Abstract
Purpose
Expression of IGFBP-2 in mice is regulated by leptin. Over-expression of IGFBP-2 is associated with reduced caloric intake and resistance to weight gain. Hormonal variations contributing to weight loss occur very early after bariatric surgery but have not been fully elucidated. We evaluated IGFBP-2 serum changes after bariatric surgery and their relationship with leptin variations to test the hypothesis that an increase of leptin sensitivity may explain some of the effects of gastric bypass.
Methods
This is a historical prospective study. Fifty-one obese patients (41 women e 10 men), 9 non-obese surgical controls and 41 lean matched controls were studied. Serum IGFBP-2 and leptin were measured after bariatric bypass surgery at various time points up to 18 months, after non-bariatric laparoscopic surgery in a control group, and in lean matched controls.
Results
Compared to lean controls, serum IGFBP-2 levels were lower in obese patients. After gastric bypass, IGFBP-2 significantly increased at 3 days and became normal before the occurrence of relevant changes in body weight, remaining stable up to 18 months after surgery. IGFBP-2/leptin ratio increased early after surgery and became normal after one year.
Conclusions
After gastric bypass, serum IGFBP-2 increases in a window of time when variations of hormones mediating the effects of bariatric surgery occur. Our results suggest that IGFBP-2, a leptin-regulated protein, may be an in-vivo marker of leptin action. If this is the case, an early improvement of leptin sensitivity might contribute to the anorectic effect of gastric bypass.
Similar content being viewed by others
References
S. Rajaram, D. Baylink, S. Mohan, Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr. Rev. 6, 801–831 (1997)
A. Hoeflich, V.C. Russo, Physiology and pathophysiology of IGFBP-1 and IGFBP-2 - consensus and dissent on metabolic control and malignant potential. Best. Pract. Res. Clin. Endocrinol. Metab. 5, 685–700 (2015)
X. Yao, S. Sun, X. Zhou, W. Guo, L. Zhang, IGF-binding protein 2 is a candidate target of therapeutic potential in cancer. Tumor Biol. 2, 1451–1459 (2016)
C.M. Boney, B.M. Moats Staats, A.D. Stiles, A.J. D’Ercole, Expression of insulin-like growth factor – 1 (IGF-I) and IGF- binding proteins during adipogenesis. Endocrinology 5, 1863–1868 (1994)
Z. Li, F. Picard, Modulation of IGFBP-2 mRNA expression in white adipose tissue upon aging and obesity. Horm. Metab. Res. 11, 787–791 (2010)
S.W. Yau, B.A. Henry, V.C. Russo, G.K. McConell, I.J. Clarke, G.A. Werther, M.A. Sabin, Leptin enhances insulin sensitivity by direct and sympathetic nervous system regulation of muscle IGFBP-2 expression: evidence from nonrodent models. Endocrinology 6, 2133–2143 (2014)
G. Xi, M.A. Solum, C. Wai, L. Maile, C.J. Rosen, D.R. Clemmons, The heparin-binding domains of igfbp-2 mediate its inhibitory effect on preadipocyte differentiation and fat development in male mice. Endocrinology 11, 4146–4157 (2013)
S.W. Yau, V.C. Russo, I.J. Clarke, F.R. Dunshea, G.A. Werther, M.A. Sabin, IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes. Int. J. Obes. 5, 770–781 (2015)
S.B. Wheatcroft, M.T. Kearney, A.M. Shah, V.E. Ezzat, J.R. Miell, M. Modo, S.C. Williams, W.P. Cawthorn, G. Medina-Gomez, A. Vidal-Puig et al. IGF-binding protein-2 protects against the development of obesity and insulin resistance. Diabetes 56, 285–294 (2007)
J. Frystyk, C. Skjærbæk, E. Vestbo, S. Fisker, H. Ørskov, Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab. Res. Rev. 15, 314–322 (1999)
R.M. Martin, J.M.P. Holly, G.D. Smith, D. Gunnel, Associations of adiposity from childhood into adulthood with Insulin Resistance and the Insulin-like growth factor system: 65-year follow-up of the Boyd Orr Cohort. J. Clin. Endocrinol. Metab. 9, 3287–3295 (2006)
W. Ruan, M. Lai, Insulin-like growth factor binding protein: a possible marker for the metabolic syndrome? Acta Diabetol. 1, 5–14 (2010)
S. Carter, Z. Li, I. Lemieux, N. Alméras, A. Tremblay, J. Bergeron, P. Poirier, Y. Deshaies, J.P. Després, F. Picard, Circulating IGFBP-2 levels are incrementally linked to correlates of the metabolic syndrome and independently associated with VLDL triglycerides. Atherosclerosis. 2, 645–651 (2014)
S.A. Halim, M.L. Neely, K.S. Pieper, S.H. Shah, W.E. Kraus, E.R. Hauser, R.M. Califf, C.B. Granger, L.K. Newby, Simultaneous consideration of multiple candidate protein biomarkers for long-term risk for cardiovascular events. Circ. Cardiovasc. Genet. 1, 168–177 (2015)
E. Asilmaz, P. Cohen, M. Miyazaki, P. Dobrzyn, K. Ueki, G. Fayzikhodjaeva, A.A. Soukas, C.R. Kahn, J.M. Ntambi, N.D. Socci et al. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J. Clin. Invest. 3, 414–424 (2004)
K. Hedbacker, K. Birsoy, R.W. Wysocki, E. Asilmaz, R.S. Ahima, I.S. Farooqi, J.M. Friedman, Antidiabetic effects of IGFBP2, a Leptin-Regulated Gene. Cell. Metab. 11, 11–22 (2010)
U.H. Neumann, S. Chen, Y.Y. Tam, R.K. Baker, S.D. Covey, P.R. Cullis, T.J. Kieffer, IGFBP2 is neither sufficient nor necessary for the physiological actions of leptin on glucose homeostasis in male ob/ob mice. Endocrinology 3, 716–725 (2014)
S. Manning, A. Pucci, N.C. Carter, M. Elkalaawy, G. Querci, S. Magno, A. Tamberi, N. Finer, A.G. Fiennes, M. Hashemi et al. Early postoperative weight loss predicts maximal weight loss after sleeve gastrectomy and Roux-en-Y gastric bypass. Surg. Endosc. 6, 1484–1491 (2015)
G. Ceccarini, A.M. Ciccarone, F. Santini, S. Del Prato, Integrating medical and surgical therapies to optimize the outcomes of type 2 diabetes. Surg. Obes. Relat. Dis. 6, 1186–1191 (2016)
V. Lonut, R.N. Bergman, Mechanisms responsible for excess weight loss after bariatric surgery. J. Diabetes. Sci. Technol. 5, 1263–1282 (2011)
D.E. Cummings, J. Overduin, K.E. Foster-Shubert, Gastric Bypass for obesity: mechanisms of weight loss and diabetes resolution. J. Clin. Endocrinol. Metab. 6, 2608–2615 (2004)
C.N. Ochner, C. Gibson, M. Shanik, V. Goel, A. Geliebter, Changes in neurohormonal gut peptides following bariatric surgery. Int. J. Obes. 2, 153–166 (2011)
M. Bose, S. Machineni, B. Oliván, J. Teixeira, J.J. McGinty, B. Bawa, N. Koshy, A. Colarusso, B. Laferrère. Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding. Obesity 6, 1085–1091 (2010)
J.M. Friedman, Leptin and the regulation of body weight. Keio J. Med. 1, 1–9 (2011)
G. Ceccarini, M. Maffei, P. Vitti, F. Santini, Fuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways. J. Endocrinol. Invest. 2, 125–131 (2015)
Z. Hao, M.B. Mumphrey, C.D. Morrison, H. Münzberg, J. Ye, H.R. Berthoud, Does gastric bypass surgery change body weight set point? Int. J. Obes. Suppl 1, S37–S43 (2016)
Società Italiana dell’Obesità e Associazione Italiana di Dietetica e Nutrizione Clinica. Standard Italiani per la Cura dell’Obesità SIO-ADI 2016/2017. http://www.sio-obesita.org/clinica. Accessed 19 Jan 2019
M.B. Ranke, R. Schweizer, M.W. Elmlinger, K. Weber, G. Binder, C.P. Schwarze, H.A. Wollmann, Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm. Res. 2, 60–68 (2000)
D.E. Arterburn, M.K. Olsen, V.A. Smith, E.H. Livingston, L. Van Scoyoc, W.S. Yancy Jr, G. Eid, H. Weidenbacher, M.L. Maciejewski, Association between bariatric surgery and long-term survival. JAMA. 313, 62–70 (2015)
L. Sjöström, Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study. Int. J. Obes. Suppl 7, S93–S97 (2008)
C.D. Morrison, Leptin resistance and the response to positive energy balance. Physiol. Behav. 5, 660–663 (2008)
H. Cui, M. López, K. Rahmouni, The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol. 6, 338–351 (2017)
Z. Li, J. Martin, P. Poirier, S.M. Caron-Cantin, F.S. Hould, S. Marceau, P. Marceau, F. Picard, Upregulation of Plasma Insulin-like growth factor binding protein 2 levels after biliopancreatic diversion in humans. Obesity. 7, 1469–1473 (2012)
J.B. Dixon, N.E. Straznicky, E.A. Lambert, M.P. Schlaich, G.W. Lambert, Surgical approaches to the treatment of obesity. Nat Rev Gastroenterol Hepatol. 8, 429–437 (2011)
M. Ahrens, O. Ammerpohl, W. von Schönfels, J. Kolarova, S. Bens, T. Itzel, A. Teufel, A. Herrmann, M. Brosch, H. Hinrichsen et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell. Metab. 2, 296–302 (2013)
W.J. Smith, L.E. Underwood, D.R. Clemmons, Effects of caloric or protein restriction on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in children and adults. J. Clin. Endocrinol. Metab. 2, 443–449 (1995)
V. Touskova, P. Trachta, P. Kavalkova, J. Drapalova, D. Haluzikova, M. Mraz, Z. Lacinova, J. Marek, M. Haluzik, Serum concentrations and tissue expression of components of insulin-like growth factor-axis in females with type 2 diabetes mellitus and obesity: the influence of very-low-calorie diet. Mol. Cell. Endocrinol. 1–2, 172–178 (2012)
Z. Hao, H. Münzberg, K. Rezai-Zadeh, M. Keenan, D. Coulon, H. Lu, H.R. Berthoud, J. Ye, Leptin deficient ob/ob mice and diet-induced obese mice responded differently to Roux-en-Y bypass surgery. Int. J. Obes. 5, 798–805 (2015)
M. Mokadem, J.F. Zechner, A. Uchida, V. Aguirre. Leptin is required for glucose homeostasis after roux-en-y gastric bypass in mice. PLoS ONE. (2015) https://doi.org/10.1371/journal.pone.0139960
J.D. Roth, B.L. Roland, R.L. Cole, J.L. Trevaskis, C. Weyer, J.E. Koda, C.M. Anderson, D.G. Parkes, A.D. Baron, Leptin responsiveness restored by amylin agonism indiet-induced obesity: Evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA 20, 7257–7262 (2008)
J.L. Trevaskis, T. Coffey, R. Cole, C. Lei, C. Wittmer, B. Walsh, C. Weyer, J. Koda, A.D. Baron, D.G. Parkes et al. Amylin-mediated restoration of leptin responsiveness indiet-induced obesity: magnitude and mechanisms. Endocrinology 11, 5679–5687 (2008)
J. Korner, R. Conroy, G. Febres, D.J. McMahon, I. Conwell, W. Karmally, L.J. Aronne, Randomized double-blind placebo-controlled study of leptin administration after gastric bypass. Obesity. 5, 951–956 (2013)
K. Miyako, L.J. Cobb, M. Francis, A. Huang, B. Peng, J.E. Pintar, H. Ariga, P. Cohen, Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions. Mol. Endocrinol. 2, 169–175 (2009)
W.J. Azar, S. Zivkovic, G.A. Werther, V.C. Russo, IGFBP-2 nuclear translocation is mediated by a functional NLS sequence and is essential for its pro-tumorigenic actions in cancer cells. Oncogene 5, 578–588 (2014)
K.W. Frommer, K. Reichenmiller, B.S. Schutt, A. Hoeflich, M.B. Ranke, G. Dodt, M.W. Elmlinger, IGF-indipendent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J. Mol. Endocrinol. 1, 13–23 (2006)
S.B. Wheatcroft, M.T. Kearney, IGF-dependent and IGF-independent actions of IGF-binding protein-1 e –2: implications for metabolic homeostasis. Trends. Endocrinol. Metab. 4, 153–162 (2009)
Acknowledgements
We thank Lucia Nardelli, Martina Passetto and Massimiliano Benvenuti for their help in managing patients’ samples.
Funding
This work was supported by the Rita Levi Montalcini program funding (year 2009). The study was partially supported by the Italian Ministry of the University, Project code 2015JSWLTN: Metabolic flexibility and ectopic fat. Adiposity phenotype, mitochondrial dysfunction, hepatic inflammation, gut microbiota, cardiac failure and genetics for a comprehensive understanding of the cross-talk among adipose tissue, liver, and musculo-skeletal system.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest related to this study.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Local Ethical Committee and with the 1964 Helsinki declaration and its later amendments.
Informed consent
Informed consent was obtained from all individuals included in this study.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ceccarini, G., Pelosini, C., Ferrari, F. et al. Serum IGF-binding protein 2 (IGFBP-2) concentrations change early after gastric bypass bariatric surgery revealing a possible marker of leptin sensitivity in obese subjects. Endocrine 65, 86–93 (2019). https://doi.org/10.1007/s12020-019-01915-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-019-01915-y