Abstract
Purpose
Leptin is an adipokine which regulates appetite and energy balance through a mechanism partially mediated by neurotensin (NT) in central nervous system. Besides acting as a neurotransmitter, NT is expressed in human intestine where it promotes fat absorption and its circulating levels associate with obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Whether a relation exists between circulating leptin and NT levels has not been investigated yet. The aim of this study was to test the hypothesis of an association between plasma leptin and NT concentration in adults with or without T2DM.
Methods
We recruited a population of 72 subjects (M/F: 39/33; age: 49.5 ± 10.6 years; BMI: 26.5 ± 4.7 kg/m2) including individuals with T2DM (n = 32) referring to our Diabetes Outpatient Clinics, Sapienza University of Rome, and healthy controls. Study participants underwent metabolic characterization; plasma leptin was measured by MILLIPLEX, Luminex, and proneurotensin (proNT), a stable precursor of NT, by chemiluminometric sandwich immunoassay.
Results
Circulating median (25°–75°) leptin levels were 2.75 (1.27–4.93) ng/mL and did not differ between T2DM and non-diabetic subjects. Leptin concentration directly correlated with proNT (r = 0.41; p = 0.015); higher leptin levels were also associated with age, male gender, obesity, higher HOMA-IR, systolic blood pressure and C-reactive protein. Belonging to the highest pro-NT quartile correlated with greater leptin levels independent of age, gender and other confounders (r2 = 0.82, p = 0.02).
Conclusions
Circulating leptin is associated with higher proNT levels independent of diabetes, obesity and metabolic syndrome components; besides its effects on central leptin signaling, NT may influence energy balance by modulating circulating leptin concentration likely through a mechanism involving gut fat absorption.
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References
Münzberg H, Morrison CD (2015) Structure, production and signaling of leptin. Metabolism 64:13–23. https://doi.org/10.1016/j.metabol.2014.09.010
Bouchard C, Tchernof A, Tremblay A (2014) Predictors of body composition and body energy changes in response to chronic overfeeding. Int J Obes 38:236–242. https://doi.org/10.1038/ijo.2013.77
Sáinz N, Barrenetxe J, Moreno-Aliaga MJ, Martínez JA (2015) Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism 64:35–46. https://doi.org/10.1016/j.metabol.2014.10.015
Guilmeau S, Buyse M, Tsocas A, Laigneau JP, Bado A (2003) Duodenal leptin stimulates cholecystokinin secretion: evidence of a positive leptin-cholecystokinin feedback loop. Diabetes 52:1664–1672
Degen L, Matzinger D, Drewe J, Nisslé S, Maecke H, Lengsfeld H, Hadvary P, Beglinger C (2006) Role of free fatty acids in regulating gastric emptying and gallbladder contraction. Digestion 74:131–139
Beall C, Hanna L, Ellacott KLJ (2017) CNS targets of adipokines. Compr Physiol 7:1359–1406. https://doi.org/10.1002/cphy.c160045
Farr OM, Gavrieli A, Mantzoros CS (2015) Leptin applications in 2015: what have we learned about leptin and obesity? Curr Opin Endocrinol Diabetes Obes 22:353–359. https://doi.org/10.1097/MED.0000000000000184
Vettor R, Fabris R, Pagano C, Federspil G (2002) Neuroendocrine regulation of eating behavior. J Endocrinol Invest 25(10):836–854 (Review. PubMed PMID: 12508946)
Brown JA, Bugescu R, Mayer TA, Gata-Garcia A, Kurt G, Woodworth HL, Leinninger GM (2017) Loss of action via neurotensin-leptin receptor neurons disrupts leptin and ghrelin-mediated control of energy balance. Endocrinology 158:1271–1288. https://doi.org/10.1210/en.2017-00122
Liu JJ, Bello NT, Pang ZP (2017) Presynaptic regulation of leptin in a defined lateral hypothalamus-ventral tegmental area neurocircuitry depends on energy state. J Neurosci 37:11854–11866. https://doi.org/10.1523/JNEUROSCI.1942-17.2017
Drewe J, Mihailovic S, D’Amato M, Beglinger C (2008) Regulation of fat-stimulated neurotensin secretion in healthy subjects. J Clin Endocrinol Metab 93:1964–1970. https://doi.org/10.1210/jc.2007-2238
Grunddal KV, Ratner CF, Svendsen B, Sommer F, Engelstoft MS, Madsen AN, Pedersen J, Nøhr MK, Egerod KL, Nawrocki AR, Kowalski T, Howard AD, Poulsen SS, Offermanns S, Bäckhed F, Holst JJ, Holst B, Schwartz TW (2016) Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157:176–194. https://doi.org/10.1210/en.2015-1600
Melander O, Maisel AS, Almgren P, Manjer J, Belting M, Hedblad B, Engström G, Kilger U, Nilsson P, Bergmann A, Orho-Melander M (2012) Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. JAMA 308:1469–1475. https://doi.org/10.1001/jama.2012.12998
Januzzi JL Jr, Lyass A, Liu Y, Gaggin H, Trebnick A, Maisel AS et al (2016) Circulating proneurotensin concentrations and cardiovascular disease events in the community: The Framingham Heart Study. Arterioscler Thromb Vasc Biol 36:1692–1697
Li J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K, Starr ME, Kim JT, Harris JW, Yiannikouris FB, Katz WS, Nilsson PM, Orho-Melander M, Chen J, Zhu H, Fahrenholz T, Higashi RM, Gao T, Morris AJ, Cassis LA, Fan TW, Weiss HL, Dobner PR, Melander O, Jia J, Evers BM (2016) An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533:411–415. https://doi.org/10.1038/nature17662
Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470
Sagher FA, Dodge JA, Johnston CF, Shaw C, Buchanan KD, Carr KE (1991) Rat small intestinal morphology and tissue regulatory peptides: effects of high dietary fat. Br J Nutr 65:21–28
Goforth PB, Leinninger GM, Patterson CM, Satin LS, Myers MG Jr (2014) Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms. J Neurosci 34:11405–11415. https://doi.org/10.1523/JNEUROSCI.5167-13.2014
Leinninger GM, Opland DM, Jo YH, Faouzi M, Christensen L, Cappellucci LA, Rhodes CJ, Gnegy ME, Becker JB, Pothos EN, Seasholtz AF, Thompson RC, Myers MG Jr (2011) Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab 14:313–323. https://doi.org/10.1016/j.cmet.2011.06.016
Cammisotto PG, Levy E, Bukowiecki LJ, Bendayan M (2010) Cross-talk between adipose and gastric leptins for the control of food intake and energy metabolism. Prog Histochem Cytochem 45:143–200. https://doi.org/10.1016/j.proghi.2010.06.001
Anini Y, Brubaker PL (2003) Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52:252–259
Tang LL, Tang XH, Li X, Yu HB, Xie ZG, Liu XY, Zhou ZG (2014) Effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in mice. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 36:614–619. https://doi.org/10.3881/j.issn.1000-503X.2014.06.010
Funding
This study was founded by Grants from Sapienza University (MGC). IB is supported by a fellowship from the “Fondazione Lilly”.
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The authors declare that they have no conflict of interest.
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The study protocol was reviewed and approved by the Ethics Committee of Policlinico Umberto I, Sapienza University of Rome and conducted in conformance with the Helsinki Declaration.
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Written informed consent was obtained from all individual participants included in the study.
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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Barchetta, I., Ciccarelli, G., Cimini, F.A. et al. Association between systemic leptin and neurotensin concentration in adult individuals with and without type 2 diabetes mellitus. J Endocrinol Invest 41, 1159–1163 (2018). https://doi.org/10.1007/s40618-018-0845-9
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DOI: https://doi.org/10.1007/s40618-018-0845-9