scholarly journals Long-Acting FGF21 Has Enhanced Efficacy in Diet-Induced Obese Mice and in Obese Rhesus Monkeys

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4192-4203 ◽  
Author(s):  
Murielle M. Véniant ◽  
Renee Komorowski ◽  
Ping Chen ◽  
Shanaka Stanislaus ◽  
Katherine Winters ◽  
...  
Keyword(s):  
Body Weight ◽  
Rhesus Monkeys ◽  
Tolerance Test ◽  
Fibroblast Growth Factor 21 ◽  
Obese Mice ◽  
Compound A ◽  
Metabolic Properties ◽  
Long Acting ◽  
Relationship Of ◽  
Different Doses

Fibroblast growth factor 21 (FGF21), a hormone with short half-life, has consistently shown strong pharmacological efficacy. We first assessed the efficacy of murine recombinant FGF21 in C57BL6 lean mice for 5 wk. We then generated a long-acting FGF21 molecule by fusing a Fc to a variant of human recombinant FGF21 (hrFGF21) that contained two engineered mutations [L98R, P171G; Fc-FGF21(RG)] and tested it in C57BL6 diet-induced obese mice and obese rhesus monkeys. We compared its metabolic properties with those of the hrFGF21. Groups of diet-induced obese mice were treated for 36 d with different doses of hrFGF21 (01, 0.3, and 1 mg/kg twice daily) and with Fc-FGF21(RG) (2.3 mg/kg, every 5 d). Body weight, glucose, insulin, cholesterol, and triglyceride levels were decreased after treatment with either compound. A glucose tolerance test (GTT) was also improved. Obese rhesus monkeys were treated with hrFGF21 (once a day) and Fc-FGF21(RG) (once a week) in a dose-escalation fashion. Doses started at 0.1 and 0.3 mg/kg and ended at 3 and 5 mg/kg for hrFGF21 and Fc-FGF21(RG), respectively. Doses were escalated every 2 wk, and animals were followed up for a washout period of 3 wk. Body weight, glucose, insulin, cholesterol, and triglyceride levels and the GTT profile were decreased to a greater extent with Fc-FGF21(RG) than with hrFGF21. The PK-PD relationship of Fc-FGF21(RG) exposure and triglyceride reduction was also conducted with a maximum response model. In conclusion, in more than one species, Fc-FGF21(RG) chronically administered once a week showed similar or greater efficacy than hrFGF21 administered daily.

scholarly journals PEX-168 Improves Insulin Resistance, Inflammatory Response and Adipokines in Simple Obese Mice and Explore the Mechanism

2021 ◽  
Author(s):  
Guo Zeyuan ◽  
Wu Yuting ◽  
Sun Xiaofang
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Blood Glucose ◽  
Statistical Difference ◽  
Low Dose ◽  
Control Group ◽  
Obese Mice ◽  
Inflammatory Status ◽  
Short Period ◽  
Different Doses

Abstract Background: Polyethylene glycxol losenatide（PEX-168）is a new anti-diabetic drug and there are no reports on its weight loss effects，so we designed this trial to investigate the effect of PEX-168 on simple obese mice. Methods: Thirty healthy C57BL/6 male mice were randomly selected and divided into a blank control group (NC, n=6) and an obesity model group (n=24), the high-fat diet-induced simple obesity mice were divided into a model control group (HF) and three different doses of PEX-168 intervention groups of low (LD), medium (MD) and high (HD) (the doses of PEX-168 were 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg), 6 animals in each group. The intervention groups were injected with different doses of PEX-168 intraperitoneally once a week for 12 weeks, and fasting blood glucose (FBG), body weight and food intake were measured from 1 to 12 weeks after the injection, and the activity of mice was observed, and serum insulin (INS), CRP, chemerin and omentin levels were measured after 12 weeks. Results: Compared with the HF group, the low dose of PEX-168 could reduce the body weight of mice in a short period of time (8 weeks), and the mice in the LD and HD groups had a significant decrease in body weight (P < 0.05)；the low dose of PEX-168 could effectively improve the blood glucose and Homa-IR of mice (FBG P < 0.05 INS, IR P < 0.001), but there was no statistical difference between different doses (P > 0.05)；CRP levels in HD and LD groups were significantly improved(P < 0.05)，the levels of serum chemerin and omentin in intervention groups were significantly improved (P < 0.01), but there was no statistical difference between the different doses (P > 0.05). Conclusion: Continuous 12W administration of PEX-168 significantly reduced body weight in simple obese mice, thereby improving inflammatory status, improving insulin resistance, reducing serum chemerin level and increasing serum omentin level, inhibiting the development of diabetes. PEX-168 may regulate the expression of chemerin and omentin mainly through its hypoglycemic effect.

scholarly journals CB1 and GLP-1 receptors cross-talk provides new therapies for obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Philippe Zizzari ◽  
Rongjun He ◽  
Sarah Falk ◽  
Luigi Bellocchio ◽  
...  
Keyword(s):  
Body Weight ◽  
Negative Energy ◽  
Obese Mice ◽  
Preclinical Models ◽  
Metabolic Complications ◽  
Functional Interactions ◽  
Long Acting ◽  
Diabetes And Obesity ◽  
Neuropsychiatric Side Effects

GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.

scholarly journals CB1 and GLP-1 receptors cross-talk provides new therapies for obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Philippe Zizzari ◽  
Rongjun He ◽  
Sarah Falk ◽  
Luigi Bellocchio ◽  
...  
Keyword(s):  
Body Weight ◽  
Negative Energy ◽  
Obese Mice ◽  
Preclinical Models ◽  
Metabolic Complications ◽  
Functional Interactions ◽  
Long Acting ◽  
Diabetes And Obesity ◽  
Neuropsychiatric Side Effects

GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.

scholarly journals Chronic Central Leptin Decreases Food Intake and Improves Glucose Tolerance in Diet-Induced Obese Mice Independent of Hypothalamic Malonyl CoA Levels and Skeletal Muscle Insulin Sensitivity

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4127-4137 ◽  
Author(s):  
Wendy Keung ◽  
Arivazhagan Palaniyappan ◽  
Gary D. Lopaschuk
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Tolerance Test ◽  
Acid Oxidation ◽  
Obese Mice ◽  
Malonyl Coa ◽  
Skeletal Muscle Insulin Sensitivity

Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice.

scholarly journals PEX-168 Improves Insulin Resistance, Inflammatory Response and Adipokines in Simple Obese Mice: A Mechanistic Exploration

2021 ◽  
Author(s):  
Zeyuan Guo ◽  
Yuting Wu ◽  
Xiaofang Sun
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Blood Glucose ◽  
Low Dose ◽  
The Body ◽  
Control Group ◽  
Obese Mice ◽  
Short Period ◽  
Significant Difference ◽  
Different Doses

Abstract Background：Polyethylene glycol losenatide (PEX-168) is a new antidiabetic drug; as such, there are not yet any reports on its weight loss effect. Therefore, this trial was designed to investigate the effect of PEX-168 on simple obese mice.Methods：Thirty healthy male C57BL/6 mice were randomly selected and divided into a control group (NC) and an obesity model group. The high-fat diet-induced simple obesity mice were divided into a model control group (HF) and three intervention groups. The intervention groups were injected with different doses of PEX-168 intraperitoneally once a week for 12 weeks (low (LD), medium (MD) and high (HD)). Fasting blood glucose (FBG), body weight and food intake were measured from 1 to 12 weeks after PEX-168 injection. The serum insulin (INS), C-reactive protein (CRP), chemerin and omentin levels were measured after 12 weeks.Results：Compared with the HF group, the low dose of PEX-168 reduced the body weight of the mice in a short period of time (8 weeks), and the mice in the LDand HD groups showed a significant decrease in body weight (P < 0.05). The low dose of PEX-168 could effectively improve the blood glucose and insulin resistance index (Homa-IR) of the mice (FBG P < 0.05 INS, Homa-IR P < 0.001), but there was no significant difference between different doses (P > 0.05). CRP levels in the HD and LD groups were significantly improved (P < 0.05). The levels of serum chemerin and omentin in the intervention groups were also significantly improved (P < 0.01), but there was no significant difference between the different doses (P > 0.05).Conclusion：PEX-168 significantly reduced the body weight of simple obese mice and prevented the development of diabetes. PEX-168 may regulate the expression of chemerin and omentin mainly through its hypoglycaemic effect, and the weight-reducing effect of PEX-168 is unlikely to be the reason for the changes in both.

scholarly journals PEX-168 Improves Insulin Resistance, Inflammatory Response and Adipokines in Simple Obese Mice: A Mechanistic Exploration

2021 ◽  
Author(s):  
Zeyuan Guo ◽  
Yuting Wu ◽  
Sun Xiaofang
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Blood Glucose ◽  
Low Dose ◽  
The Body ◽  
Control Group ◽  
Obese Mice ◽  
Short Period ◽  
Significant Difference ◽  
Different Doses

Abstract Background: Polyethylene glycol losenatide (PEX-168) is a new antidiabetic drug; as such, there are not yet any reports on its weight loss effect. Therefore, this trial was designed to investigate the effect of PEX-168 on simple obese mice.Methods: Thirty healthy male C57BL/6 mice were randomly selected and divided into a control group (NC, n=6) and an obesity model group (n=24). The high-fat diet-induced simple obesity mice were divided into a model control group (HF) and three intervention groups receiving different doses of PEX-168 (low (LD), medium (MD) and high (HD), receiving PEX-168 doses of 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, respectively), with 6 animals in each group. The intervention groups were injected with different doses of PEX-168 intraperitoneally once a week for 12 weeks. Fasting blood glucose (FBG), body weight and food intake were measured from 1 to 12 weeks after PEX-168 injection. The activity of the mice was observed, and serum insulin (INS), C-reactive protein (CRP) chemerin and omentin levels were measured after 12 weeks.Results: Compared with the HF group, the low dose of PEX-168 reduced the body weight of the mice in a short period of time (8 weeks), and the mice in the LD and HD groups showed a significant decrease in body weight (P < 0.05). The low dose of PEX-168 could effectively improve the blood glucose and insulin resistance index (Homa-IR) of the mice (FBG P < 0.05 INS, Homa-IR P < 0.001), but there was no significant difference between different doses (P > 0.05). CRP levels in the HD and LD groups were significantly improved (P < 0.05). The levels of serum chemerin and omentin in the intervention groups were also significantly improved (P < 0.01), but there was no significant difference between the different doses (P > 0.05).Conclusion: PEX-168 significantly reduced the body weight of simple obese mice and prevented the development of diabetes. PEX-168 may regulate the expression of chemerin and omentin mainly through its hypoglycaemic effect, and the weight-reducing effect of PEX-168 is unlikely to be the reason for the changes in both.

scholarly journals Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

2016 ◽  
Vol 113 (15) ◽  
pp. 4140-4145 ◽  
Author(s):  
Peng-Yu Yang ◽  
Huafei Zou ◽  
Elizabeth Chao ◽  
Lance Sherwood ◽  
Vanessa Nunez ◽  
...  
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
Transdermal Delivery ◽  
Half Life ◽  
Fasting Blood Glucose ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Binding Motif ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.

Co-agonist of glucagon and GLP-1 reduces cholesterol and improves insulin sensitivity independent of its effect on appetite and body weight in diet-induced obese C57 mice

2013 ◽  
Vol 91 (12) ◽  
pp. 1009-1015 ◽  
Author(s):  
Vishal Patel ◽  
Amit Joharapurkar ◽  
Nirav Dhanesha ◽  
Samadhan Kshirsagar ◽  
Kartik Patel ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Treated Group ◽  
Tolerance Test ◽  
Fibroblast Growth Factor 21 ◽  
Reduced Body ◽  
Glucagon Like Peptide 1

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg–1 of co-agonist or 2.5 mg·kg–1 of glucagon or 8 μg·kg–1 of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist.

scholarly journals PEX-168 improves insulin resistance, inflammatory response and adipokines in simple obese mice: a mechanistic exploration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zeyuan Guo ◽  
Yuting Wu ◽  
Lihua Zhu ◽  
Yong Wang ◽  
Daorong Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Blood Glucose ◽  
Low Dose ◽  
The Body ◽  
Control Group ◽  
Obese Mice ◽  
Short Period ◽  
Significant Difference ◽  
Different Doses

Abstract Background Polyethylene glycol loxenatide (PEX-168) is a new antidiabetic drug; as such, there are not yet any reports on its weight loss effect. Therefore, this trial was designed to investigate the effect of PEX-168 on simple obese mice. Methods Thirty healthy male C57BL/6 mice were randomly selected and divided into a control group (NC) and an obesity model group. The high-fat diet-induced simple obesity mice were divided into a model control group (HF) and three intervention groups. The intervention groups were injected with different doses of PEX-168 intraperitoneally once a week for 12 weeks (low (LD), medium (MD) and high (HD)). Fasting blood glucose (FBG), body weight and food intake were measured from 1 to 12 weeks after PEX-168 injection. The serum insulin (INS), C-reactive protein (CRP), chemerin and omentin levels were measured after 12 weeks. Results Compared with the HF group, the low dose of PEX-168 reduced the body weight of the mice in a short period of time (8 weeks), and the mice in the MD and HD groups showed a significant decrease in body weight (P < 0.05). The low dose of PEX-168 could effectively improve the blood glucose and homeostasis model assessment of insulin resistance (Homa-IR) of the mice (FBG P < 0.05 INS, Homa-IR P < 0.001), but there was no significant difference between different doses (P > 0.05). CRP levels in the MD and HD groups were significantly improved (P < 0.05). The levels of serum chemerin and omentin in the intervention groups were also significantly improved (P < 0.01), but there was no significant difference between the different doses (P > 0.05). Conclusions PEX-168 significantly reduced the body weight of simple obese mice and improved the insulin resistance. PEX-168 may regulate the expression of chemerin and omentin through its hypoglycaemic effect, and the weight-reducing effect of PEX-168 is unlikely to be the reason for the changes in both.

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