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Keywords:

  • adiposity;
  • glucose tolerance;
  • insulin sensitivity;
  • gene expression

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Objective: To investigate the effect of S 23521, a new glucagon-like peptide-1-(7-36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis.

Research Methods and Procedures: Lean and diet-induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 μg/kg) or subcutaneously (100 μg/kg) for 14 and 20 days, respectively. Because the low-dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end-points.

Results: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle-treated counterparts (3401 ± 65 vs. 3898 ± 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein-1, uncoupling protein-3, leptin, resistin, and peroxisome proliferator-activated receptor (PPAR)-γ were observed.

Discussion: S 23521 is an effective glucagon-like peptide-1-(7-36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet-induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Glucagon-like peptide-1-(7-36) amide (GLP-1)1 is secreted mainly from the endocrine L-cells of the distal ileum and colon (1,2). It physiologically enhances postprandial insulin secretion from pancreatic β-cells, acting as an incretin hormone (1,2). In addition, several actions further contributing to its glucose-lowering properties have been described, including suppression of glucagon secretion, β-cell regeneration, reduction in food intake, a delay in gastric emptying, and other extrapancreatic actions in liver, muscle, and adipose tissue (1,2,3). Therefore, GLP-1 has been proposed as a promising therapeutic molecule for treatment of type 2 diabetes.

The discovery of GLP-1 and GLP-1 receptor (GLP-1R) expression in brain regions involved in the control of food intake suggested their role in the regulation of energy intake (4). Although several observations regarding this had been previously reported (5,6), a definitive decision in considering GLP-1 as a satiety factor came from the study performed by Turton et al. (7). In this study, intracerebroventricular administration of GLP-1 to rats transiently reduced food intake and body weight, supporting the role of GLP-1 as a short-term regulator of appetite and body weight (3,8). Furthermore, co-administration with exendin-(9-39), a GLP-1R antagonist, abolished these effects (7).

Because of the short half-life of GLP-1 in the circulation (9), subcutaneous and intraperitoneal injections of this hormone have little or no effect on food intake and body weight in rats (7,10). Thus, continuous or repeated infusion is necessary to reach sustained elevated plasma levels. This issue is being partially solved by the research and development of more stable and effective analogues.

S 23521 is an analogue of GLP-1 with two chemical modifications compared with GLP-1-(7-37)-NH2. These modifications, a substitution of alanine at position 8 by a d-alanine and the removal of arginine at position 36, preserve its activity and increase the metabolic stability in vitro and in vivo compared with GLP-1-(7-37)-NH2 (11). Recently, central and peripheral administration of GLP-1R agonists has been reported to be effective in reducing food intake and body weight in different animal models (10,12,13,14,15). In this study, the affinity and activity of S 23521 was first evaluated on murine GLP-1 receptors expressed in RIN T3 cells. Given that S 23521 is a potent and stable GLP-1 analogue, we decided to study its effects in a model of dietary obesity in rats.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Animals, Diets, and Induction of Obesity

Male Wistar rats (IFFA CREDO, L'Arbresse, France), weighing 220 to 240 grams, were caged individually in a 12:12-hour light-dark cycle, temperature- and humidity-controlled environment. Animals were divided into two dietary conditions. One group was fed standard chow diet (which supplied 8% of calories as fat, type AO4; Panlab, Barcelona, Spain). To induce obesity, a second group was fed cafeteria diet (65% of the energy derived from lipids). Cafeteria diet consisted of a daily offering of cookies, liver pate, bacon, standard chow, and whole milk supplemented with 333 g/liter of sucrose and 10 g/liter of a mineral and vitamin complex (Gevral; Cynamid Ibérica, Madrid, Spain) as previously described (16). All of the food items were weighed daily and presented in excess.

Based on pilot studies, animals were considered obese when a mean difference of 40% in body weight gain between the dietary groups was achieved. During the diet-induced obesity period, body weight and selective food consumption (corrected by the amount of water lost for each item) were recorded daily.

All procedures were conducted in accordance with the principles of laboratory animal care (European Community and local government guidelines), and protocols were approved by the Animal Research Committee of the University of Barcelona.

S 23521 Treatment

After the diet-induced obesity period, rats were divided into different experimental groups according to treatment. Intraperitoneal injections of either vehicle (BSA 0.1%) or S 23521 (pure peptide at 10 and 100 μg/kg) were administered to lean and diet-induced obese rats for 14 days. Subcutaneous treatment (vehicle or S 23521 at 100 μg/kg) was carried out in different groups of lean and diet-induced obese rats for 20 days. Animals received the treatment twice daily, adjusted to the rodent feeding patterns (at light-dark transition and 6 hours after). During this period, body weight and selective food consumption (corrected by the amount of water lost for each item) were recorded daily. Dietary conditions (standard chow or cafeteria diet) were maintained during the whole treatment period.

Blood Sampling and Biochemical Measurements

Food-deprived (6 hours) blood samples were collected from the tail using a capillary blood collection system with EDTA (Sarstedt, Nümbrecht, Germany). Tubes were kept on ice until centrifugation, and the resulting plasma was stored at −80 °C before being analyzed. Plasma triglycerides and nonesterified fatty acid levels were measured using colorimetric kits from Sigma (St. Louis, MO) and Roche (Mannheim, Germany), respectively. Total plasma ghrelin levels were determined by radioimmunoassay (Linco Research, St. Charles, MO).

Oral Glucose Tolerance Test

Lean, obese, and treated obese rats were submitted to an oral glucose tolerance test (OGTT) at the beginning and at the end of the treatment period. Rats were fasted for 6 hours before the administration of a glucose bolus (2 g/kg; Braun Medical, Rubí, Spain). Glycemia was determined at 0, 15, 30, 60, 120, and 150 minutes after glucose administration with the AccuTrend glucose sensor (Roche). Blood samples were collected at the same time-points to determine plasma insulin levels by ELISA (Mercodia, Uppsala, Sweden). OGTT was carried out 1 hour after the last treatment.

Intraperitoneal Insulin Sensitivity Test

Nonfasted lean, obese, and treated obese rats were submitted to an insulin sensitivity test at the beginning and at the end of the treatment period. Insulin (1 U/kg; Eli Lilly, Indianapolis, IN) was intraperitoneally injected, and blood glucose levels were measured at 0, 15, 30, 60, 120, and 180 minutes after injection.

Tissue Collection

At the end of the experimental period, rats from each experimental group were killed. Gastrocnemius muscle (gM), interscapular brown adipose tissue (iBAT), and epididymal white adipose tissue (eWAT) were excised, weighed, and rapidly frozen in liquid nitrogen. Epididymal adiposity and iBAT percentage were estimated by the percentage ratio of eWAT or iBAT mass and whole body weight of each animal.

RNA Isolation and Northern Blot Analysis

Total RNA was purified from tissues by either Trizol (Invitrogen, Carlsbad, CA) or guanidinium isothiocyanate-phenol chloroform extraction (Invitrogen). Total RNA (15 μg) derived from gM, iBAT, and eWAT tissues was electrophoresed on 1.2% formaldehyde-agarose gels and transferred to Nytran-plus membranes (Schleicher & Schuell, Keene, NH). mRNA was cross-linked to the membranes using an ultraviolet cross-linker (Stratagene, San Diego, CA). Membranes were hybridized with specific [α-32P]dCTP (Amersham Pharmacia Biotech, Buckinghamshire, UK) random primed-labeled cDNA probes for uncoupling protein (UCP)-1, UCP-3, resistin, leptin, and peroxisome proliferator-activated receptor (PPAR)-γ. Probes were generated from total RNA using oligo dT primers for reverse transcription and amplification by gene-specific primers. Blots were quantified with a Phosphorimager analyser and QuantityOne software (Bio-Rad Laboratories, Hercules, CA). As a loading control, the membranes were reprobed with a 28S ribosomal cDNA. Data were quantified as densitometric units, and values were normalized to signal obtained with the 28S ribosomal protein.

Statistical Analysis

All results were expressed as means ± SE. Differences between groups were determined by an ANOVA followed by a Dunnett post hoc analysis or by the nonparametric Mann-Whitney U test. A p value <0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Effect of Intraperitoneal Administration of S 23521 on Food Intake, Body Weight, and Adiposity

Administration of high-fat palatable diet increased body weight gain by 41% (n = 120) compared with standard diet-fed rats (n = 48; p < 0.01). The estimated cumulative energy intake during this period was 2-fold higher in cafeteria diet-fed rats than in those fed with standard chow diet (23, 923 ± 1205 vs. 10, 693 ± 387 kcal/kg; p < 0.01).

As a first approach, we tested the effect of intraperitoneal administration of 10 and 100 μg/kg of S 23521 on body weight and food intake. Preliminary acute and chronic toxicological studies performed in rats showed no side effects of the compound at the doses used in this study (unpublished data). Furthermore, no effects of treatment on behavior were recorded. Low-dose treatment to obese rats failed to produce changes in either food intake or body weight, suggesting that, at this dose, S 23521 was ineffective in our experimental model. On the other hand, highest-dose treatment significantly decreased cumulative energy intake of obese rats compared with vehicle-treated obese rats (4353 ± 101 vs. 4861 ± 101 kcal/kg per 14 days; n = 24/group; p < 0.05). Consistent with this observation, body weight gain of treated obese rats was significantly reduced by 87% in relation to vehicle-treated counterparts (5 ± 4 vs. 39 ± 3 g/14 days, n = 24/group; p < 0.001). Nevertheless, epididymal adiposity at the end of the treatment period was not significantly different from vehicle-injected obese rats (3.21 ± 0.15% vs. 3.16 ± 0.17%, n = 13/group).

Effect of Intraperitoneal Administration of S 23521 on Metabolic Parameters

After the diet-induced obesity period, obese rats showed increased basal blood glucose (104 ± 1 vs. 97 ± 1 mg/dL; p < 0.05), plasma triglycerides (242 ± 15 vs. 126 ± 12 mg/dL; p < 0.01), and nonesterified fatty acid levels (14.48 ± 0.44 vs. 11.34 ± 0.70 nmol/μL; p < 0.05) compared with lean rats.

S 23521 treatment at all of the doses tested did not change plasma biochemical parameters (data not shown) except for plasma triglyceride levels. Thus, low doses of S 23521 induced a noticeable but nonsignificant decrease of this parameter in obese treated rats compared with vehicle-treated obese ones (227 ± 39 vs. 281 ± 54 mg/dL). Furthermore, high-dose treatment significantly lowered it compared with the same experimental group (174 ± 36 vs. 281 ± 54 mg/dL; p < 0.05). On the other hand, high dose-treated obese rats showed increased plasma ghrelin levels compared with their vehicle-treated obese counterparts, achieving similar values to those exhibited by vehicle-treated lean rats (Figure 1).

image

Figure 1. Plasma ghrelin levels after twice-per-day intraperitoneal injection of 100 μg/kg of S 23521 or vehicle for 14 days. Results are expressed as mean ± SE (n = 5 rats/group). Statistical comparisons were made using the Mann-Whitney test. *p < 0.05, vehicle-treated obese rats vs. vehicle-treated lean rats; †p < 0.05, S 23521-treated obese rats vs. vehicle-treated obese rats.

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Effect of Subcutaneous Administration of S 23521 on Food Intake, Body Weight, and Adiposity

In the second approach of the study, we decided to retain only the dose of 100 μg/kg, which was effective in decreasing body weight gain. We also changed the intraperitoneal for the subcutaneous administration, prolonging the treatment period to 20 days. Under these experimental conditions, S 23521 significantly decreased food intake (Table 1) and body weight gain (Figure 2). It is noteworthy that subcutaneous administration induced sustained and more effective actions of S 23521 on body weight reduction than the intraperitoneal administration during the whole treatment period. Thus, subcutaneous-treated obese rats gained 110% less weight than their vehicle-treated counterparts (Figure 2). Moreover, and in contrast to the intraperitoneally-treated obese rats, adiposity was significantly reduced in subcutaneously-treated obese rats compared with vehicle-treated ones, whereas no changes in iBAT mass were observed after S 23521 treatment (Table 1).

Table 1.  Effect of subcutaneous administration of S 23521 on food intake and adipose tissue mass at the end of treatment
 Lean + vehicleObese + vehicleObese + S 23521 (100 μg/kg)
  • Results are expressed as mean ± SE. Numbers in parenthesis represent the number of animals per group. Statistical significance was determined by ANOVA followed by Dunnett post hoc analysis.

  • *

    p < 0.05 vs. vehicle-treated lean rats.

  • p < 0.05 vs. vehicle-treated obese rats.

Cumulative energy intake (kcal/kg/20 days)1382 ± 25 (23)3898 ± 72* (24)3401 ± 65* (24)
Epididymal adiposity (%)2.60 ± 0.10 (10)5.12 ± 0.31* (9)4.10 ± 0.16* (10)
iBAT (%)0.099 ± 0.0016 (8)0.124 ± 0.013* (13)0.121 ± 0.010* (10)
image

Figure 2. Body weight gain after twice-per-day subcutaneous injection of 100 μg/kg of S 23521 or vehicle for 20 days. Triangles, vehicle-treated lean rats (n = 24); squares, vehicle-treated obese rats (n = 24); rhombus, S 23521-treated (100 μg/kg) obese rats (n = 24). Results are expressed as mean ± SE. Statistical comparisons were made using ANOVA followed by Dunnett test. **p < 0.01, S 23521-treated obese rats vs. vehicle-treated lean rats; ***p < 0.001, S 23521-treated obese rats vs. vehicle-treated obese rats.

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Glucose Tolerance and Insulin Sensitivity after Subcutaneous Administration of S 23521

Induction of obesity by cafeteria diet administration led to an impairment of glucose tolerance and insulin sensitivity (data not shown). S 23521 at 100 μg/kg normalized the OGTT pattern during the first 60 minutes after glucose administration in obese rats. However, after this interval of time, glycemia remained stable, reaching similar values to those shown by the vehicle-treated obese rats (Figure 3A). Between 0 and 30 minutes after the glucose load, plasma insulin levels of S 23521-treated obese rats were comparable with those of lean rats, but thereafter, this parameter increased, and high plasma insulin levels were sustained during the rest of the test (Figure 3B). On the other hand, S 23521-treated obese rats displayed a significant improvement in insulin sensitivity compared with vehicle-treated obese rats as assessed by the intraperitoneal insulin tolerance test (Figure 3C).

image

Figure 3. (A) Profile of blood glucose and (B) plasma insulin levels in response to an oral glucose challenge after twice-per-day subcutaneous injection of 100 μg/kg of S 23521 or vehicle for 20 days. (C) Integrated blood glucose concentration after an insulin sensitivity test. AUC, area under the curve. Triangles, vehicle-treated lean rats (n = 8); squares and open bars, vehicle-treated obese rats (n = 8); rhombus and hatched bars, S 23521-treated obese rats (n = 8). Results are expressed as mean ± SE. Statistical comparisons were made using the Mann-Whitney test. *p < 0.05, vehicle-treated obese rats vs. vehicle-treated lean rats. p < 0.05 vehicle- and S 23521-treated obese rats vs. vehicle-treated lean rats; **p < 0.01, S 23521-treated obese rats vs. vehicle-treated lean and obese rats; p < 0.05, vehicle-treated obese rats vs. S 23521-treated obese rats.

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Effects of S 23521 on Gene Expression of Proteins Involved in Energy Metabolism

In an attempt to elucidate the mechanisms involved in the weight-reducing effects of subcutaneously administered S 23521 in dietary obese rats, we decided to analyze the gene expression profile of several molecules related to energy balance in different tissues. Thus, leptin, resistin, and PPAR-γ mRNA levels were assessed in eWAT. Diet-induced obesity significantly increased the expression of leptin and PPAR-γ compared with standard chow-fed rats (leptin: 0.66 ± 0.20 vs. 0.30 ± 0.08 arbitrary units, p < 0.05; PPAR-γ: 0.50 ± 0.13 vs. 0.33 ± 0.07 arbitrary units, p < 0.05). However, S 23521 treatment failed to produce changes in the mRNA levels of leptin, resistin, or PPAR-γ (data not shown). UCP-1 and UCP-3 gene expression were analyzed in iBAT and gM, respectively. Diet-induced obese rats showed increased expression levels of UCP-1 in iBAT compared with standard chow-fed rats (2.62 ± 0.60 vs. 1.22 ± 0.08 arbitrary units, p < 0.05). As previously described, UCP-3 gene expression was decreased in gM from obese rats compared with that of lean ones (0.54 ± 0.04 vs. 1.23 ± 0.01 arbitrary units, p < 0.05). Nevertheless, treatment did not modify UCP-1 and UCP-3 gene expression levels (data not shown) in either iBAT or gM.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

In the last few years, several research groups have suggested a role for GLP-1 as a regulator of appetite. Thus, GLP-1 and GLP-1 analogues have received wide attention as putative antiobesity agents (3). In this study, we have described the effects of S 23521, a new GLP-1 analogue, on food intake and body weight in a rat model of dietary-induced obesity.

In the first in vivo attempt, we tested intraperitoneal doses of 10 and 100 μg/kg. Although low-dose treatment did not produce any effect, administration of 100 μg/kg of S 23521 significantly decreased food intake and decelerated body weight gain of obese rats. Nevertheless, treatment did not induce a net body weight loss, consistent with the absence of changes in epididymal adiposity after treatment.

Sustained and elevated plasma concentration of GLP-1 or GLP-1 analogues is required for the achievement of a maintained reduction in food intake and body weight (12,15,17). To produce a slow and prolonged release of the analogue, we decided to test the highest dose of S 23521 by subcutaneous administration and to extend the treatment period to 20 days. Under these conditions, we observed a more sustained anorectic effect of S 23521, accompanied by a significant reduction in adiposity and body weight gain.

S 23521 is a potent anorectic agent, decreasing food intake even when a highly palatable diet is offered. Although several studies have suggested that the GLP-1 anorectic effects could be associated with visceral illness (18), there is also evidence supporting a dissociation of aversive and anorectic effects (5,7). In this study, no aversion response to S 23521 treatment was observed.

S 23521 treatment was associated with an improvement in glucose tolerance and insulin resistance. Thus, treated rats showed lower blood glucose levels 30 minutes after an oral glucose load. However, from this time-point onward, the pattern obtained was characterized by high and sustained blood glucose and plasma insulin levels. These data suggest a putative slower gastric emptying and enhancement of insulin secretion by S 23521, mimicking the properties of GLP-1 and contributing to the observed elevated and prolonged levels of blood glucose and plasma insulin. Moreover, these effects may contribute to a prolonged sensation of satiety, further increasing the anorectic effects of our GLP-1 analogue (13,14).

On the other hand, the amelioration in insulin sensitivity observed by S 23521 treatment has also been described after chronic, but not acute, administration of GLP-1 or exendin-4 to type 2 diabetes animal models (15,19).

Because PPAR-γ and resistin have been involved in different aspects of insulin resistance (20,21), we also determined gene expression of these molecules. As previously described, diet-induced obesity increases the expression of PPAR-γ levels (22), but controversial data have been reported concerning resistin expression (23). However, thetreatment did not modify PPAR-γ or resistin gene expression in our study.

In agreement with other reports (14), treated obese rats had normalized triglyceride plasma levels similar to those reached by lean rats, an effect likely mediated by the decrease in food intake (14) and body weight. On the other hand, because ghrelin has been involved in the regulation of feeding behavior (24), the plasma levels of this orexigenic peptide were also determined. After S 23521 treatment, obese rats showed a significant increase in plasma ghrelin levels compared with vehicle-treated obese ones. Similar changes in plasma concentration of ghrelin have been reported for fasting rats (25). Thus, one might speculate that the decrease in food intake exhibited by the obese treated rats led to a stimulated synthesis of ghrelin, probably as a protective mechanism for preventing the excess of body weight loss.

Leptin plays a key role in food intake and body weight regulation. S 23521, at the highest dose and subcutaneously administered, did not modify leptin mRNA levels in adipose tissue. However, considering the maintenance in leptin mRNA levels with the parallel decrease in eWAT adiposity, it is conceivable to think that plasma leptin levels might be increased and might contribute to decreased food intake, body weight, and adiposity. Nevertheless, several studies have shown the anorectic effects of GLP-1 or GLP-1R agonists in experimental models with disturbances in the leptin system (7,8,10,12,13). Moreover, preliminary data concerning S 23521 treatment on Zucker diabetic fatty (ZDF) rats showed a significant reduction in food intake and body weight (P. Delagrange, unpublished results). Thus, some of the effects of S 23521 might not be mediated by leptin.

In general, anorectic agents decrease energy expenditure proportionally to weight loss. Furthermore, peripheral as well as central administration of GLP-1 have been involved in the regulation of body temperature (26,27). In this regard, we analyzed the gene expression profile of several thermogenic proteins. However, S 23521 treatment did not change the expression levels of these proteins and also failed to modify iBAT mass, the most important thermogenic organ in rodents. Thus, these results suggest that S 23521 might decrease energy expenditure without modifying gene expression of proteins involved in energy homeostasis.

The precise site of the anorectic action of S 23521 is still unknown, but probably involves a combination of peripheral and central effects as have been described for GLP-1 and GLP-1R agonists (3). It is well accepted that the satiety effects induced by GLP-1 are mediated mainly by central actions, namely in the lateral and medial hypothalamus (28). Moreover, several studies have shown the capacity of GLP-1 and other analogues to cross the blood-brain barrier (29,30,31), but we cannot rule out the possibility of peripheral stimulation on vagal afferent fibers or blood-brain barrier—free central regions such as the subfornical organ and the area postrema (32).

In summary, peripheral treatment with S 23521, a new GLP-1 analogue, decreased food intake and decelerated body weight gain in diet-induced obese rats. When administered subcutaneously, these anorectic effects were accompanied by a reduction in adiposity, a normalization of plasma triglyceride levels, and an improvement in glucose tolerance and insulin sensitivity. Thus, these results strongly support S 23521 as a putative therapeutical compound for the treatment of obesity.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The authors thank Josep Moreno, Beatriz Navarro, and Joaquina Navarro for excellent technical assistance with animals and diets. We also thank Dr. Roser Casamitjana for leptin and ghrelin determinations and Dr. Alain Kervran for the characterization of S 23521 on GLP-1 receptors. This work was supported by Ministerio de Sanidad y Consumo (Spain) Grants C03/08, G03/212 and PIO20483. M. C. was supported by Ministerio de Ciencia y Tecnología (Spain) Grants SAF2000–0053 and SAF2003-06018. S 23521 was provided by the Institut de Recherches Internationales Servier.

Footnotes
  • 1

    Nonstandard abbreviations: GLP-1, glucagon-like peptide-1-(7-36) amide; GLP-1R, glucagon-like peptide-1-(7-36) amide receptor; OGTT, oral glucose tolerance test; gM, gastrocnemius muscle; iBAT, interscapular brown adipose tissue; eWAT, epididymal white adipose tissue; UCP, uncoupling protein; PPAR, peroxisome proliferator-activated receptor.

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  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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