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Lipids

, Volume 52, Issue 9, pp 771–780 | Cite as

Nutrient Restriction Increases Circulating and Hepatic Ceramide in Dairy Cows Displaying Impaired Insulin Tolerance

  • Amanda N. Davis
  • J. L. Clegg
  • C. A. Perry
  • J. W. McFaddenEmail author
Original Article

Abstract

The progression of insulin resistance in dairy cows represents a maternal adaptation to support milk production during heightened energy demand; however, excessive adipose tissue lipolysis can develop. In diabetic non-ruminants, the mechanisms that mediate insulin resistance involve the sphingolipid ceramide. We tested the hypothesis that ceramide accumulates in dairy cows experiencing lipolysis and insulin resistance. Nine dairy cows were utilized in a replicated 3 × 3 Latin square design. Cows were ad libitum fed, nutrient-restricted (NR), or NR with nicotinic acid (NA; 5 mg of NA/h per kg BW; delivered i.v.) for 34 h. When provided access, cows were ad libitum fed a mixed ration of grass hay and ground corn to meet requirements. Intake for NR cows was limited to vitamins and minerals. Nicotinic acid was administered to suppress lipolysis. Saline was infused in cows not provided NA. At 32 and 33 h of treatment, a liver biopsy and insulin tolerance test were performed, respectively. Samples were analyzed using colorimetry, immunoassay, and mass spectrometry. Nutrient restriction increased serum fatty acids and ceramide levels, and impaired insulin sensitivity; however, NA infusion was unable to prevent these responses. We also show that NR increases hepatic ceramide accumulation, a response that was positively associated with serum ceramide supply. Our data demonstrate that circulating and hepatic 24:0-Cer are inversely associated with systemic insulin tolerance, an effect not observed for the 16:0 moiety. In conclusion, our results suggest that ceramide accrual represents a metabolic adaptation to nutrient restriction and impaired insulin action in dairy cows.

Keywords

Ceramides Hepatic lipid metabolism Hyperlipidemia 

Abbreviations

AUC

Area under the curve

BW

Body weight

Cer

Ceramide

CR

Clearance rate

FFA

Unesterified fatty acids

ITT

Insulin tolerance test

NA

Nicotinic acid

NR

Nutrient-restricted

PDE3B

Phosphodiesterase 3B

SPT

Serine palmitoyltransferase

Notes

Acknowledgements

This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2014-67016-21611 from the USDA National Institute of Food and Agriculture and the West Virginia University Ruby Distinguished Doctoral Fellows Program. We recognize Protea Biosciences (Morgantown, WV) for assisting with the mass spectrometry analysis and Vetagro, S.p.A. (Reggio Emilia, Italy) for supplying the NA. We also gratefully acknowledge Alice Mathews, J. Eduardo Rico, Sina Saed Samii, Yu Zang, and the farm staff from West Virginia University for their technical assistance.

References

  1. 1.
    Bell AW, Bauman DE (1997) Adaptations of glucose metabolism during pregnancy and lactation. J Mammary Gland Biol Neoplasia 2:265–278CrossRefGoogle Scholar
  2. 2.
    McNamara JP, Hillers JK (1986) Adaptations in lipid metabolism of bovine adipose tissue in lactogenesis and lactation. J Lipid Res 27:150–157PubMedGoogle Scholar
  3. 3.
    Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179CrossRefGoogle Scholar
  4. 4.
    Chavez JA, Summers SA (2012) A ceramide-centric view of insulin resistance. Cell Metab 15:585–594CrossRefGoogle Scholar
  5. 5.
    Powell DJ, Hajduch E, Kular G, Hundal HS (2003) Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKC-dependent mechanism. Mol Cell Biol 23:7794–7808CrossRefGoogle Scholar
  6. 6.
    Hajduch E, Turban S, Le Liepvre X, Le Lay S, Lipina C, Dimopoulos N, Dugail I, Hundal HS (2008) Targeting of PKCζ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem J 410:369–379CrossRefGoogle Scholar
  7. 7.
    Mei J, Holst LS, Landstrom TR, Holm C, Brindley D, Manganiello V, Degerman E (2002) C2-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3–L1 adipocytes. Diabetes 51:631–637CrossRefGoogle Scholar
  8. 8.
    Holm C (2003) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Biochem Soc Trans 31:1120–1124CrossRefGoogle Scholar
  9. 9.
    Rico JE, Bandaru VVR, Dorskind JM, Haughey NJ, McFadden JW (2015) Plasma ceramides are elevated in overweight Holstein dairy cows experiencing greater lipolysis and insulin resistance during the transition from late pregnancy to early lactation. J Dairy Sci 98:7757–7770CrossRefGoogle Scholar
  10. 10.
    Rico JE, Saed Samii S, Mathews AT, Lovett J, Haughey NJ, McFadden JW (2017) Temporal changes in sphingolipids and systemic insulin sensitivity during the transition from gestation to lactation. PLoS One 12:e0176787CrossRefGoogle Scholar
  11. 11.
    Rico JE, Mathews AT, Lovett J, Haughey NJ, McFadden JW (2016) Palmitic acid feeding increases ceramide supply in association with increased milk yield, circulating nonesterified fatty acids, and adipose tissue responsiveness to a glucose challenge. J Dairy Sci 99:8817–8830CrossRefGoogle Scholar
  12. 12.
    Mathews AT, Rico JE, Sprenkle NE, Lock AL, McFadden JW (2016) Increasing palmitic acid intake enhances milk production and prevents glucose-stimulated fatty acid disappearance without modifying systemic glucose tolerance in mid-lactation dairy cows. J Dairy Sci 99:8802–8816CrossRefGoogle Scholar
  13. 13.
    Pires JA, Pescara JB, Grummer RR (2007) Reduction of plasma NEFA concentration by nicotinic acid enhances the response to insulin in feed-restricted Holstein cows. J Dairy Sci 90:4635–4642CrossRefGoogle Scholar
  14. 14.
    Pires JA, Grummer RR (2007) The use of nicotinic acid to induce sustained low plasma nonesterified fatty acids in feed-restricted Holstein cows. J Dairy Sci 90:3725–3732CrossRefGoogle Scholar
  15. 15.
    Heemskerk MM, van den Berg SA, Pronk AC, van Klinken JB, Boon MR, Havekes LM, Rensen PC, van Dijk KW, van Harmelen V (2014) Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B. Am J Physiol Endocrinol Metab 306:E808–E813CrossRefGoogle Scholar
  16. 16.
    Pires JA, Stumpf LF, Soutullo ID, Pescara JB, Stocks SE, Grummer RR (2016) Effects of abomasal infusion of nicotinic acid on responses to glucose and β-agonist challenges in underfed lactating cows. J Dairy Sci 99:1–11CrossRefGoogle Scholar
  17. 17.
    Wildman EE, Jones GM, Wagner PE, Bowman RL (1982) A dairy cow body condition scoring system and its relationship to selected production characteristics. J Dairy Sci 65:495–501CrossRefGoogle Scholar
  18. 18.
    National Research Council (2001) Nutrient requirements of dairy cattle, 7th, rev edn. National Academy of Sciences, Washington, DCGoogle Scholar
  19. 19.
    Livingstone C, Mary Collison (2002) Sex steroids and insulin resistance. Clin Sci 102:151–166CrossRefGoogle Scholar
  20. 20.
    Pires JA, Souza AH, Grummer RR (2007) Induction of hyperlipidemia by intravenous infusion of tallow emulsion causes insulin resistance in Holstein cows. J Dairy Sci 90:2735–2744CrossRefGoogle Scholar
  21. 21.
    Hughes JP (1962) A simplified instrument for obtaining liver biopsies in cattle. Am J Vet Res 23:1111–1113PubMedGoogle Scholar
  22. 22.
    Hara A, Radin NS (1978) Lipid extraction of tissues with a low-toxicity solvent. Anal Biochem 90:420–426CrossRefGoogle Scholar
  23. 23.
    Piepenbrink MS, Overton TR (2003) Liver metabolism and production of cows fed increasing amounts of rumen-protected choline during the periparturient period. J Dairy Sci 86:1722–1733CrossRefGoogle Scholar
  24. 24.
    Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas JL, Pardo CA, Turchan J, Nath A, Mattson MP (2004) Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 55:257–267CrossRefGoogle Scholar
  25. 25.
    Bandaru VV, Mielke MM, Sacktor N, McArthur JC, Grant I, Letendre S, Chang L, Wojna V, Pardo C, Calabresi P, Munsaka S, Haughey NJ (2013) A lipid storage-like disorder contributes to cognitive decline in HIV-infected subjects. Neurol 81:1492–1499CrossRefGoogle Scholar
  26. 26.
    Sävendahl L, Underwood LE (1999) Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans. J Nutr 129:2005–2008CrossRefGoogle Scholar
  27. 27.
    Boon J, Hoy AJ, Stark R, Brown RD, Meex RC, Henstridge DC, Schenk S, Meikle PJ, Horowitz JF, Kingwell BA, Bruce CR, Watt MJ (2013) Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes 62:401–410CrossRefGoogle Scholar
  28. 28.
    Raichur S, Wang ST, Chan PW, Li Y, Ching J, Chaurasia B, Dogra S, Ohman MK, Takeda K, Sugii S, Pewzner-Jung Y, Futerman AH, Summers SA (2014) CerS2 haploinsufficiency inhibits β-oxidations and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab 20:687–695CrossRefGoogle Scholar
  29. 29.
    Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, Mauer J, Xu E, Hammerschmidt P, Brönneke HS, Trifunovic A, LoSasso G, Wunderlich FT, Kornfed JW, Blüher M, Krönke M, Bruning JC (2014) Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain 566 and glucose intolerance. Cell Metab 20:678–686CrossRefGoogle Scholar
  30. 30.
    Haus JM, Kashyap SR, Kasumov T, Zhang R, Kelly KR, DeFronzo RA, Kirwan JP (2009) Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58:337–343CrossRefGoogle Scholar
  31. 31.
    Watt MJ, Barnett AC, Bruce CR, Schenk S, Horowitz JF, Hoy AJ (2012) Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia 55:2741–2746CrossRefGoogle Scholar
  32. 32.
    Oikawa S, Oetzel GR (2006) Decreased insulin response in dairy cows following a four-day fast to induce hepatic lipidosis. J Dairy Sci 89:2999–3005CrossRefGoogle Scholar
  33. 33.
    Xia JY, Holland WL, Kusminski CM, Sun K, Sharma AX, Pearson MJ, Sifuented AJ, McDonald JG, Grodillo R, Scherer PE (2015) Targeted induction of ceramide degradation leads to improved systemic metabolism and improved hepatic steatosis. Cell Metab 22:266–278CrossRefGoogle Scholar
  34. 34.
    Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45:42–72CrossRefGoogle Scholar
  35. 35.
    Funaki M (2009) Saturated fatty acids and insulin resistance. J Med Invest 56:88–92CrossRefGoogle Scholar
  36. 36.
    Stratford S, Hoehn KL, Liu F, Summers SA (2004) Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 279:36608–36615CrossRefGoogle Scholar
  37. 37.
    Aschenbach JR, Kristensen NB, Donkin SS, Hammon HM, Penner GB (2010) Gluconeogenesis in dairy cows: the secret of making sweet milk from sour dough. Life 62:869–877PubMedGoogle Scholar
  38. 38.
    Merrill AH (2002) De novo sphingolipid biosynthesis: a necessary but dangerous pathway. J Biol Chem 277:25843–25846CrossRefGoogle Scholar
  39. 39.
    Tanno O, Ota Y, Kitamura N, Katsube T, Inoue S (2000) Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol 143:524–531CrossRefGoogle Scholar
  40. 40.
    Wadsworth JM, Clarke DJ, McMahon SA, Lowther JP, Beattie AE, Langridge-Smith PRR, Broughton HB, Dunn TM, Naismith JH, Campopiano DJ (2013) The chemical basis of serine palmitoyltransferase inhibition by myriocin. J Am Chem Soc 135:14276–14285CrossRefGoogle Scholar
  41. 41.
    Hirabayashi Y, Igarashi Y, Merrill AH (2006) Sphingolipids synthesis, transport and cellular signaling. Sphingolipid biology. Springer, Japan, pp 3–22CrossRefGoogle Scholar
  42. 42.
    Meikle PJ, Wong G, Barlow CK, Weir JM, Greeve MA, MacIntosh GL, Almasy L, Comuzzie AG, Mahaney MC, Kowalczyk A, Haviv I, Grantham N, Magliano DJ, Jowett JBM, Zimmet P, Curran JE, Blangero J, Shaw J (2013) Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS One 8:e74341CrossRefGoogle Scholar

Copyright information

© AOCS 2017

Authors and Affiliations

  • Amanda N. Davis
    • 1
  • J. L. Clegg
    • 1
  • C. A. Perry
    • 1
  • J. W. McFadden
    • 1
    • 2
    Email author
  1. 1.Division of Animal and Nutritional SciencesWest Virginia UniversityMorgantownUSA
  2. 2.Cornell UniversityIthacaUSA

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