Research articleEGLP-1 lowers body weight better than exendin-4 by reducing food intake and increasing basal energy expenditure in diet-induced obese mice
Introduction
Obesity, which has become a global epidemic, is characterized by excessive accumulation of fat, which makes individuals susceptible to metabolic disorders such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension and accelerated atherosclerosis [1]. Although the pathophysiology underlying these disorders remains unknown, insulin resistance appears to be a major contributor [[2], [3], [4], [5]]. Obesity is a risk factor for inducing insulin resistance. In obesity, lipid deposition in skeletal muscle and the accumulation of lipid metabolites is a major cause of insulin resistance in skeletal muscle [6,7]. Although physical activity, behavioral change, and diet are the basis of weight management, their weight loss by lifestyle changes alone is often limited and difficult to maintain. Adaptive physiological response offsets increased energy expenditure and reduced calorie intake [8]. This phenomenon, called adaptive thermogenic or metabolic adaptation, hinders weight loss and helps with weight recovery [9]. Anti-obesity drug therapy is a strategy that counteracts adaptive changes in appetite and energy expenditure due to weight loss, and improves compliance with lifestyle interventions [10].
Glucagon-like peptide-1 (GLP-1), which is released from the intestinal L cells into the circulation following oral ingestion of nutrients [11,12], possesses multiple biological activities. GLP-1 delays gastric emptying, and reduces appetite [13], promotes insulin biosynthesis and secretion, inhibits glucagon release, improves insulin sensitivity, increase β-cell mass [[14], [15], [16]]. Because of these effects, GLP-1 receptor agonists have been used to treat T2DM and obesity [17,18]. In addition to functioning by activating GLP-1R, GLP-1 (9–36) amide, a product of GLP-1 (7–36) amide degradation by the dipeptidyl peptidase Ⅳ (DPP-Ⅳ), has extra-pancreatic actions on insulin-sensitive tissues such as heart, vasculature, muscle, and liver [[19], [20], [21]]. GLP-1 (9–36) amide inhibits weight gain in diet-induced obese mice [22]. The nonapeptide GLP-1(28–36) amide, cleaved by another peptidase neutral endopeptidase (NEP) 24.11, reduces body weight gain in high-fat diet-fed mice [23,24]. Tomas reported that GLP-1(32–36) amide increases basal energy expenditure and inhibits weight gain in obese mice [25]. Collectively, these reports indicate GLP-1 not only reduces appetite but also improves basal energy metabolism.
Exendin-4 is a single GLP-1R receptor agonist that successfully mimics the insulinotropic effects of GLP-1, including stimulating insulin release, inhibiting glucagon secretion, delaying gastric emptying, and reducing appetite. However, exendin-4 does not contain the peptide of GLP-1 (28–36) amide and GLP-1 (32–36) amide at the C-terminus of GLP-1, so it does not have a weight loss effect by increasing basal energy expenditure. Earlier, we have reported that EGLP-1, a GLP-1 analogue, not only reduces hyperglycemia in streptozotocin (STZ)-induced hyperglycemic mice, but also reduces serum Triglyceride (TG) and non-esterifed fatty acid (NEFA) concentrations [26]. The peptide EGLP-1 was designed as follows: the Ala8 was replaced by Gly, and a sequence of SSGAPPPS obtained from Exendin-4 was linked to the end of the GLP-1 (sup Fig. 1) [26]. Therefore, in this paper, we discuss whether EGLP-1 has the dual function of reducing food intake and increasing basal metabolic rate, both of which are beneficial for weight loss.
Section snippets
Peptide synthesis
Exendin-4 and EGLP-1 were synthesized chemically by GL Biochem (Shanghai, China).
Animal studies
C57BL/6 J male mice (5–6 weeks old) were obtained from the Model Animal Research Center of Nanjing University (Nanjing, China). Mice were housed five per cage under a light/dark cycle of 12 h with free access to food and water. Mice were fed a regular laboratory chow or a high-fat diet (HFD) (60 Kcal % fat, D12492; Research Diets) throughout the studies. All animals were fed according to the protocols of National
EGLP-1 increases oxidative phosphorylation in C2C12 myotubes
In the early days, we have reported that EGLP-1 activates GLP-1R, reduces food intake, inhibits hyperglycemia, and improves lipid metabolism [21]. So, we further explore the effects of EGLP-1 on oxidative phosphorylation in the myotubes. The incubation of myotubes with EGLP-1 (1 nmol/L) for 16 h increased both phosphorylation (inhibitory) of acetyl CoA carboxylase (ACC) and the ratio between phosphorylation of ACC and the total expression of ACC (pACC/ACC). Otherwise, exendin-4 did not increase
Discussion
GLP-1R agonists have a variety of physiological activities including inhibition of feeding, increase in beta cell mass, promotion of insulin secretion, and improvement of insulin resistance, and thus, they are used for the treatment of type 2 diabetes and obesity, such as exendin-4. In addition to functioning by activating GLP-1R, GLP-1 also had some extra-pancreatic actions [19,20]. For example, GLP-1(32–36) amide, which is cleaved by another peptidase neutral endopeptidase (NEP) 24.11,
Author contributions
Yanfeng Zhang and Liang Jin designed the experiments. Huashan Gao performed all the experiments and prepared figures. Qian Zhao, Kaiying Li, Fujian Qin, Xin Yin, Zhou Lu, Ziwei Song, You Wu helped perform the animal experiments and collected the sample data. Huashan Gao and Qian Zhao wrote the manuscript, Yumeng Shen, Yi Pan reviewed the manuscript. All authors contributed to discuss the research in the experimental period.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by National Natural Science Foundation of China (Grant No. 81570696, No.81702941, and No. 31270985); Supported by Excellent Youth Foundation of Jiangsu Scientific Committee (BK20140029); Priority Academic Program Development of Jiangsu Higher Education Institutions; Key Research Projects of Henan Higher Education Institutions (20B350006); Key Scientific Research Project of Colleges and Universities in Henan Province (202102310478); Pingdingshan University High-level
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These authors contributed equally to this study.