Skip to main content
SpringerLink
Log in

Intestinal Electrical Stimulation Alters Hypothalamic Expression of Oxytocin and Orexin and Ameliorates Diet-Induced Obesity in Rats

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

Abstract

Background

Intestinal electrical stimulation (IES) has been proposed as a potential treatment for obesity. The aim of this study was to explore the central mechanism underlying the reduction of food intake and body weight by IES by studying the expression of anorexigenic- and orexigenic-peptide-containing neurons in the hypothalamus.

Materials and Methods

Diet-induced obese (DIO) rats were divided into three groups to receive sham, IES, and pair-feeding for 4 weeks. Food intake was measured automatically and presented as daily and body weight measured weekly. The expressions of oxytocin, an anorexigenic neuropeptide, in the paraventricular nucleus of the hypothalamus (PVN) and the supraoptic nuclei of the hypothalamus (SON) and orexin-A, an orexigenic neuropeptide, in the lateral hypothalamic area (LHA) were studied using immunohistochemistry.

Results

Compared with sham, IES reduced daily food intake by 28.3% at week 1, 35.6% at week 2, 15.6% at week 3, and 27.1% at week 4. Consistently, IES reduced body weight by 6.3%, compared with a weight gain of 7.2% in sham, and a slight weight loss of 0.5% in pair-feeding. Compared with sham, IES increased the expression of oxytocin-immunoreactive neurons in PVN and SON. Compared with sham, IES decreased the expression of orexin-immunoreactive neurons in LHA. Rats with pair-feeding also showed a relative decease in weight without any changes in the central hormones.

Conclusion

IES reduces food intake and body weight and improves glucose tolerance and insulin sensitivity in DIO rats. Its central mechanisms involve enhancement of anorexigenic peptides and suppression of orexigenic peptides in the hypothalamus.

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

Similar content being viewed by others

References

  1. Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440–50.

    Article  PubMed  Google Scholar 

  2. Kim DD, Basu A. Estimating the medical care costs of obesity in the United States: systematic review, meta-analysis, and empirical analysis. Value Health J Int Soc Pharmacoecon Outcomes Res. 2016;19(5):602–13.

    Article  Google Scholar 

  3. De Luca M, Angrisani L, Himpens J, et al. Indications for surgery for obesity and weight-related diseases: position statements from the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO). Obes Surg. 2016;26(8):1659–96.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sagar PM. Surgical treatment of morbid obesity. Br J Surg. 1995;82(6):732–9.

    Article  CAS  PubMed  Google Scholar 

  5. Crookes PF. Surgical treatment of morbid obesity. Annu Rev Med. 2006;57:243–64.

    Article  CAS  PubMed  Google Scholar 

  6. Dargent J. Gastric electrical stimulation as therapy of morbid obesity: preliminary results from the French study. Obes Surg. 2002;12(Suppl 1):21S–5S.

    Article  Google Scholar 

  7. Cigaina V. Gastric pacing as therapy for morbid obesity: preliminary results. Obes Surg. 2002;12(Suppl 1):12S–6S.

    Article  PubMed  Google Scholar 

  8. Greenstein RJ, Belachew M. Implantable gastric stimulation (IGS) as therapy for human morbid obesity: report from the 2001 IFSO symposium in Crete. Obes Surg. 2002;12(Suppl 1):3S–5S.

    Article  PubMed  Google Scholar 

  9. Favretti F, De Luca M, Segato G, et al. Treatment of morbid obesity with the transcend implantable gastric stimulator (IGS): a prospective survey. Obes Surg. 2004;14(5):666–70.

    Article  PubMed  Google Scholar 

  10. Horbach T, Thalheimer A, Seyfried F, et al. Abiliti closed-loop gastric electrical stimulation system for treatment of obesity: clinical results with a 27-month follow-up. Obes Surg. 2015;25(10):1779–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu X, Lei Y, Chen JDZ. Duodenum electrical stimulation delays gastric emptying, reduces food intake and accelerates small bowel transit in pigs. Obes Silver Spring Md. 2011;19(2):442–8.

    Article  Google Scholar 

  12. Li S, Chen JDZ. Pulse width-dependent effects of intestinal electrical stimulation for obesity: role of gastrointestinal motility and hormones. Obes Surg. 2017;27(1):70–7.

    Article  PubMed  Google Scholar 

  13. Sun Y, Chen J. Intestinal electric stimulation decreases fat absorption in rats: therapeutic potential for obesity. Obes Res. 2004;12(8):1235–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aberle J, Busch P, Veigel J, et al. Duodenal electric stimulation: results of a first-in-man study. Obes Surg. 2016;26(2):369–75.

    Article  PubMed  Google Scholar 

  15. Yin J, Zhang J, Chen JDZ. Inhibitory effects of intestinal electrical stimulation on food intake, weight loss and gastric emptying in rats. Am J Physiol Regul Integr Comp Physiol. 2007;293(1):R78–82.

    Article  CAS  PubMed  Google Scholar 

  16. Tang M, Zhang J, Xu L, et al. Implantable gastric stimulation alters expression of oxytocin- and orexin-containing neurons in the hypothalamus of rats. Obes Surg. 2006;16(6):762–9.

    Article  PubMed  Google Scholar 

  17. Allen YS, Adrian TE, Allen JM, et al. Neuropeptide Y distribution in the rat brain. Science. 1983;221(4613):877–9.

    Article  CAS  PubMed  Google Scholar 

  18. Park ES, Yi SJ, Kim JS, et al. Changes in orexin-A and neuropeptide Y expression in the hypothalamus of the fasted and high-fat diet fed rats. J Vet Sci. 2004;5(4):295–302.

    Article  PubMed  Google Scholar 

  19. Blevins JE, Ho JM. Role of oxytocin signaling in the regulation of body weight. Rev Endocr Metab Disord. 2013;14(4):311–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Arletti R, Benelli A, Bertolini A. Oxytocin inhibits food and fluid intake in rats. Physiol Behav. 1990;48(6):825–30.

    Article  CAS  PubMed  Google Scholar 

  21. Rinaman L, Rothe EE. GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats. Am J Physiol Regul Integr Comp Physiol. 2002;283(1):R99–106.

    Article  CAS  PubMed  Google Scholar 

  22. Olson BR, Drutarosky MD, Chow MS, et al. Oxytocin and an oxytocin agonist administered centrally decrease food intake in rats. Peptides. 1991;12(1):113–8.

    Article  CAS  PubMed  Google Scholar 

  23. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.

    Article  CAS  PubMed  Google Scholar 

  24. Farley C, Cook JA, Spar BD, et al. Meal pattern analysis of diet-induced obesity in susceptible and resistant rats. Obes Res. 2003;11(7):845–51.

    Article  PubMed  Google Scholar 

  25. Zhang J, Maude-Griffin R, Zhu H, et al. Gastric electrical stimulation parameter dependently alters ventral medial hypothalamic activity and feeding in obese rats. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G912–8.

    Article  CAS  PubMed  Google Scholar 

  26. Tai MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care. 1994;17(2):152–4.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang G, Bai H, Zhang H, et al. Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron. 2011;69(3):523–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shikora SA, Bergenstal R, Bessler M, et al. Implantable gastric stimulation for the treatment of clinically severe obesity: results of the SHAPE trial. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2009;5(1):31–7.

    Article  Google Scholar 

  29. Madsen AN, Hansen G, Paulsen SJ, et al. Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol. 2010;206(3):287–96.

    Article  CAS  PubMed  Google Scholar 

  30. Maejima Y, Yokota S, Nishimori K, et al. The anorexigenic neural pathways of oxytocin and their clinical implication. Neuroendocrinology. 2018;107(1):91–104.

    Article  CAS  PubMed  Google Scholar 

  31. Hill JW. PVN pathways controlling energy homeostasis. Indian J Endocrinol Metab. 2012;16(Suppl 3):S627–36.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Altirriba J, Poher A-L, Rohner-Jeanrenaud F. Chronic oxytocin administration as a treatment against impaired leptin signaling or leptin resistance in obesity. Front Endocrinol. 2015;6:119.

    Article  Google Scholar 

  33. Morton GJ, Thatcher BS, Reidelberger RD, et al. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab. 2012;302(1):E134–44.

    Article  CAS  PubMed  Google Scholar 

  34. Wu Z, Xu Y, Zhu Y, et al. An obligate role of oxytocin neurons in diet induced energy expenditure. PLoS One. 2012;7(9):e45167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deblon N, Veyrat-Durebex C, Bourgoin L, et al. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One. 2011;6(9):e25565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Blais A, Drouin G, Chaumontet C, et al. Impact of orexin-A treatment on food intake, energy metabolism and body weight in mice. PLoS One. 2017;12(1):e0169908.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Van den Pol AN. Lateral hypothalamic damage and body weight regulation: role of gender, diet, and lesion placement. Am J Phys. 1982;242(3):R265–74.

    Google Scholar 

  38. Kirchgessner AL, Liu M. Orexin synthesis and response in the gut. Neuron. 1999;24(4):941–51.

    Article  CAS  PubMed  Google Scholar 

  39. Kim GW, Lin JE, Valentino MA, et al. Regulation of appetite to treat obesity. Expert Rev Clin Pharmacol. 2011;4(2):243–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu J, Qiao X, Hou X, et al. Effect of intestinal pacing on small bowel transit and nutrient absorption in healthy volunteers. Obes Surg. 2009;19(2):196–201.

    Article  PubMed  Google Scholar 

  41. Sun Y, Chen JDZ. Intestinal electric stimulation accelerates whole gut transit and promotes fat excrement in conscious rats. Int J Obes 2005. 2009;33(8):817–23.

    CAS  Google Scholar 

  42. Li S, Zhu W, Zhang S, et al. Chronic intestinal electrical stimulation improves glucose intolerance and insulin resistance in diet-induced obesity rats. Obes Silver Spring Md. 2017;25(6):1061–8.

    Article  CAS  Google Scholar 

  43. Näslund E, Gutniak M, Skogar S, et al. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998;68(3):525–30.

    Article  PubMed  Google Scholar 

  44. Roslin MS, Cripps CN. Bariatric surgery in managing diabetes mellitus. Curr Opin Gastroenterol. 2016;32(6):481–6.

    Article  CAS  PubMed  Google Scholar 

  45. Maisiyiti A, Chen JD. Systematic review on gastric electrical stimulation in obesity treatment. Expert Rev Med Devices. 2019;16(10):855–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by a Merit Review Award #I01BX002010 (to M.M.) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Program and partly by grant R01DK107754 (to J. C.) from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Veterans Research Education Foundation, Oklahoma City Veterans Health Care System, Oklahoma City, OK, USA

    Shiying Li, Yeram Kim & Mohammad F. Madhoun

  2. Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA

    Shiying Li & Jiande D. Z. Chen

  3. Division of Digestive Diseases and Nutrition, Department of Internal Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Mohammad F. Madhoun

Authors
  1. Shiying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yeram Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiande D. Z. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad F. Madhoun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad F. Madhoun.

Ethics declarations

Conflict of Interest

All authors declare that they have no conflict of interest.

Ethical Approval Statement

All applicable institutional and/or national guidelines for the care and use of animals were followed. The study was performed according to the National Institutes of Health Guidelines on the use of laboratory animals and approved by the Animal Care and Use Committee of the Oklahoma City Veterans Health Care System (Oklahoma City, OK).

Informed Consent Statement

Informed consent does not apply.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Kim, Y., Chen, J.D.Z. et al. Intestinal Electrical Stimulation Alters Hypothalamic Expression of Oxytocin and Orexin and Ameliorates Diet-Induced Obesity in Rats. OBES SURG 31, 1664–1672 (2021). https://doi.org/10.1007/s11695-020-05177-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11695-020-05177-w

Keywords

Search

Navigation