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GLP1, an Important Regulator of Intestinal Lipid Metabolism

2015; Lippincott Williams & Wilkins; Volume: 35; Issue: 5 Linguagem: Inglês

10.1161/atvbaha.115.305479

1524-4636

Geesje M. Dallinga‐Thie, Max Nieuwdorp,

Liver Disease Diagnosis and Treatment

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 35, No. 5GLP1, an Important Regulator of Intestinal Lipid Metabolism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBGLP1, an Important Regulator of Intestinal Lipid Metabolism Geesje M. Dallinga-Thie and Max Nieuwdorp Geesje M. Dallinga-ThieGeesje M. Dallinga-Thie From the Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (G.M.D.-T., M.N.); Department of Internal Medicine, VUMC Diabetes Center, VUMC, Amsterdam, The Netherlands (M.N.); and Wallenberg Laboratory, University of Gothenberg, Gothenberg, Sweden (M.N.). and Max NieuwdorpMax Nieuwdorp From the Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (G.M.D.-T., M.N.); Department of Internal Medicine, VUMC Diabetes Center, VUMC, Amsterdam, The Netherlands (M.N.); and Wallenberg Laboratory, University of Gothenberg, Gothenberg, Sweden (M.N.). Originally published1 May 2015https://doi.org/10.1161/ATVBAHA.115.305479Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:1048–1049Plasma triglycerides have since long been recognized as risk for cardiovascular disease.1,2 Recently, large population studies have further used this relationship and established renewed evidence for a causal relationship, which even extended toward nonfasting triglyceride levels. These studies provide further evidence for a causal role of triglyceride-rich lipoproteins in cardiovascular disease. Patients with type 2 diabetes mellitus are characterized by an increased plasma triglyceride levels and decreased high-density lipoprotein cholesterol levels, the atherogenic lipoprotein phenotype.3 More pronounced is the abnormal postprandial lipid response. Most of the circulating triglycerides are originating from dietary origin and provide an instrumental role for the intestine in triglyceride homeostasis. Yet, the regulation of the process of the intestinal lipid absorption is still largely unknown.See accompanying article on page 1092The central regulation of the brain may be instrumental in the regulation of triglyceride homeostasis. The autonomous nervous system, consisting of parasympathetic and sympathetic nerves, has been related to triglyceride metabolism by regulating adipose tissue activation and liver triglyceride homeostasis.4,5 The hypothalamus is the center of nerve signaling to densely innervated abdominal organs such as adipose tissue and liver. Hence, hepatic triglyceride production, reflected by very-low-density lipoprotein-triglyceride secretion, was attenuated during intracerebroventricular injection of neuropeptide Y in hyperinsulinemic mice as well as in rats.6,7 Inline, neuropeptide Y signaling decreases sympathetic outflow to adipose tissue resulting in decreased lipolysis in white as well as brown adipose tissue. In contrast, stimulation of the melanocortin-driven neurons induces more catabolic effects represented by increased white adipose tissue lipolysis, brown adipose tissue activation, and reductions in hepatic very-low-density lipoprotein-triglyceride secretion and hepatic triglyceride content.After ingestion of a meal, the small intestine rapidly secretes various hormones including the incretin hormone glucagon-like protein-1 (GLP1) that has been implicated as an important regulator of satiety through MC4R (melanocortin 4 receptor)-mediated sympathetic nerve activity in different animal models. Also, GLP1 directly affects triglyceride homeostasis by reducing hepatic and adipose tissue lipid stores.5,8 Indeed, it has been shown that exogenous increases in plasma GLP1 including inhibitors of the enzyme dipeptidyl peptidase 4 (that degrades GLP1) and longacting GLP1 receptor agonists rapidly reduce plasma triglyceride levels and hepatic triglyceride stores. As GLP1 is synthesized in L-cells located in the small intestine, it has already been suggested that GLP1 may affect intestinal lipid absorption and thus postprandial triglyceride excursions. However, the role of the central nerve system in this process has never been investigated.Farr et al9 tested the hypothesis that central GLP1-mediated neuronal signaling may underlie chylomicron secretion in an insulin-resistant environment using the Syrian hamster, a unique model, which closely resembles the human lipoprotein features with apoB48 synthesis only in the intestine and apoB100 production in the liver. Chylomicron secretion was measured after an oral dose of olive oil and Pluronic F-127, a compound that inhibits lipoprotein lipase-mediated lipoprotein clearance. When GLP1 receptor agonist was administered intracerebroventricular, it resulted in a significant reduction in postprandial plasma triglyceride-rich lipoprotein (TRL)-apoB48 and triglycerides, suggesting an important role for central GLP1 in intestinal chylomicron secretion. Indeed, intracerebroventricular administration of a GLP1R antagonist has a similar effect on postprandial lipid response, whereas a smaller effect was noted on intracerebroventricular injection of a dipeptidyl peptidase 4 inhibitor. Peripheral administration of the GLP1 agonist also reduces postprandial TRL-triglycerides and apoB48 response independent of cerebral GLP1R activation. In conclusion, one can postulate that endogenous GLP1 exerts its triglyceride reducing effect through interaction with both peripheral GLP1 receptors and GLP1-receptors located on central neurons in which MC4R signaling is involved.What do we learn from these studies with regard to human (postprandial) triglyceride physiology in insulin resistance? Dipeptidyl peptidase 4 inhibitors (which are currently in phase III clinical development phase) have all shown to improve postprandial plasma TRL-triglycerides and apoB48 levels, whereas no changes were found in hepatic very- low-density lipoprotein secretion and plasma triglycerides and apoB100 levels.10 A similar observation was made for the GLPI receptor agonist exendin 4.11,12 In line, kinetic stable isotope-based studies reveal that exendin 4 affects chylomicron secretion independent of changes in bodyweight, satiety, and gastric emptying. Thus, the reported lack of effect on GLP1 on hepatic lipoprotein metabolism in humans may be a consequence of the absence of GLP1 receptors in the liver. However, GLP1 involves a central (brain)signaling as GLP1 receptor blockade by exendin 3 to 39 was able to block the effect of exendin 4 on food intake and satiety.13 Overall, the GLP1 analogues and the dipeptidyl peptidase 4 inhibitors are excellent drugs to improve insulin sensitivity in patients with type 2 diabetes mellitus, yet their effect on plasma lipids remains to be studied.DisclosuresNone.FootnotesThis manuscript was sent to Theo van Berkel, Consulting Editor, for review by expert referees, editorial decision, and final disposition.Correspondence to Geesje M. Dallinga-Thie, PhD, Department of Experimental Vascular Medicine G1.113, AMC, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands. E-mail [email protected]References1. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study.Clin Chem. 2014; 60:737–746. doi: 10.1373/clinchem.2013.219881.CrossrefMedlineGoogle Scholar2. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease.Lancet. 2014; 384:626–635. doi: 10.1016/S0140-6736(14)61177-6.CrossrefMedlineGoogle Scholar3. Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes.Atherosclerosis. 2015; 239:483–495. doi: 10.1016/j.atherosclerosis.2015.01.039.CrossrefMedlineGoogle Scholar4. Bartelt A, Heeren J. Adipose tissue browning and metabolic health.Nat Rev Endocrinol. 2014; 10:24–36. doi: 10.1038/nrendo.2013.204.CrossrefMedlineGoogle Scholar5. Geerling JJ, Boon MR, Kooijman S, Parlevliet ET, Havekes LM, Romijn JA, Meurs IM, Rensen PC. Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies.J Lipid Res. 2014; 55:180–189. doi: 10.1194/jlr.R045013.CrossrefMedlineGoogle Scholar6. van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM, Pijl H. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin.Diabetes. 2004; 53:2529–2534.CrossrefMedlineGoogle Scholar7. Bruinstroop E, Pei L, Ackermans MT, Foppen E, Borgers AJ, Kwakkel J, Alkemade A, Fliers E, Kalsbeek A. Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system.Diabetes. 2012; 61:1043–1050. doi: 10.2337/db11-1142.CrossrefMedlineGoogle Scholar8. van Genugten RE, Moller-Goede DL, van Raalte DH, Diamant M. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes.Diabetes Obes Metab. 2013; 15:593–606.CrossrefMedlineGoogle Scholar9. Farr S, Baker C, Naples M, Taher J, Iqbal J, Hussain M, Adeli K. Central nervous system regulation of intestinal lipoprotein metabolism by glucagon-like peptide-1 via a brain-gut axis.Arterioscler Thromb Vasc Biol. 2015; 35:1092–1100. doi: 10.1161/ATVBAHA.114.304873.LinkGoogle Scholar10. Matikainen N, Mänttäri S, Schweizer A, Ulvestad A, Mills D, Dunning BE, Foley JE, Taskinen MR. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes.Diabetologia. 2006; 49:2049–2057. doi: 10.1007/s00125-006-0340-2.CrossrefMedlineGoogle Scholar11. Xiao C, Bandsma RH, Dash S, Szeto L, Lewis GF. Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans.Arterioscler Thromb Vasc Biol. 2012; 32:1513–1519. doi: 10.1161/ATVBAHA.112.246207.LinkGoogle Scholar12. Schwartz EA, Koska J, Mullin MP, Syoufi I, Schwenke DC, Reaven PD. Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus.Atherosclerosis. 2010; 212:217–222. doi: 10.1016/j.atherosclerosis.2010.05.028.CrossrefMedlineGoogle Scholar13. van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans.Diabetes. 2014; 63:4186–4196. doi: 10.2337/db14-0849.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jendle J, Hyötyläinen T, Orešič M and Nyström T (2021) Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride, Cardiovascular Diabetology, 10.1186/s12933-021-01431-2, 20:1, Online publication date: 1-Dec-2021. Yaribeygi H, Maleki M, Butler A, Jamialahmadi T, Sahebkar A and Sasaoka T (2021) The Impact of Incretin-Based Medications on Lipid Metabolism, Journal of Diabetes Research, 10.1155/2021/1815178, 2021, (1-10), Online publication date: 29-Dec-2022. Madsbad S (2019) Liraglutide for the prevention of major adverse cardiovascular events in diabetic patients, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2019.1615444, 17:5, (377-387), Online publication date: 4-May-2019. Tavares R, Escada-Rebelo S, Silva A, Sousa M, Ramalho-Santos J and Amaral S Antidiabetic therapies and male reproductive function: where do we stand?, Reproduction, 10.1530/REP-17-0390, 155:1, (R13-R37) Murad A, Cohen R, de Godoy E, Scheibe C, Campelo G, Ramos A, de Lima R, Pinto L, Coelho D, Costa H, Pinto Í, Pereira T, Teófilo F and Valadão J (2017) A Prospective Single-Arm Trial of Modified Long Biliopancreatic and Short Alimentary Limbs Roux-En-Y Gastric Bypass in Type 2 Diabetes Patients with Mild Obesity, Obesity Surgery, 10.1007/s11695-017-2933-x, 28:3, (599-605), Online publication date: 1-Mar-2018. Engelbrechtsen L, Lundgren J, Wewer Albrechtsen N, Mahendran Y, Iepsen E, Finocchietto P, Jonsson A, Madsbad S, Holst J, Vestergaard H, Hansen T and Torekov S (2017) Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB, Obesity Science & Practice, 10.1002/osp4.133, 3:4, (425-433), Online publication date: 1-Dec-2017. Pelusi C (2022) The Effects of the New Therapeutic Treatments for Diabetes Mellitus on the Male Reproductive Axis, Frontiers in Endocrinology, 10.3389/fendo.2022.821113, 13 Rajpal D, Klein J, Mayhew D, Boucheron J, Spivak A, Kumar V, Ingraham K, Paulik M, Chen L, Van Horn S, Thomas E, Sathe G, Livi G, Holmes D, Brown J and Blachier F (2015) Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models, PLOS ONE, 10.1371/journal.pone.0145499, 10:12, (e0145499) May 2015Vol 35, Issue 5 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.115.305479PMID: 25903650 Originally publishedMay 1, 2015 Keywordsglucagon-like peptide 1Editorialscentral nervous systemchylomicronsPDF download Advertisement