Skip to main content
SpringerLink
Log in

Duodenal-Jejunal Bypass Surgery Suppresses Hepatic De Novo Lipogenesis and Alleviates Liver Fat Accumulation in a Diabetic Rat Model

  • Original Contributions
  • Published:
Obesity Surgery Aims and scope Submit manuscript

Abstract

Background

Duodenal-jejunal bypass (DJB) surgery can induce rapid and durable remission of type 2 diabetes mellitus (T2DM), but the intrinsic mechanisms remain to be elucidated. Recent studies indicated that improved hepatic insulin resistance and insulin signaling transduction might contribute to the diabetic control after DJB. Given the important role of liver adiposity in hepatic insulin resistance, this study was aimed at investigating the effects of DJB on glucose homeostasis and liver fat accumulation in a T2DM rat model induced by high-fat diet (HFD) and small dose of streptozotocin (STZ).

Methods

Forty adult male diabetic rats induced by HFD and small dose of STZ were randomly assigned to sham and DJB groups. Body weight, calorie intake, hormone levels, glucose, and lipid parameters were measured at indicated time points. Subsequently, hepatic triglycerides (TG) content and the protein levels of sterol regulatory element binding protein-1 (SREBP-1), carbohydrate response element binding protein (ChREBP), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) were evaluated at 2 and 8 weeks postoperatively.

Results

Compared with sham group, DJB induced rapid and significant improvements in glucose homeostasis and insulin sensitivity independently of weight loss and calorie restriction. The DJB-operated rats exhibited lower liver TG content and decreased hepatic SREBP-1, ChREBP, ACC, and FAS at 8 weeks postoperatively.

Conclusions

DJB alleviated hepatic fat accumulation and downregulated the key transcriptional regulators and enzymes involved in hepatic de novo lipogenesis, which might contribute to improved hepatic insulin sensitivity and glucose homeostasis after DJB.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004;239(1):1–11. PMID: 14685093.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Jiao J, Bae EJ, Bandyopadhyay G, et al. Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats. Diabetes. 2013;62(4):1074–83. PMID: 23248171.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Wang TT, Hu SY, Gao HD, et al. Ileal transposition controls diabetes as well as modified duodenal jejunal bypass with better lipid lowering in a nonobese rat model of type II diabetes by increasing GLP-1. Ann Surg. 2008;247(6):968–75. PMID: 18520224.

    Article  PubMed  Google Scholar 

  4. Sun D, Wang K, Yan Z, et al. Duodenal-jejunal bypass surgery up-regulates the expression of the hepatic insulin signaling proteins and the key regulatory enzymes of intestinal gluconeogenesis in diabetic goto-kakizaki rats. Obes Surg. 2013;23(11):1734–42. PMID: 23700236.

    Article  PubMed  Google Scholar 

  5. DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982;23(4):313–9. PMID: 6754515.

    Article  CAS  PubMed  Google Scholar 

  6. Leclercq IA, Da Silva MA, Schroyen B, et al. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol. 2007;47(1):142–56. PMID: 17512085.

    Article  CAS  PubMed  Google Scholar 

  7. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133(2):496–506. PMID: 17681171.

    Article  CAS  PubMed  Google Scholar 

  8. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87(7):3023–8. PMID: 12107194.

    Article  CAS  PubMed  Google Scholar 

  9. Kotronen A, Juurinen L, Tiikkainen M, et al. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 2008;135(1):122–30. PMID: 18474251.

    Article  CAS  PubMed  Google Scholar 

  10. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279(31):32345–53. PMID: 15166226.

    Article  CAS  PubMed  Google Scholar 

  11. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31(1):165–9. PMID: 17934148.

    Article  CAS  PubMed  Google Scholar 

  12. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–31. PMID: 11961152.

    Article  CAS  PubMed  Google Scholar 

  13. Medina J, Fernandez-Salazar LI, Garcia-Buey L, et al. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care. 2004;27(8):2057–66. PMID: 15277442.

    Article  PubMed  Google Scholar 

  14. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002;23(2):201–29. PMID: 11943743.

    Article  CAS  PubMed  Google Scholar 

  15. Mottin CC, Moretto M, Padoin AV, et al. Histological behavior of hepatic steatosis in morbidly obese patients after weight loss induced by bariatric surgery. Obes Surg. 2005;15(6):788–93. PMID: 15978148.

    Article  PubMed  Google Scholar 

  16. Weiner RA. Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis. 2010;28(1):274–9. PMID: 20460923.

    Article  CAS  PubMed  Google Scholar 

  17. Dixon JB, Bhathal PS, O’Brien PE. Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic improvement. Obes Surg. 2006;16(10):1278–86. PMID: 17059735.

    Article  PubMed  Google Scholar 

  18. Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135(1):48–58. PMID: 14694300.

    Article  PubMed  Google Scholar 

  19. Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6(12):1396–402. PMID: 18986848.

    Article  PubMed  Google Scholar 

  20. Kindel TL, Yoder SM, Seeley RJ, et al. Duodenal-jejunal exclusion improves glucose tolerance in the diabetic, Goto-Kakizaki rat by a GLP-1 receptor-mediated mechanism. J Gastrointest Surg. 2009;13(10):1762–72. PMID: 19488823.

    Article  PubMed  Google Scholar 

  21. Ben-Shlomo S, Zvibel I, Shnell M, et al. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol. 2011;54(6):1214–23. PMID: 21145820.

    Article  CAS  PubMed  Google Scholar 

  22. de Jonge C, Rensen SS, Koek GH, et al. Endoscopic duodenal-jejunal bypass liner rapidly improves plasma parameters of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2013;11(11):1517–20. PMID: 23920034.

    Article  PubMed  Google Scholar 

  23. Reed MJ, Meszaros K, Entes LJ, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000;49(11):1390–4. PMID: 11092499.

    Article  CAS  PubMed  Google Scholar 

  24. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. PMID: 3899825.

    Article  CAS  PubMed  Google Scholar 

  25. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70. PMID: 10480510.

    Article  CAS  PubMed  Google Scholar 

  26. Jurowich CF, Rikkala PR, Thalheimer A, et al. Duodenal-jejunal bypass improves glycemia and decreases SGLT1-mediated glucose absorption in rats with streptozotocin-induced type 2 diabetes. Ann Surg. 2013;258(1):89–97. PMID: 23478528.

    Article  PubMed  Google Scholar 

  27. Liu S, Zhang G, Wang L, et al. The entire small intestine mediates the changes in glucose homeostasis after intestinal surgery in Goto-Kakizaki rats. Ann Surg. 2012;256(6):1049–58. PMID: 23001083.

    Article  PubMed  Google Scholar 

  28. Speck M, Cho YM, Asadi A, et al. Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. Am J Physiol Endocrinol Metab. 2011;300(5):E923–32. PMID: 21304061.

    Article  CAS  PubMed  Google Scholar 

  29. Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring). 2009;17(9):1671–7. PMID: 19360006.

    Article  CAS  Google Scholar 

  30. Cummings BP, Bettaieb A, Graham JL, et al. Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats. Dis Model Mech. 2013;6(2):443–56. PMID: 23264565.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Kohli R, Kirby M, Setchell KD, et al. Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. Am J Physiol Gastrointest Liver Physiol. 2010;299(3):G652–60. PMID: 20595624.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Cummings BP, Bettaieb A, Graham JL, et al. Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats. Endocrinology. 2012;153(8):3620–32. PMID: 22719048.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J. 2006;25(7):1419–25. PMID: 16541101.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Ma K, Saha PK, Chan L, et al. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116(4):1102–9. PMID: 16557297.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113(10):1408–18. PMID: 15146238.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9. PMID: 16400329.

    Article  CAS  PubMed  Google Scholar 

  37. Ryysy L, Hakkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000;49(5):749–58. PMID: 10905483.

    Article  CAS  PubMed  Google Scholar 

  38. Araujo AC, Bonfleur ML, Balbo SL, et al. Duodenal-jejunal bypass surgery enhances glucose tolerance and beta-cell function in Western diet obese rats. Obes Surg. 2012;22(5):819–26. PMID: 22411572.

    Article  PubMed  Google Scholar 

  39. Cummings BP, Strader AD, Stanhope KL, et al. Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat. Gastroenterology. 2010;138(7):2437–46. 2446 e1. PMID: 20226188.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829–38. PMID: 18317565.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741–9. PMID: 17060767.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997;46(1):3–10. PMID: 8971073.

    Article  CAS  PubMed  Google Scholar 

  43. Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010;12 Suppl 2:83–92. PMID: 21029304.

    Article  CAS  PubMed  Google Scholar 

  44. Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005;87(1):81–6. PMID: 15733741.

    Article  CAS  PubMed  Google Scholar 

  45. Mencarelli A, Renga B, D'Amore C, et al. Dissociation of intestinal and hepatic activities of FXR and LXRalpha supports metabolic effects of terminal ileum interposition in rodents. Diabetes. 2013;62(10):3384–93. PMID: 23835330.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Foretz M, Pacot C, Dugail I, et al. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol. 1999;19(5):3760–8. PMID: 10207099.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Ide T, Shimano H, Yahagi N, et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat Cell Biol. 2004;6(4):351–7. PMID: 15048126.

    Article  CAS  PubMed  Google Scholar 

  48. Poupeau A, Postic C. Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors. Biochim Biophys Acta. 2011;1812(8):995–1006. PMID: 21453770.

    Article  CAS  PubMed  Google Scholar 

  49. Dentin R, Benhamed F, Hainault I, et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes. 2006;55(8):2159–70. PMID: 16873678.

    Article  CAS  PubMed  Google Scholar 

  50. Liu SZ, Sun D, Zhang GY, et al. A high-fat diet reverses improvement in glucose tolerance induced by duodenal-jejunal bypass in type 2 diabetic rats. Chin Med J (Engl). 2012;125(5):912–9. PMID: 22490596.

    CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Natural Science Foundation of China (no. 81270888/H0713, no. 81370496/H0308, no. 81300286/H0308), Shandong Provincial Outstanding Medical Academic Professional Program, Natural Science Foundation of Shandong Province Grants (no. ZR2012HQ030), and the Taishan Scholar Foundation.

Conflicts of Interest

We declare that all authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, 107#, Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

    Haifeng Han, Chunxiao Hu, Lei Wang, Guangyong Zhang, Shaozhuang Liu, Feng Li, Dong Sun & Sanyuan Hu

Authors
  1. Haifeng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunxiao Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guangyong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shaozhuang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sanyuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanyuan Hu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, H., Hu, C., Wang, L. et al. Duodenal-Jejunal Bypass Surgery Suppresses Hepatic De Novo Lipogenesis and Alleviates Liver Fat Accumulation in a Diabetic Rat Model. OBES SURG 24, 2152–2160 (2014). https://doi.org/10.1007/s11695-014-1308-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11695-014-1308-9

Keywords

Search

Navigation