Article | Published:

Bariatric surgery

Unlike calorie restriction, Roux-en-Y gastric bypass surgery does not increase hypothalamic AgRP and NPY in mice on a high-fat diet

International Journal of Obesity (2019) | Download Citation

Abstract

Objectives

Dieting often fails because weight loss triggers strong counter-regulatory biological responses such as increased hunger and hypometabolism that are thought to be critically dependent on the master fuel sensor in the mediobasal hypothalamus (MBH). Because prolonged starvation has been shown to increase AgRP and NPY, the expression level of these two orexigenic genes has been taken as an experimental readout for the presence or absence of hunger. Roux-en-Y gastric bypass (RYGB) surgery leads to a significant weight loss without inducing the associated hunger, indicating possible changes in hypothalamic neuropeptides and/or signaling. Our goal was to assess key genes in the MBH involved in regulating body weight, appetite, and inflammation/oxidative stress after RYGB surgery in mice.

Methods

Obese mice on a high-fat diet were subjected to either sham or RYGB surgery, or caloric restriction to match the weight of RYGB group. Chow-fed mice without surgery served as an additional control group. After 2 or 12 weeks post-surgery, hypothalamic genes were analyzed by real-time qPCR.

Results

During the rapid weight loss phase at 2 weeks after RYGB surgery, hypothalamic AgRP and NPY gene expression was not increased compared to mice with sham surgery, indicating that the mice are not hungry. In contrast, the same weight loss induced by caloric restriction promptly triggered increased AgRP and NPY expression. This differential effect of RYGB and caloric restriction was no longer observed during the weight-maintenance phase at 12 weeks after surgery. A similar differential effect was observed for ObRb, but not for POMC and CART expression. Furthermore, RAGE and IBA-1, two markers for inflammation/oxidative stress, were significantly suppressed after RYGB compared to caloric restriction at 2 weeks post-surgery.

Conclusions

These findings suggest that RYGB prevents the biologically adaptive hunger response triggered by undernutrition and weight loss, and suppresses weight loss-induced hypothalamic inflammation markers.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Swart I, Jahng JW, Overton JM, Houpt TA. Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice. Am J Physiol Regul Integr Comp Physiol. 2002;283:R1020–6.

  2. 2.

    Bertile F, Oudart H, Criscuolo F, Maho YL, Raclot T. Hypothalamic gene expression in long-term fasted rats: relationship with body fat. Biochem Biophys Res Commun. 2003;303:1106–13.

  3. 3.

    Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann Surg. 2008;247:401–7.

  4. 4.

    Morinigo R, Moize V, Musri M, Lacy AM, Navarro S, Marin JL, et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2006;91:1735–40.

  5. 5.

    Scholtz S, Miras AD, Chhina N, Prechtl CG, Sleeth ML, Daud NM, et al. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut. 2014;63:891–902.

  6. 6.

    Barkholt P, Pedersen PJ, Hay-Schmidt A, Jelsing J, Hansen HH, Vrang N. Alterations in hypothalamic gene expression following Roux-en-Y gastric bypass. Mol Metab. 2016;5:296–304.

  7. 7.

    Grayson BE, Hakala-Finch AP, Kekulawala M, Laub H, Egan AE, Ressler IB, et al. Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats. Stress. 2014;17:484–93.

  8. 8.

    Cavin JB, Voitellier E, Cluzeaud F, Kapel N, Marmuse JP, Chevallier JM, et al. Malabsorption and intestinal adaptation after one anastomosis gastric bypass compared with Roux-en-Y gastric bypass in rats. Am J Physiol Gastrointest Liver Physiol. 2016;311:G492–500.

  9. 9.

    Liu JY, Mu S, Zhang SP, Guo W, Li QF, Xiao XQ, et al. Roux-en-Y gastric bypass surgery suppresses hypothalamic PTP1B protein level and alleviates leptin resistance in obese rats. Exp Ther Med. 2017;14:2536–42.

  10. 10.

    Hao Z, Mumphrey MB, Townsend RL, Morrison CD, Munzberg H, Ye J, et al. Body composition, food intake, and energy expenditure in a murine model of Roux-en-Y gastric bypass surgery. Obes Surg. 2016;26:2173–82.

  11. 11.

    Hao Z, Zhao Z, Berthoud HR, Ye J. Development and verification of a mouse model for Roux-en-Y gastric bypass surgery with a small gastric pouch. PLoS One. 2013;8:e52922.

  12. 12.

    Paxinos G, Franklin K. The mouse brain in streotaxic coordinates, 2nd edn. Academic Press; 2004.

  13. 13.

    Clemmensen C, Muller TD, Woods SC, Berthoud HR, Seeley RJ, Tschop MH. Gut-brain cross-talk in metabolic control. Cell. 2017;168:758–74.

  14. 14.

    Beck B, Jhanwar-Uniyal M, Burlet A, Chapleur-Chateau M, Leibowitz SF, Burlet C. Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status. Brain Res. 1990;528:245–9.

  15. 15.

    Shimokawa I, Fukuyama T, Yanagihara-Outa K, Tomita M, Komatsu T, Higami Y, et al. Effects of caloric restriction on gene expression in the arcuate nucleus. Neurobiol Aging. 2003;24:117–23.

  16. 16.

    Brady LS, Smith MA, Gold PW, Herkenham M. Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology. 1990;52:441–7.

  17. 17.

    Kawasaki T, Ohta M, Kawano Y, Masuda T, Gotoh K, Inomata M, et al. Effects of sleeve gastrectomy and gastric banding on the hypothalamic feeding center in an obese rat model. Surg Today. 2015;45:1560–6.

  18. 18.

    Nestoridi E, Kvas S, Kucharczyk J, Stylopoulos N. Resting energy expenditure and energetic cost of feeding are augmented after Roux-en-Y gastric bypass in obese mice. Endocrinology. 2012;153:2234–44.

  19. 19.

    Liou AP, Paziuk M, Luevano JM Jr., Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5:178ra41.

  20. 20.

    Bake T, Baron J, Duncan JS, Morgan DGA, Mercer JG. Arcuate nucleus homeostatic systems reflect blood leptin concentration but not feeding behaviour during scheduled feeding on a high-fat diet in mice. J Neuroendocrinol. 2017;29:8.

  21. 21.

    Romanova IV, Ramos EJ, Xu Y, Quinn R, Chen C, George ZM, et al. Neurobiologic changes in the hypothalamus associated with weight loss after gastric bypass. J Am Coll Surg. 2004;199:887–95.

  22. 22.

    Shin AC, Zheng H, Townsend RL, Sigalet DL, Berthoud HR. Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery. Endocrinology. 2010;151:1588–97.

  23. 23.

    Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V, et al. Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. Diabetes. 2011;60:810–8.

  24. 24.

    Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122:153–62.

  25. 25.

    Kirchner H, Hofmann SM, Fischer-Rosinsky A, Hembree J, Abplanalp W, Ottaway N, et al. Caloric restriction chronically impairs metabolic programming in mice. Diabetes. 2012;61:2734–42.

  26. 26.

    Dalvi PS, Chalmers JA, Luo V, Han DY, Wellhauser L, Liu Y, et al. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-alpha on appetite-regulating NPY neurons. Int J Obes (Lond). 2017;41:149–58.

  27. 27.

    Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250–2.

  28. 28.

    Korner J, Savontaus E, Chua SC Jr., Leibel RL, Wardlaw SL. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J Neuroendocrinol. 2001;13:959–66.

  29. 29.

    Marsh DJ, Miura GI, Yagaloff KA, Schwartz MW, Barsh GS, Palmiter RD. Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues. Brain Res. 1999;848:66–77.

  30. 30.

    Mizuno TM, Makimura H, Silverstein J, Roberts JL, Lopingco T, Mobbs CV. Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. Endocrinology. 1999;140:4551–7.

  31. 31.

    Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology. 1999;140:814–7.

  32. 32.

    Shimizu-Albergine M, Ippolito DL, Beavo JA. Downregulation of fasting-induced cAMP response element-mediated gene induction by leptin in neuropeptide Y neurons of the arcuate nucleus. J Neurosci. 2001;21:1238–46.

  33. 33.

    Boswell T, Nicholson MA, Bunger L. Neuropeptide Y gene expression in lines of mice subjected to long-term divergent selection on fat content. J Mol Endocrinol. 1999;23:77–83.

  34. 34.

    Palou M, Sanchez J, Rodriguez AM, Priego T, Pico C, Palou A. Induction of NPY/AgRP orexigenic peptide expression in rat hypothalamus is an early event in fasting: relationship with circulating leptin, insulin and glucose. Cell Physiol Biochem. 2009;23:115–24.

  35. 35.

    Xu B, Kalra PS, Farmerie WG, Kalra SP. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction. Endocrinology. 1999;140:2868–75.

  36. 36.

    Champy MF, Selloum M, Piard L, Zeitler V, Caradec C, Chambon P, et al. Mouse functional genomics requires standardization of mouse handling and housing conditions. Mamm Genome. 2004;15:768–83.

  37. 37.

    Swoap SJ, Gutilla MJ, Liles LC, Smith RO, Weinshenker D. The full expression of fasting-induced torpor requires beta 3-adrenergic receptor signaling. J Neurosci. 2006;26:241–5.

Download references

Acknowledgements

This study was supported by NIH DK099463 (ACS) and NIH DK047348 (HRB).

Author information

Affiliations

  1. Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, 79409, USA

    • Presheet P. Patkar
    •  & Andrew C. Shin
  2. Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA

    • Zheng Hao
    • , Michael B. Mumphrey
    • , R. Leigh Townsend
    •  & Hans-Rudolf Berthoud

Authors

  1. Search for Presheet P. Patkar in:

  2. Search for Zheng Hao in:

  3. Search for Michael B. Mumphrey in:

  4. Search for R. Leigh Townsend in:

  5. Search for Hans-Rudolf Berthoud in:

  6. Search for Andrew C. Shin in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Andrew C. Shin.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41366-019-0328-x