Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus
Clinical Medicine Research
Volume 8, Issue 2, March 2019, Pages: 32-38
Received: Apr. 14, 2019; Accepted: May 28, 2019; Published: Jun. 12, 2019
Views 56      Downloads 15
Huangna Quan, Department of Endocrinology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou City, China
Xue-jun Yang, Department of Endocrinology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou City, China
Article Tools
Follow on us
To explore the role of blood glucose regulation in gastric bypass surgery is a hot point in the treatment of diabetes in recent years. Current evidence is very clear that the gastric bypass surgery is one of the most promising therapy to cure type 2 diabetes. However, the mechanisms are not yet understood. Studying the mechanism of surgical treatment can not only understand the pathogenesis of diabetes, but also have important scientific and practical significance for clinically and safely carrying out this therapy. As is known to all, the body's energy metabolism and glucose homeostasis are regulated by the hypothalamus. Thus, we summarize the process mechanism of central regulation of glucose homeostasis in post-surgery and find that the hypothalamus after gastric bypass surgery showed enhanced expression of peripheral signal receptors, enhancement of leptin signal and insulin signal, and expression changes of certain related genes, then issued neuroendocrine signals to control peripheral insulin sensitivity and glucose metabolism. Then, we prove that the improvement of peripheral metabolic status is caused by the decisive role of central regulation in post-surgery. These funding provide scientific basis to improve the understanding of the neuroendocrine mechanism of diabetes and the development of clinical implication of gastric bypass surgery.
Gastric Bypass Surgery, Hypothalamus, Glucose Homeostasis, Neuroendocrine, Diabetes
To cite this article
Huangna Quan, Xue-jun Yang, Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus, Clinical Medicine Research. Vol. 8, No. 2, 2019, pp. 32-38. doi: 10.11648/j.cmr.20190802.11
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Yarmush, M. L., M. D'Alessandro, and N. Saeidi, Regulation of Energy Homeostasis After Gastric Bypass Surgery. Annu Rev Biomed Eng, 2017. 19: p. 459-484.
Schauer, P. R., et al., Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-Year Outcomes. N Engl J Med, 2017. 376 (7): p. 641-651.
Adams, T. D., et al., Weight and Metabolic Outcomes 12 Years after Gastric Bypass. N Engl J Med, 2017. 377 (12): p. 1143-1155.
Paranjape, S. A., et al., Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action. Diabetologia, 2013. 56 (9): p. 2055-8.
Williams, G., J. A. Harrold, and D. J. Cutler, The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. Proc Nutr Soc, 2000. 59 (3): p. 385-96.
Jorgensen, N. B., et al., Exaggerated glucagon-like peptide 1 response is important for improved beta-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes, 2013. 62 (9): p. 3044-52.
Dolo, P. R., et al., The effect of distal-ileal exclusion after Roux-en-Y gastric bypass on glucose tolerance and GLP-1 response in type-2 diabetes Sprague-Dawley rat model. Surg Obes Relat Dis, 2018. 14 (10): p. 1552-1560.
Mithieux, G., Influence of diabetes surgery on a gut-brain-liver axis regulating food intake and internal glucose production. Nutr Hosp, 2013. 28 Suppl 2: p. 109-14.
Li, J. V., et al., Metabolic Surgery Profoundly Influences Gut Microbial-Host Metabolic Crosstalk. Gut, 2011. 60 (9): p. 1214-23.
Palleja, A., et al., Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med, 2016. 8 (1): p. 67.
Zhai, H., et al., Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass. EBioMedicine, 2018. 32: p. 201-14.
Nergard, B. J., et al., Mucosal glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide cell numbers in the super-obese human foregut after gastric bypass. Surg Obes Relat Dis, 2015. 11 (6): p. 1237-46.
Tang-Christensen, M., N. Vrang, and P. Larsen, Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int. J. Obes. Relat. Metab. Disord., 2001. 25 Suppl 5: p. S42-7.
Sandoval, D. A., et al., Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes, 2008. 57 (8): p. 2046-2054.
Zynat, J., et al., The Improvement of Hyperglycemia after RYGB Surgery in Diabetic Rats Is Related to Elevated Hypothalamus GLP-1 Receptor Expression. Int J Endocrinol, 2016. 2016: p. 5308347.
Nishizawa, M., et al., Intraportal GLP-1 stimulates insulin secretion predominantly though the hepatoportal-pancreatic vagal reflex pathways. American Journal of Physiology-Endocrinology and Metabolism, 2013. 305 (3): p. E376-E387.
Berthoud, H. R., A. C. Shin, and H. Zheng, Obesity surgery and gut-brain communication. Physiol Behav, 2011. 105 (1): p. 106-19.
Yamamoto, H., et al., Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J Neurosci, 2003. 23 (7): p. 2939-46.
Spinelli, V., et al., Influence of Roux-en-Y gastric bypass on plasma bile acid profiles: a comparative study between rats, pigs and humans. Int J Obes (Lond), 2016. 40 (8): p. 1260-7.
Peiris, M., et al., Effects of Obesity and Gastric Bypass Surgery on Nutrient Sensors, Endocrine Cells, and Mucosal Innervation of the Mouse Colon. Nutrients, 2018. 10 (10).
Potthoff, M. J., et al., Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol, 2013. 304 (4): p. G371-80.
Frikke-Schmidt, H., et al., Does bariatric surgery improve adipose tissue function? Obes Rev, 2016. 17 (9): p. 795-809.
Lou, G., et al., GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS One, 2014. 9 (4): p. e93567.
Kumar, D. P., et al., Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet alpha Cells to Promote Glucose Homeostasis. J Biol Chem, 2016. 291 (13): p. 6626-40.
Vettorazzi, J. F., et al., The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells. Metabolism, 2016. 65 (3): p. 54-63.
Vassileva, G., et al., Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice. Journal of Endocrinology, 2010. 205 (3): p. 225-232.
Poole, D. P., et al., Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil, 2010. 22 (7): p. 814-25, e227-8.
McMillin, M., et al., Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. Mol Endocrinol, 2015. 29 (12): p. 1720-30.
Luo, Q., et al., Endocannabinoid hydrolase and cannabinoid receptor 1 are involved in the regulation of hypothalamus-pituitary-adrenal axis in type 2 diabetes. Metab Brain Dis, 2018. 33 (5): p. 1483-1492.
Mano, N., et al., Presence of protein-bound unconjugated bile acids in the cytoplasmic fraction of rat brain. J Lipid Res, 2004. 45 (2): p. 295-300.
Xia, Z., et al., Influence of bariatric surgery on the expression of nesfatin-1 in rats with type 2 diabetes mellitus. Curr Pharm Des, 2015. 21 (11): p. 1464-71.
Chen, K., et al., Saxagliptin Upregulates Nesfatin-1 Secretion and Ameliorates Insulin Resistance and Metabolic Profiles in Type 2 Diabetes Mellitus. Metab Syndr Relat Disord, 2018. 16 (7): p. 336-341.
Prinz, P., et al., Peripheral and central localization of the nesfatin-1 receptor using autoradiography in rats. Biochem Biophys Res Commun, 2016. 470 (3): p. 521-527.
Bonnet, M. S., et al., Central NUCB2/Nesfatin-1-expressing neurones belong to the hypothalamic-brainstem circuitry activated by hypoglycaemia. J Neuroendocrinol, 2013. 25 (1): p. 1-13.
Gonzalez, R., et al., Nutrient responsive nesfatin-1 regulates energy balance and induces glucose-stimulated insulin secretion in rats. Endocrinology, 2011. 152 (10): p. 3628-37.
Pan, W., H. Hsuchou, and A. J. Kastin, Nesfatin-1 crosses the blood-brain barrier without saturation. Peptides, 2007. 28 (11): p. 2223-8.
Yang, M., et al., Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. Diabetes, 2012. 61 (8): p. 1959-68.
Su, Y., et al., The novel function of nesfatin-1: anti-hyperglycemia. Biochem Biophys Res Commun, 2010. 391 (1): p. 1039-42.
Ballsmider, L. A., et al., Sleeve gastrectomy and Roux-en-Y gastric bypass alter the gut-brain communication. Neural Plast, 2015. 2015: p. 601985.
Lam, C. K., et al., Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes, 2011. 60 (1): p. 107-13.
Yue, J. T., et al., Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity. Nat Commun, 2016. 7: p. 13501.
Aicher, S. A., S. Sharma, and V. M. Pickel, N-methyl-D-aspartate receptors are present in vagal afferents and their dendritic targets in the nucleus tractus solitarius. Neuroscience, 1999. 91 (1): p. 119-32.
Berthoud, H. R., et al., Food-related gastrointestinal signals activate caudal brainstem neurons expressing both NMDA and AMPA receptors. Brain Res, 2001. 915 (2): p. 143-54.
Wang, P. Y., et al., Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature, 2008. 452 (7190): p. 1012-6.
Tsumori, T., et al., Intrapancreatic ganglia neurons receive projection fibers from melanocortin-4 receptor-expressing neurons in the dorsal motor nucleus of the vagus nerve of the mouse. Brain Res, 2013. 1537: p. 132-42.
La Pierre, M. P., et al., Glucagon signalling in the dorsal vagal complex is sufficient and necessary for high-protein feeding to regulate glucose homeostasis in vivo. EMBO Rep, 2015. 16 (10): p. 1299-307.
Yan, Y., et al., Roux-en-Y Gastric Bypass Surgery Suppresses Hepatic Gluconeogenesis and Increases Intestinal Gluconeogenesis in a T2DM Rat Model. Obes Surg, 2016. 26 (11): p. 2683-2690.
Soty, M., et al., A gut-brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health. Mol Metab, 2015. 4 (2): p. 106-17.
Mu, S., et al., Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down-Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats. Obes Facts, 2017. 10 (3): p. 191-206.
Liu, J. Y., 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 (3): p. 2536-2542.
Bence, K. K., et al., Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med, 2006. 12 (8): p. 917-24.
Tsou, R. C., et al., Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor. Mol Metab, 2014. 3 (3): p. 301-12.
Yu, I. C., et al., Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-kappaB-mediated PTP1B expression. Diabetes, 2013. 62 (2): p. 411-23.
Kwon, I. G., et al., Roux-en-Y gastric bypass stimulates hypothalamic miR-122 and inhibits cardiac and hepatic miR-122 expressions. J Surg Res, 2015. 199 (2): p. 371-7.
Wu, Q., et al., Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery. Int J Obes (Lond), 2015. 39 (7): p. 1126-34.
Fong, M. Y., et al., Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol, 2015. 17 (2): p. 183-94.
Scott, W. R., et al., Differential pre-mRNA splicing regulates Nnat isoforms in the hypothalamus after gastric bypass surgery in mice. PLoS One, 2013. 8 (3): p. e59407.
Yang, J., et al., Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer. Oncogenesis, 2015. 4: p. e158.
Asahara, S. I., Neuronatin and glucose-induced stress in pancreatic beta cells. J Diabetes Investig, 2018.
Joe, M. K., et al., Crucial roles of neuronatin in insulin secretion and high glucose-induced apoptosis in pancreatic beta-cells. Cell Signal, 2008. 20 (5): p. 907-15.
Gu, T., et al., Molecular characterization of the Neuronatin gene in the porcine placenta. PLoS One, 2012. 7 (8): p. e43325.
Vrang, N., et al., The imprinted gene neuronatin is regulated by metabolic status and associated with obesity. Obesity (Silver Spring), 2010. 18 (7): p. 1289-96.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186