Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

Fax +41 61 306 12 34E-Mail [email protected]

Original Paper

Horm Res Paediatr 2012;78:47–53 DOI: 10.1159/000338464

Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

Clinton T. Elfers a Jill H. Simmons b Christian L. Roth a

a Seattle Children’s Research Institute, Seattle, Wash. , and b Division of Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn. , USA

Introduction

Craniopharyngioma (CP) is an epithelial neoplasm of non-glial origin occupying the sellar region which com-prises 4.1% of primary brain and central nervous system (CNS) tumors in children ages 0–14 years and 2.9% in children ages 15–19 years [1] . Excessive weight gain sec-ondary to hypothalamic injury due to tumor infiltration is common amongst patients with hypothalamic tumors at the time of diagnosis [2] . Risk factors for the develop-ment of severe obesity include large hypothalamic tu-mors affecting several medial hypothalamic nuclei in-cluding the arcuate nucleus (ARC), ventromedial nucleus (VMN), and dorsomedial nucleus (DMN), and tumors that reach the floor of the third ventricle, transcranial surgical tumor removal, aggressiveness of resection, re-operation for tumor reoccurrence, and hypothalamic ir-radiation [3–6] .

Hypothalamic obesity (HO) is characterized by de-creased basal metabolic rate, hyperinsulinemia, and leptin resistance due to hypothalamic disruption [3, 7–10] . After resection or radiotherapy of CP, a distinct trend in weight gain has been observed in children with HO. Specifically, a rapid gain in body mass index SDS for

Key Words

Hypothalamic lesion � Exendin-4 � Exenatide � GLP-1 � Body weight � Food intake � Germ cell tumor

Abstract

Background: Hypothalamic obesity caused by damage of medial hypothalamic nuclei presents a therapeutic chal-lenge. Glucagon-like peptide-1 agonist exenatide (synthetic version of exendin-4 (Ex4)), used for treatment of diabetes, causes weight loss via hindbrain signaling. Methods: We tested Ex4 in an established rat model of medial hypotha-lamic lesions. Lesion and control animals were administered either daily intraperitoneal injections of 1 � g·kg –1 Ex4 or sa-line for 9 days. Results: In our rat model, a significant differ-ence in percent baseline food intake (lesion –20.8%, control –13.6%; p ! 0.001) and percent change in body weight (lesion –4.9%/9 days, control –3.2%/9 days; p ! 0.05) was observed during Ex4 treatment compared with saline. Conclusion: Ex4 resulted in reduction of food intake and body weight. Fol-low-up studies are required to further elucidate its effects on energy homeostasis and to establish Ex4 as a potential drug for treatment of hypothalamic obesity.

Copyright © 2012 S. Karger AG, Basel

Received: January 17, 2012 Accepted: March 28, 2012 Published online: July 20, 2012

HORMONERESEARCH IN PÆDIATRICS

Christian L. Roth, MD Division of Endocrinology Seattle Children’s Hospital Research Institute 1900 Ninth Avenue, Seattle, WA 98101 (USA) Tel. +1 206 987 5428, E-Mail christian.roth @ seattlechildrens.org

© 2012 S. Karger AG, Basel1663–2818/12/0781–0047$38.00/0

Accessible online at:www.karger.com/hrp

http://dx.doi.org/10.1159%2F000338464

Elfers /Simmons /Roth

Horm Res Paediatr 2012;78:47–5348

the first 6 months followed by an attenuation of weight gain yielding long-term stabilization [11] is common. De-spite patient reports of hyperphagia, recent studies have shown an overall decrease in energy intake in patients with HO as compared to controls [9, 10] . However, the reduction in energy intake is offset by a greater relative decrease in basal metabolic rate [9, 10] and physical ac-tivity-related energy expenditure [9, 10] in HO patients. Despite these findings, weight loss through caloric re-striction and exercise has been largely unsuccessful [12, 13] . Pharmacological treatment of HO and hyperphagia have shown success in a few case reports and clinical tri-als [12, 14–17] , although weaker reductions were observed compared to uncomplicated obesity [15] .

Animal models of HO using electrolytically and chemically generated lesions produce similar effects to those observed clinically and are thereby an excellent model in which to study therapeutic interventions [18–21] . We recently developed a novel combined medial hy-pothalamic lesion (CMHL) model that utilizes electro-lytic lesions in the ARC, VMG, and DMN of the medial hypothalamus to model the sequelae commonly observed in HO secondary following the resection and/or radio-therapy of CP [22] . We found similar results when com-bining electrolytic lesions of the VMN with chemical le-sions of the ARC [17] . The CMHL model best mimics the complex metabolic abnormalities observed in CP pa-tients with HO including rapid weight gain, hyperphagia, hyperinsulinemia, and hyperleptinemia.

Glucagon-like peptide-1 (GLP-1) is an incretin secret-ed by ileal L cells in response to ingestion of nutrients [23] . Physiological levels of GLP-1 enhance glucose-in-duced insulin secretion and delay gastric emptying [24–26] . Additionally, GLP-1 is hypothesized to function as a satiety hormone, promoting reduced food intake (FI) and meal termination. GLP-1 binds receptors in key appetite-related sites in the brainstem (specifically the nucleus of the solitary tract) and the hypothalamus (e.g. arcuate and dorsomedial nuclei) [27–29] .

Peripheral administration of GLP-1 or GLP-1 receptor agonists, such as exenatide (synthetic version of exen-din-4 (Ex4)), reduces blood glucose (BG) and FI in hu-mans, and long-term treatment results in loss of body weight (BW) [30, 31] . Similar results have been observed in rodents, [30, 31], however, it has been shown that high doses of Ex4 result in an acute increase in BG levels due to activation of the sympathetic nervous system [32] . In the murine model, it has been demonstrated that Ex4 acts as a meal termination signal via receptors located in the hindbrain [33] , which are generally spared in patients

with hypothalamic tumors. In contrast, other drugs exert appetite inhibition via signaling pathways that involve medial hypothalamic nuclei, an area that is frequently damaged in patients with HO [3] .

In this study, we tested the effect of Ex4 on FI and BW gain in our CMHL rat model of HO. We hypothesized that treatment with Ex4 would decrease FI and attenuate BW gain in severely obese CMHL rats.

Materials and Methods

Animals Young adult male Sprague-Dawley rats, weighing 250–265 g,

were purchased from Charles River Laboratory (Wilmington, Mass., USA). Animals were individually housed on a 12 h/12 h light/dark cycle (lights on at 07: 00 h) in a temperature (23 ° C) and humidity (50 8 10%) controlled room. Ad libitum access to regu-lar chow (5053 Pico Lab Rodent Diet; Purina LabDiet, Richmond, Calif., USA) and water was provided. Following surgery, the ani-mals’ BW and FI were recorded. All procedures performed were approved by the Institutional Animal Care and Use Committee at the Seattle Children’s Research Institute and were in accor-dance with the NIH Guide for the Care and Use of Laboratory Animals.

Electrolytic Lesion To electrolytically induce the CMHL, animals were placed un-

der a surgical-plane of anesthesia (isoflurane/oxygen mix, 5% in-duction, 2–4% throughout the procedure) and were mounted in a Kopf stereotaxic frame (Tujunga, Calif., USA). The upper incisor bar was 3.5 mm above the interaural line. Lesions were targeted to the ARC, VMN, and DMN through the placement of an insu-lated stainless steel electrode at stereotaxic coordinates based on our previous study [22] . Specifically, an anodal electric current (110 V, 1.7 mA for 15 s) was passed through the tip of the electrode while placed 2.6 mm posterior to the bregma, 0.5 mm lateral to the midsagittal line, and both 10 mm (ARC) and 8.6 mm (VMN/DMN) ventral from the skull.

Injection of Ex4 and Data Collection Effects of Ex4 on FI and BW were recorded. In addition,

changes in BG levels were assessed using a handheld glucometer (HemoCue � Glucose 201+; HemoCue AB, Sweden) both before and 75 min after the last Ex4 injection. Nine days prior to the start of the injections, FI was recorded and averaged to determine base-line values (CMHL group n = 9, control group n = 7). Each group was split to receive either daily intraperitoneal (IP) injections of 1 � g � kg –1 Ex4 (exendin-4; California Peptide Research Inc., Ca-lif., USA) or the same volume of IP saline injections (0.9% sodium chloride injection, USP; Hospira) for a period of 9 days. Admin-istration of all injections as well as measurement of FI and BW occurred in the evening (18: 30 h, 30 min prior to lights out). Lee adiposity index (BW –1/3 /snout-to-anus length (mm)) measures were taken before surgery and at termination as an indicator of total adiposity.

Effect of Ex4 on FI and BW Gain in a CMHL Rat Model of HO

Horm Res Paediatr 2012;78:47–53 49

Statistical Analysis Statistical analyses were performed using GraphPad Prism

Software (La Jolla, Calif., USA). Outcome variables between study groups were compared using Student’s t tests for continuous vari-ables and single intervention comparisons (e.g. sham surgery vs. lesion). Two-way ANOVA modeling with a Bonferroni post hoc test was used for contrasting effects of two interventions in mul-tiple groups (lesion and drug treatment).

Results

Presurgery BW and Lee adiposity index were compa-rable in CMHL and control groups ( table 1 ). An immedi-ate increase in FI resulted in a significantly increased BW 1 day after surgery in the CMHL group. At the time of Ex4 treatment (6 weeks after surgery), FI in lesioned rats dropped to the amount of control rats (CMHL 97.6 8 6.2 kcal/day, control 93.6 8 3.9 kcal/day metaboliz-able energy; p = 0.581), similar to our previous studies [22] .

Food Intake We assessed daily FI during 9 days before (evening

day –9 to evening day 0) and during the drug interven-tion (evening day 0 to evening day 9). During treat-ment, FI was slightly, though insignificantly, reduced in rats receiving saline injections (controls –5.7%, CMHL –3.5%; fig. 1 , white bars). There was a significant reduc-tion in FI in rats who received Ex4 compared with those who received saline injections in both CMHL lesioned rats and controls ( difference between saline and Ex4 in-jected rats, CMHL –20.8%, control –13.6%, when ad-justed to effect of saline injection ( table 2 ; fig. 1 , black bars).

Body Weight BW was measured 9 days prior to drug intervention

(day –9, reference point) and BW changes were assessed during the 9 days before (day –9 to day 0), during (day 0 to day 9), and 9 days directly following the drug interven-tion (day 9 to day 18). Both CMHL and control groups exhibited weight gain during the 9 days of saline injec-tion, whereas weight gain was almost completely abol-ished in CMHL as well as control rats who received Ex4 ( difference in rate of BW change between saline and Ex4 injection: CMHL –4.9%/9 days, control –3.2%/9 days; ta-ble 2 ; fig. 2 ).

Table 1. C haracteristics of experiment groups

C ontrol group Lesion group p value

saline (n = 3) Ex4 (n = 4) saline (n = 4) Ex4 (n = 5) control vs. lesion

Before surgery BW, g 289.789.9 294.584.1 304.587.2 290.086.3 0.563Before surgery Lee index 0.30980.003 0.30680.002 0.31280.002 0.30780.002 0.5211 day after surgery BW, g 297.088.9 303.882.5 324.5810.9 321.287.0 0.0083 weeks after surgery BW, g 390.0824.2 384.383.8 434.0825.9 415.0816.3 0.0483 weeks after surgery FI, kcal 93.886.6 87.083.3 102.786.6 103.388.7 0.058Before treatment BW, g 471.3831.5 460.888.1 515.5835.1 512.0823.4 0.054Terminal Lee index 0.32580.005 0.32080.002 0.34280.011 0.34580.012 0.025

Dat a are mean 8 SEM. All control group (sham surgery) vs. all lesion group (CMHL) by Student’s t test.

Control Lesion

a

0

20

40

60

80

100

120

% b

asel

ine

food

inta

kea

Fig. 1. FI of control (sham surgery) and lesion (CMHL) groups during treatment with Ex4 (black bars) or saline (white bars) rela-tive to 9-day interval (baseline) before treatment. a p = 0.0005 for Ex4 intervention in a two-way ANOVA analysis.



Injection of Ex4 and BG No significant difference in baseline BG was found be-

tween saline and Ex4 treatments in either CMHL or con-trol rats, however there was a trend towards lower BG levels in Ex4 treated animals. Two-way ANOVA analysis of BG 75 min after the last injection shows that Ex4 treat-ment leads to a significant reduction of BG levels ( table 2 ).

Discussion

One of the most striking examples of dysfunctional hypothalamic signaling is observed in patients with HO, a dramatic condition caused by damaged medial hypo-

thalamic nuclei. HO is common, as about 20% of patients with CP are obese at the time of diagnoses, and greater than 50% develop posttreatment obesity [11, 34–36] . In the current study, we tested Ex4 in our CMHL rat model mimicking metabolic disturbances typically observed in patients with HO. In this model of CMHLs [22] , Ex4 in-jections resulted in significant reduction of FI and an at-tenuation of weight gain.

The hypothalamus is central to the regulation of en-ergy homeostasis. Hypothalamic nuclei are the target of circulating peptides, including leptin, insulin, peptide YY 3–36 (PYY), and ghrelin, as well as nutrients such as free fatty acids, glucose and amino acids, all of which provide information about feeding status and result in either an-orexigenic or orexigenic activity. These hypothalamic nu-clei are targets for anti-obesity drugs such as sibutramine that may require intact hypothalamic signaling pathways for appetite inhibition. Patients with HO secondary to CP frequently have damaged medial hypothalamic nuclei and consequently aberrant hypothalamic signaling pathways [3, 22] . In one pediatric study utilizing sibutramine, which requires intact hypothalamic signaling pathways, signifi-cant weight loss occurred in patients with HO although it was less pronounced than in patients with uncomplicated obesity [15] . Therefore, therapies targeting other compo-nents of appetite regulation are necessary, as patients with HO have a reduced ability to respond to therapies requir-ing intact hypothalamic nuclei. Gut hormones PYY 3–36 , GLP-1, pancreatic polypeptide, and cholecystokinin re-duce FI following peripheral administration to rodents via binding to receptors in the hindbrain, which activates an-orexic signaling [37, 38] . We therefore hypothesized that a GLP-1 agonist would be a more promising approach, as anorexic effects are transmitted via the hindbrain, a struc-ture spared in many patients with HO [3, 22] . To test this hypothesis, we utilized our novel rodent model of HO.

Table 2. Effects of treatment in experimental groups

C ontrol group Lesion group Two-way ANOVA (p value)

saline (n = 3) Ex4 (n = 4) saline (n = 4) Ex4 (n = 5) treatment lesion interaction

Baseline BG, mg/dl 151.784.8 143.586.2 144.089.5 134.282.4 NS NS NS75 min after Ex4 BG, mg/dl 150.082.0 139.087.2 144.086.9 121.085.3a 0.019 0.079 NSAfter treatment BW, g 489.7832.7 464.3810.8 543.5839.3 515.8834.6 NS NS NS% � BW during treatment 3.980.2 0.781.0 5.380.8 0.482.4 0.036 NS NS% � FI during treatment –5.783.5 –19.380.8 –3.583.9 –24.384.2b 0.001 NS NS

Da ta are mean 8 SEM. a p < 0.05 vs. saline lesion; b p < 0.01 vs. saline lesion, by Bonferroni post hoc test.

Baseline Day 9 Day 18–5

0

5

10

15

Control – saline

Control – Ex4Lesion – Ex4

Treatment Posttreatment

Lesion – saline

a

b

% c

han

ge

in B

W

Fig. 2. Percent change of BW during treatment with Ex4 (solid symbols) or saline (outlined symbols) compared to baseline (day 0), directly before treatment. Single intervention analysis of Ex4 treatment was performed by t test. a p = 0.012 control (sham sur-gery) change in BW during Ex4 treatment versus 9-day baseline. b p = 0.041 lesion (CMHL) change in BW during Ex4 treatment versus 9-day baseline.



Animal studies provide evidence that pharmacologic doses of IP GLP-1 decrease FI through both vagal afferent signals and through direct CNS effects [39] . GLP-1 recep-tors are expressed in numerous brain regions, particu-larly the brainstem [40] . Neurons in the caudal nucleus of the solitary tract produce GLP-1 and project to numerous brain regions, leading to further CNS GLP-1 receptor ac-tivation [40] . This is also the mechanism of action of cho-lecystokinin, and systemic administration of either cho-lecystokinin or Ex4 in rats induces expression of c-Fos protein, a marker of neuronal activation, in hindbrain ar-eas (solitary tract nucleus, area postrema) that process afferent input from satiety signals [33] . While the hypo-thalamus does express GLP-1 receptors, it may not play a critical role in GLP-1 signaling. A decerebrate rat model showed that caudal brainstem processing may be suffi-cient to preserve GLP-1-mediated FI reduction and de-layed gastric emptying [41] .

While these rodent studies have helped elucidate CNS sites of action of GLP-1 in a normal animal, little is known regarding the role of hypothalamic long-term adipostatic circuitry in regulating the response to GLP-1, and the consequences of hypothalamic damage on brainstem sa-tiety signaling. In the current study, we questioned whether an intact brainstem-hypothalamic pathway is required in order to exert anorexigenic effects of Ex4 or if the anorexigenic effects are disturbed by the hypotha-lamic lesion. FI and BW were decreased similarly in CMHL rats compared with intact rats, indicating that Ex4 did not lose its effectiveness because of damaged hy-pothalamic structures, an area that expresses major orex-igenic and anorexigenic peptides [42, 43] .

It is useful to note that the administration schedule and dosage used in this experiment is based on the utili-zation of the anorectic effect commonly associated with Ex4. Given that rats predominantly feed during the dark cycle, it is not necessary to administer a second dose of the peptide for the reduction of food intake as would be

necessary if using the drug for glycemic control. Addi-tionally, dosages needed to produce a sustained weight loss were based on previous studies and were significant-ly higher in rats than in humans [26, 44–48] .

This is an exploratory study showing novel data. How-ever, we are aware that several limitations exist. First, the observation was made in a relatively small number of rats. Given the potential variability of the lesions, the study size (n = 3–5 per group) is rather small and will be ex-panded in future studies. The rats were treated for a rela-tively short duration (9 days), it is possible that the an-orexic effect of Ex4 will decrease over time; therefore a longer exposure is needed in future rodent experiments. In addition, we did not perform body composition analy-ses. We analyzed BG changes at only one time point after injection and we did not focus upon the hormone chang-es associated with this model and treatment. These ef-fects should be considered in future studies. Finally, Ex4 injections were only administered once per day in the evening. Future experiments should also include a proto-col of twice daily injections to exert a strong effect at day-time. With these limitations in mind, we think that our results are important for planning future studies for treatment of HO.

In conclusion, the results of this exploratory study in-dicate that treatment with GLP-1 agonist Ex4 was effec-tive at reducing FI and weight gain in a HO rat model. These results are significant, as the effects were similar in obese rats with hypothalamic lesions compared with in-tact controls. Therefore, drugs that exert inhibition of FI and weight gain after binding to hindbrain receptors may offer therapeutic potential for HO, a condition that is of-ten resistant to therapeutic approaches. Future mecha-nistic studies are required to further elucidate the effect of GLP-1 agonists on energy balance in HO and to con-sider GLP-1 agonists in combination with other weight-lowering drugs.

References 1 Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2008. Hinsdale/IL, CBTRUS, 2008.

2 Muller HL, Emser A, Faldum A, Bruhnken G, Etavard-Gorris N, Gebhardt U, Oeverink R, Kolb R, Sorensen N: Longitudinal study on growth and body mass index before and after diagnosis of childhood craniopharyn-gioma. J Clin Endocrinol Metab 2004; 89: 3298–3305.

3 Roth CL, Gebhardt U, Muller HL: Appetite-regulating hormone changes in patients with craniopharyngioma. Obesity (Silver Spring) 2011; 19: 36–42.

4 Muller HL, Gebhardt U, Wessel V, Schroder S, Kolb R, Sorensen N, Maroske J, Hanisch E: First experiences with laparoscopic adjust-able gastric banding in the treatment of pa-tients with childhood craniopharyngioma and morbid obesity. Klin Padiatr 2007; 219: 323–325.



5 Vinchon M, Weill J, Delestret I, Dhellemmes P: Craniopharyngioma and hypothalamic obesity in children. Childs Nerv Syst 2009; 25: 347–352.

6 Gardner PA, Kassam AB, Snyderman CH, Carrau RL, Mintz AH, Grahovac S, Stefko S: Outcomes following endoscopic, expanded endonasal resection of suprasellar cranio-pharyngiomas: a case series. J Neurosurg 2008; 109: 6–16.

7 Kim RJ, Shah R, Tershakovec AM, Zemel BS, Sutton LN, Grimberg A, Moshang T: Energy expenditure in obesity associated with cra-niopharyngioma. Childs Nerv Syst 2010; 26: 913–917.

8 Guran T, Turan S, Bereket A, Akcay T, Unlu-guzel G, Bas F, Gunoz H, Saka N, Bundak R, Darendeliler F, Isguven P, Yildiz M, Adal E, Sarikaya S, Baygin LA, Memioglu N, Onal H, Ercan O, Haklar G: The role of leptin, soluble leptin receptor, resistin, and insulin secre-tory dynamics in the pathogenesis of hypo-thalamic obesity in children. Eur J Pediatr 2009; 168: 1043–1048.

9 Harz KJ, Muller HL, Waldeck E, Pudel V, Roth C: Obesity in patients with craniopha-ryngioma: assessment of food intake and movement counts indicating physical activ-ity. J Clin Endocrinol Metab 2003; 88: 5227–5231.

10 Holmer H, Pozarek G, Wirfalt E, Popovic V, Ekman B, Bjork J, Erfurth EM: Reduced en-ergy expenditure and impaired feeding-re-lated signals but not high-energy intake re-inforces hypothalamic obesity in adults with childhood-onset craniopharyngioma. J Clin Endocrinol Metab 2010; 95: 5395–5402.

11 Ahmet A, Blaser S, Stephens D, Guger S, Rut-kas JT, Hamilton J: Weight gain in cranio-pharyngioma – a model for hypothalamic obesity. J Pediatr Endocrinol Metab 2006; 19: 121–127.

12 Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, Rai SN, Lensing SY, Wu S, Xiong X: Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2003; 88: 2586–2592.

13 Eyal O, Sundararajan S, Inge TH, Rose SR: Obesity in patients with craniopharyngio-ma. Endocrinologist 2006; 16: 286–293.

14 Mason PW, Krawiecki N, Meacham LR: The use of dextroamphetamine to treat obesity and hyperphagia in children treated for cra-niopharyngioma. Arch Pediatr Adolesc Med 2002; 156: 887–892.

15 Danielsson P, Janson A, Norgren S, Marcus C: Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. J Clin Endocrinol Metab 2007; 92: 4101–4106.

16 Hamilton JK, Conwell LS, Syme C, Ahmet A, Jeffery A, Daneman D: Hypothalamic obe-sity following craniopharyngioma surgery: results of a pilot trial of combined diazoxide and metformin therapy. Int J Pediatr Endo-crinol 2011; 2011: 417949.

17 Elfers C, Ralston M, Roth CL: Studies of dif-ferent female rat models of hypothalamic obesity. J Pediatr Endocrinol Metab 2011; 24: 131–137.

18 Dawson R Jr, Simpkins JW, Wallace DR: Age- and dose-dependent effects of neonatal monosodium glutamate administration to female rats. Neurotoxicol Teratol 1989; 11: 331–337.

19 Tokunaga K, Bray GA, Matsuzawa Y: Im-proved yield of obese rats using a double co-ordinate system to locate the ventromedial or paraventricular nucleus. Brain Res Bull 1993; 32: 191–194.

20 Schoelch C, Hubschle T, Schmidt I, Nuesslein-Hildesheim B: MSG lesions de-crease body mass of suckling-age rats by at-tenuating circadian decreases of energy ex-penditure. Am J Physiol Endocrinol Metab 2002; 283:E604–E611.

21 Leitner C, Bartness TJ: Food deprivation-in-duced changes in body fat mobilization after neonatal monosodium glutamate treatment. Am J Physiol Regul Integr Comp Physiol 2008; 294:R775–R783.

22 Roth CL, Blevins JE, Ralston M, Elfers C, Ogimoto K, Kaiyala KJ, Morton GJ: A novel rodent model that mimics the metabolic se-quelae of obese craniopharyngioma patients. Pediatr Res 2011; 69: 230–236.

23 Drucker DJ, Nauck MA: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–1705.

24 Aaboe K, Krarup T, Madsbad S, Holst JJ: GLP-1: physiological effects and potential therapeutic applications. Diabetes Obes Metab 2008; 10: 994–1003.

25 Roth CL, Reinehr T: Roles of gastrointestinal and adipose tissue peptides in childhood obesity and changes after weight loss due to lifestyle intervention. Arch Pediatr Adolesc Med 2010; 164: 131–138.

26 Raman VS, Mason KJ, Rodriguez LM, Has-san K, Yu X, Bomgaars L, Heptulla RA: The role of adjunctive exenatide therapy in pedi-atric type 1 diabetes. Diabetes Care 2010; 33: 1294–1296.

27 Bloom S, Wynne K, Chaudhri O: Gut feeling – the secret of satiety? Clin Med 2005; 5: 147–152.

28 Bojanowska E: Physiology and pathophysiol-ogy of glucagon-like peptide-1 (GLP-1): the role of GLP-1 in the pathogenesis of diabetes mellitus, obesity, and stress. Med Sci Monit 2005; 11:RA271-RA278.

29 Gutzwiller JP, Degen L, Heuss L, Beglinger C: Glucagon-like peptide-1 and eating. Physiol Behav 2004; 82: 17–19.

30 Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL: Effects of glucagon-like pep-tide-1 receptor agonists on weight loss: sys-tematic review and meta-analyses of ran-domised controlled trials. BMJ 2012; 344:d7771.

31 Gedulin BR, Nikoulina SE, Smith PA, Gedu-lin G, Nielsen LL, Baron AD, Parkes DG, Young AA: Exenatide (exendin-4) improves insulin sensitivity and � -cell mass in insu-lin-resistant obese fa/fa Zucker rats indepen-dent of glycemia and body weight. Endocri-nology 2005; 146: 2069–2076.

32 Pérez-Tilve D, González-Matías L, Aulinger BA, Alvarez-Crespo M, Gil-Lozano M, Alva-rez E, Andrade-Olivie AM, Tschöp MH, D’Alessio DA, Mallo F: Exendin-4 increases blood glucose levels acutely in rats by activa-tion of the sympathetic nervous system. Am J Physiol Endocrinol Metab 2010; 298:E1088–E1096.

33 Williams DL, Baskin DG, Schwartz MW: Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimula-tion. Diabetes 2006; 55: 3387–3393.

34 O’Gorman CS, Simoneau-Roy J, Pencharz P, MacFarlane J, MacLusky I, Narang I, Adeli K, Daneman D, Hamilton J: Sleep-disor-dered breathing is increased in obese adoles-cents with craniopharyngioma compared with obese controls. J Clin Endocrinol Metab 2010; 95: 2211–2218.

35 Muller HL, Bueb K, Bartels U, Roth C, Harz K, Graf N, Korinthenberg R, Bettendorf M, Kuhl J, Gutjahr P, Sorensen N, Calaminus G: Obesity after childhood craniopharyngioma – German multicenter study on preoperative risk factors and quality of life. Klin Padiatr 2001; 213: 244–249.

36 Muller HL: Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. Horm Res 2008; 69: 193–202.

37 Batterham RL, Cowley MA, Small CJ, Her-zog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR: Gut hormone PYY 3–36 physiolog-ically inhibits food intake. Nature 2002; 418: 650–654.

38 Small CJ, Parkinson JR, Bloom SR: Novel therapeutic targets for appetite regulation. Curr Opin Investig Drugs 2005; 6: 369–372.

39 Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR: Peripheral and central GLP-1 re-ceptor populations mediate the anorectic ef-fects of peripherally administered GLP-1 re-ceptor agonists, liraglutide and exendin-4. Endocrinology 2011; 152: 3103–3112.

40 Hayes MR, De Jonghe BC, Kanoski SE: Role of the glucagon-like peptide-1 receptor in the control of energy balance. Physiol Behav 2010; 100: 503–510.

41 Hayes MR, Skibicka KP, Grill HJ: Caudal brainstem processing is sufficient for behav-ioral, sympathetic, and parasympathetic re-sponses driven by peripheral and hindbrain glucagon-like peptide-1 receptor stimula-tion. Endocrinology 2008; 149: 4059–4068.

42 Bertile F, Oudart H, Maho YL, Raclot T: Re-combinant leptin in the hypothalamic re-sponse to late fasting. Biochem Biophys Res Commun 2003; 310: 949–955.



43 Zhang LN, Mitchell SE, Hambly C, Morgan DG, Clapham JC, Speakman JR: Physiologi-cal and behavioral responses to intermittent starvation in C57BL/6J mice. Physiol Behav 2012; 105: 376–387.

44 Bojanowska E, Nowak A: Interactions be-tween leptin and exendin-4, a glucagon-like peptide-1 agonist, in the regulation of food intake in the rat. J Physiol Pharmacol 2007; 58: 349–360.

45 Washington MC, Raboin SJ, Thompson W, Larsen CJ, Sayegh AI: Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor. Brain Res 2010; 1344: 124–133.

46 Murthy SN, Hilaire RC, Casey DB, Badejo AM, McGee J, McNamara DB, Kadowitz PJ, Fonseca VA: The synthetic GLP-I receptor agonist, exenatide, reduces intimal hyper-plasia in insulin-resistant rats. Diab Vasc Dis Res 2010; 7: 138–144.

47 Yamamoto H, Kishi T, Lee CE, Choi BJ, Fang H, Hollenberg AN, Drucker DJ, Elmquist JK: Glucagon-like peptide-1-responsive cate-cholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with cen-tral autonomic control sites. J Neurosci 2003; 23: 2939–2946.

48 Williams DL, Hyvarinen N, Lilly N, Kay K, Dossat A, Parise E, Torregrossa AM: Main-tenance on a high-fat diet impairs the an-orexic response to glucagon-like peptide-1 receptor activation. Physiol Behav 2011; 103: 557–564.

Documents

Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity