title: GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.
abstract: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).
  
  
  
  In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.
  
  
  
  Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.
  
  
  
  For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.
  
  
  
  ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. ofarr@bidmc.harvard.edu.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Farr
authors.affiliation: Department of Pathology, St Savvas Anticancer-Oncology Hospital, Athens, Greece.
authors.forename: Michail
authors.initials: M
authors.lastname: Sofopoulos
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tsoukas
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Fadime
authors.initials: F
authors.lastname: Dincer
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Bindiya
authors.initials: B
authors.lastname: Thakkar
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Ayse
authors.initials: A
authors.lastname: Sahin-Efe
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Filippaios
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bowers
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Srnka
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gavrieli
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.|Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Joon
authors.initials: BJ
authors.lastname: Ko
authors.affiliation: Department of Pathology, St Savvas Anticancer-Oncology Hospital, Athens, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Liakou
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Nickole
authors.initials: N
authors.lastname: Kanyuch
authors.affiliation: First Department of Pathology, University of Athens, Medical School, Athens, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Tseleni-Balafouta
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA.
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D000069450:Liraglutide / Q000494:pharmacology* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: Brain; Diabetes; GLP-1; Immunohistochemistry; Liraglutide; MRI; fMRI
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