Amino Acids 37:751–760

    Article  PubMed  CAS  Google Scholar 

  • Enerback S (2010) Human brown adipose tissue. Cell Metab 11:248–252

    Article  PubMed  Google Scholar 

  • Felig P, Marliss E, Cahill GF Jr (1969) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281:811–816

    Article  PubMed  CAS  Google Scholar 

  • Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    PubMed  CAS  Google Scholar 

  • Ford SP, Zhang L, Zhu M et al (2009) Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. Am J Physiol Regul Integr Comp Physiol 297:R835–R843

    Article  PubMed  CAS  Google Scholar 

  • Fu WJ, Haynes TE, Kohli R et al (2005) Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr 135:714–721

    PubMed  CAS  Google Scholar 

  • Garcia-Macedo R, Sanchez-Munoz F, Almanza-Perez JC et al (2008) Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3-L1 cells. Eur J Pharmacol 587:317–321

    Article  PubMed  CAS  Google Scholar 

  • Gaudiot N, Jaubert AM, Charbonnier E et al (1998) Modulation of white adipose tissue lipolysis by nitric oxide. J Biol Chem 273:13475–13481

    Article  PubMed  CAS  Google Scholar 

  • Geng MM, Li TJ, Kong XF et al (2011) Reduced expression of intestinal N-acetylglutamate synthase in suckling piglets: a novel molecular mechanism for arginine as a nutritionally essential amino acid for neonates. Amino Acids 40:1513–1522

    Article  PubMed  CAS  Google Scholar 

  • Gilbert JS, Nijland MJ (2008) Sex differences in the developmental origins of hypertension and cardiorenal disease. Am J Physiol Regul Integr Comp Physiol 295:R1941–R1952

    Article  PubMed  CAS  Google Scholar 

  • Gopalakrishnan G, Rhind SM, Stephenson T et al (2001) Effect of maternal nutrient restriction at defined periods in early to mid gestation on placento-fetal, kidney and adipose tissue weights at 110 days gestation in sheep. Early Hum Dev 63:58–59

    Google Scholar 

  • Hayashi TT, Baldridge RC, Olmsted PS et al (1964) Purine nucleotide catabolism in the placenta. Am J Obstet Gynecol 88:470–478

    PubMed  CAS  Google Scholar 

  • Holmes E, Loo RL, Stamler J et al (2008) Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 453:396–400

    Article  PubMed  CAS  Google Scholar 

  • Jobgen WS, Fried SK, Fu WJ et al (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 17:571–588

    Article  PubMed  CAS  Google Scholar 

  • Jobgen W, Fu WJ, Gao H et al (2009a) High fat feeding and dietary l-arginine supplementation differentially regulate gene expression in rat white adipose tissue. Amino Acids 37:187–198

    Article  PubMed  CAS  Google Scholar 

  • Jobgen W, Meininger CJ, Jobgen SC et al (2009b) Dietary l-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats. J Nutr 139:230–237

    PubMed  CAS  Google Scholar 

  • Khan IY, Dekou V, Douglas G et al (2005) A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol 288:R127–R133

    Article  PubMed  CAS  Google Scholar 

  • Kohli R, Meininger CJ, Haynes TE et al (2004) Dietary l-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr 134:600–608

    PubMed  CAS  Google Scholar 

  • Kwon H, Spencer TE, Bazer FW et al (2003) Developmental changes of amino acids in ovine fetal fluids. Biol Reprod 68:1813–1820

    Article  PubMed  CAS  Google Scholar 

  • Lassala A, Bazer FW, Cudd TA et al (2009) Intravenous administration of l-citrulline to pregnant ewes is more effective than l-arginine for increasing arginine availability in the fetus. J Nutr 139:660–665

    Article  PubMed  CAS  Google Scholar 

  • Lassala A, Bazer FW, Cudd TA et al (2010) Parenteral administration of l-arginine prevents fetal growth restriction in undernourished ewes. J Nutr 140:1242–1248

    Article  PubMed  CAS  Google Scholar 

  • Le Gouill E, Jimenez M, Binnert C et al (2007) Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation. Diabetes 56:2690–2696

    Article  PubMed  Google Scholar 

  • Li X, Bazer FW, Gao H et al (2009a) Amino acids and gaseous signaling. Amino Acids 37:65–78

    Article  PubMed  Google Scholar 

  • Li P, Kim SW, Li XL et al (2009b) Dietary supplementation with cholesterol and docosahexaenoic acid affects concentrations of amino acids in tissues of young pigs. Amino Acids 37:709–716

    Article  PubMed  Google Scholar 

  • Li X, Rezaei R, Li P et al (2011a) Composition of amino acids in feed ingredients for animal diets. Amino Acids 40:1159–1168

    Article  PubMed  CAS  Google Scholar 

  • Li FN, Yin YL, Tan BE et al (2011b) Leucine nutrition in animals and humans: mTOR signaling and beyond. Amino Acids 41:1185–1193

    Article  PubMed  CAS  Google Scholar 

  • Lucotti P, Setola E, Monti LD et al (2006) Beneficial effects of a long-term oral l-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. Am J Physiol Endocrinol Metab 291:E906–E912

    Article  PubMed  CAS  Google Scholar 

  • March-of-Dimes (2009) PeriStats. http://www.marchofdimes.org

  • McCurdy CE, Bishop JM, Williams SM et al (2009) Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest 119:323–335

    PubMed  CAS  Google Scholar 

  • McKnight JR, Satterfield MC, Jobgen WS et al (2010) Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health. Amino Acids 39:349–357

    Article  PubMed  CAS  Google Scholar 

  • Mendez JD, Balderas F (2001) Regulation of hyperglycemia and dyslipidemia by exogenous l-arginine in diabetic rats. Biochimie 83:453–458

    Article  PubMed  CAS  Google Scholar 

  • Muhlhausler BS, Duffield JA, McMillen IC (2007a) Increased maternal nutrition increases leptin expression in perirenal and subcutaneous adipose tissue in the postnatal lamb. Endocrinology 148:6157–6163

    Article  PubMed  CAS  Google Scholar 

  • Muhlhausler BS, Duffield JA, McMillen IC (2007b) Increased maternal nutrition stimulates peroxisome proliferator activated receptor-gamma, adiponectin, and leptin messenger ribonucleic acid expression in adipose tissue before birth. Endocrinology 148:878–885

    Article  PubMed  CAS  Google Scholar 

  • National Research Council (NRC) (1985) Nutrient requirements of sheep. National Academy Press, Washington, DC

    Google Scholar 

  • Osgerby JC, Gadd TS, Wathes DC (2003) Effect of maternal body condition on placental and fetal growth and the insulin-like growth factor axis in Dorset ewes. Reproduction 125:717–731

    Article  PubMed  CAS  Google Scholar 

  • Petrovic V, Buzadzic B, Korac A et al (2010) NO modulates the molecular basis of rat interscapular brown adipose tissue thermogenesis. Comp Biochem Physiol C Toxicol Pharmacol 152:147–159

    Article  PubMed  Google Scholar 

  • Pfannenberg C, Werner MK, Ripkens S et al (2010) Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 59:1789–1793

    Article  PubMed  CAS  Google Scholar 

  • Power GG (1989) Biology of temperature: the mammalian fetus. J Dev Physiol 12:295–304

    PubMed  CAS  Google Scholar 

  • Saito M, Okamatsu-Ogura Y, Matsushita M et al (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531

    Article  PubMed  CAS  Google Scholar 

  • Samuelsson AM, Matthews PA, Argenton M et al (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51:383–392

    Article  PubMed  CAS  Google Scholar 

  • Satterfield MC, Wu G (2011) Brown adipose tissue growth and development: significance and nutritional regulation. Front Biosci 16:1589–1608

    Article  PubMed  CAS  Google Scholar 

  • Satterfield MC, Bazer FW, Spencer TE (2006) Progesterone regulation of preimplantation conceptus growth and galectin 15 (LGALS15) in the ovine uterus. Biol Reprod 75:289–296

    Article  PubMed  CAS  Google Scholar 

  • Satterfield MC, McKnight JR, Li XL et al (2011a) Nutrition, epigenetics, and vascular function. In: Maulik N (ed) Nutrition, epigenetic mechanisms, and human disease. CRC Press, New York, pp 125–139

    Google Scholar 

  • Satterfield MC, Dunlap KA, Keisler DH et al (2011b) Arginine nutrition and fetal brown adipose tissue development in nutrient-restricted sheep. Amino Acids. doi:10.1007/s00726-011-1168-8

    Google Scholar 

  • Stock MJ, Rothwell NJ (1983) Role of brown adipose tissue thermogenesis in overfeeding: a review. J Royal Soc Med 76:71–73

    CAS  Google Scholar 

  • Stover P, Schirch V (1990) Serine hydroxymethyltransferase catalyzes the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate. J Biol Chem 265:14227–14233

    PubMed  CAS  Google Scholar 

  • Symonds ME, Lomax MA (1992) Maternal and environmental influences on thermoregulation in the neonate. Proc Nutr Soc 51:165–172

    Article  PubMed  CAS  Google Scholar 

  • Symonds ME, Mostyn A, Pearce S et al (2003) Endocrine and nutritional regulation of fetal adipose tissue development. J Endocrinol 179:293–299

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Aoki A, Takimoto T et al (2008) Dietary supplementation of glycine modulates inflammatory response indicators in broiler chickens. Br J Nutr 100:1019–1028

    Article  PubMed  CAS  Google Scholar 

  • Tan B, Yin Y, Liu Z et al (2009) Dietary l-arginine supplementation increases muscle gain and reduces body fat mass in growing-finishing pigs. Amino Acids 37:169–175

    Article  PubMed  CAS  Google Scholar 

  • Tan B, Yin Y, Liu Z et al (2011) Dietary l-arginine supplementation differentially regulates expression of lipid-metabolic genes in porcine adipose tissue and skeletal muscle. J Nutr Biochem 22:441–445

    Article  PubMed  CAS  Google Scholar 

  • Taylor PD, McConnell J, Khan IY et al (2005) Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy. Am J Physiol Regul Integr Comp Physiol 288:R134–R139

    Article  PubMed  CAS  Google Scholar 

  • Thorburn GD (1991) The placenta, prostaglandins and parturition: a review. Reprod Fert Dev 3:277–294

    Article  CAS  Google Scholar 

  • Vernon RG (1986) The growth and metabolism of adipocytes. In: Buttery PJ, Haynes NB, Lindsay DB (eds) Control and manipulation of animal growth. Butterworths, London, pp 67–83

    Google Scholar 

  • Virtanen KA, Lidell ME, Orava J et al (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  PubMed  CAS  Google Scholar 

  • Wallace JM, Milne JS, Aitken RP (2005) The effect of overnourishing singleton-bearing adult ewes on nutrient partitioning to the gravid uterus. Br J Nutr 94:533–539

    Article  PubMed  CAS  Google Scholar 

  • Wang JJ, Wu ZL, Li DF et al (2012) Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal. doi:10.1089/ars.2011.4381

    Google Scholar 

  • Wei J, Carroll RJ, Harden KK et al (2011) Comparisons of treatment means when factors do not interact in two-factorial studies. Amino Acids. doi:10.1007/s00726-011-0924-0

    Google Scholar 

  • Williams CL, Gulli MT, Deckelbaum RJ (2001) Prevention and treatment of childhood obesity. Curr Atheroscler Rep 3:486–497

    Article  PubMed  CAS  Google Scholar 

  • Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17

    Article  PubMed  Google Scholar 

  • Wu G (2010) Functional amino acids in growth, reproduction and health. Adv Nutr 1:31–37

    PubMed  CAS  Google Scholar 

  • Wu G, Meininger CJ (2009) Nitric oxide and vascular insulin resistance. BioFactors 35:21–27

    Article  PubMed  Google Scholar 

  • Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA, Flynn NE et al (1996) Arginine degradation in developing porcine enterocytes. Am J Physiol Gastrointest Liver Physiol 271:G913–G919

    CAS  Google Scholar 

  • Wu G, Davis PK, Flynn NE et al (1997) Endogenous synthesis of arginine plays an important role in maintaining arginine homeostasis in postweaning growing pigs. J Nutr 127:2342–2349

    PubMed  CAS  Google Scholar 

  • Wu G, Ott TL, Knabe DA et al (1999) Amino acid composition of the fetal pig. J Nutr 129:1031–1038

    PubMed  CAS  Google Scholar 

  • Wu G, Collins JK, Perkins-Veazie P et al (2007) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Davis TA et al (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Burghardt RC et al (2011) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40:1053–1063

    Article  PubMed  CAS  Google Scholar 

  • Yoneshiro T, Aita S, Matsushita M et al (2011) Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 19:13–16

    Article  Google Scholar 

  • Zhu MJ, Han B, Tong J et al (2008) AMP-activated protein kinase signalling pathways are down regulated and skeletal muscle development impaired in fetuses of obese, over-nourished sheep. J Physiol 586:2651–2664

    Article  PubMed  CAS  Google Scholar 

  • Zhu MJ, Du M, Nijland MJ et al (2009) Down-regulation of growth signaling pathways linked to a reduced cotyledonary vascularity in placentomes of over-nourished, obese pregnant ewes. Placenta 30:405–410

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Kendrick LeBlanc for assistance with animal husbandry, Xilong Li, Peng Li, Reza Rezai, and Jason McKnight for technical assistance, and the members of the Laboratory for Uterine Biology and Pregnancy for assistance with tissue collection. This work was supported, in part, by National Institutes of Health 1R21 HD049449 and National Research Initiative Competitive Grants from the Animal Growth & Nutrient Utilization Program (2009-35206-05211) of the USDA National Institute of Food and Agriculture.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

    M. Carey Satterfield, Kathrin A. Dunlap, Fuller W. Bazer & Guoyao Wu

  2. Division of Animal Sciences, University of Missouri, Columbia, MO, 65211, USA

    Duane H. Keisler

Authors
  1. M. Carey Satterfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathrin A. Dunlap
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Duane H. Keisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fuller W. Bazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guoyao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guoyao Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carey Satterfield, M., Dunlap, K.A., Keisler, D.H. et al. Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep. Amino Acids 43, 1593–1603 (2012). https://doi.org/10.1007/s00726-012-1235-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-012-1235-9

Keywords

Search

Navigation