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 Deficiency in Interferon-γ Results in Reduced Body Weight and Better Glucose Tolerance in Mice

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3690-3699 ◽  
Author(s):  
Nicole Wong ◽  
Barbara C. Fam ◽  
Gitta R. Cempako ◽  
Gregory R. Steinberg ◽  
Ken Walder ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Mrna Expression ◽  
Tolerance Test ◽  
Interferon Γ ◽  
Reduced Body

Obesity is a chronic low-grade inflammatory disease caused by increased energy intake and reduced energy expenditure. Studies using animal models with deletion of inflammatory cytokines have produced conflicting results with some showing increased weight gain and others showing no effect or even reduced body weights. Clearly, more work is necessary to understand the role of cytokines on body weight control. The aim of this study was to determine the effect of interferon-γ deletion (IFNγ−/−) on body weight regulation and glucose metabolism. Male IFNγ−/− and wild-type C57BL/6 mice were fed a low-fat chow diet, and body weight, food intake, and energy expenditure were monitored over 20 wk. At the end of the study, ip glucose tolerance test, insulin tolerance test, basal glucose turnover, and hyperinsulinemic/euglycemic clamps were performed. Expression levels of arcuate nucleus neuropeptide Y, Agouti-related peptide, and proopiomelanocortin mRNA as well as circulating leptin levels were also determined. IFNγ−/− mice had improved glucose tolerance with reduced rate of glucose appearance and increased insulin sensitivity due to greater suppression of endogenous glucose output, which was associated with decreased hepatic glucose-6-phosphatase activity. In addition, we also observed reduced body weight associated with decreased food intake and increased physical activity. Neuropeptide Y and Agouti-related peptide mRNA expression was reduced, whereas proopiomelanocortin mRNA expression was increased, as were plasma leptin levels. Global deletion of IFNγ in mice resulted in reduced body weight associated with negative energy balance, improved glucose tolerance, and hepatic insulin sensitivity. Our findings demonstrate that IFNγ plays a critical role in the regulation of body weight and glucose metabolism.

Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice

2012 ◽  
Vol 302 (8) ◽  
pp. E924-E931 ◽  
Author(s):  
Toru Kusakabe ◽  
Ken Ebihara ◽  
Takeru Sakai ◽  
Licht Miyamoto ◽  
Daisuke Aotani ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Calorie Restriction ◽  
Tolerance Test ◽  
Body Weight Reduction ◽  
Glucose Levels ◽  
Diet Induced Obesity ◽  
Antidiabetic Treatment ◽  
Triglyceride Content

Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg−1·day−1), amylin (A; 100 μg·kg−1·day−1), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.

scholarly journals The Hypolipidemic Effect of Aqueous Extract of Hibiscus sabdariffa on Paracetamol-induced Hepatotoxicity in Albino Wistar Rats

2020 ◽  
pp. 54-60
Author(s):  
E. B. Umoren ◽  
J. F. Ekpenyong ◽  
O. E. Oyama ◽  
A. O. Obembe
Keyword(s):  
Body Weight ◽  
Aqueous Extract ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Treated Group ◽  
The Body ◽  
Control Group ◽  
Hypolipidemic Effect ◽  
Low Density ◽  
Hibiscus Sabdariffa

Aim of the Study: This study was undertaken to ascertain if Hibiscus sabdariffa extract can affect the lipid profile (Total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), very low density lipoprotein (VLDL), and low density lipoprotein (LDL)) levels in a paracetamol- induced hepatotoxicity using albino Wistar rat as a model. Materials and Methods: Thirty (30) rats used for this study were divided into three groups. Group A (n=10) served as control. Group B (n=10) was administered paracetamol only at a dose of 750 mg/kg body weight. Group C (n=10) was administered paracetamol (dose 750 mg/kg body weight) and aqueous extract of H. sabdariffa (dose 10 ml/kg body weight) of the animal for 3 weeks. All animals were allowed free access to clean drinking water and normal rat chow. Results: Results of the study revealed that TC was significantly lower (p<0.05) in the paracetamol + H. sabdariffa-treated group as compared to paracetamol-treated group and control respectively. Similar trend was observed with TG, VLDL-c, LDL-c and HDL-c. However, the decrease in HDL-c was not statistically significant when compared to control. Conclusion: The presence of bioactive constituents vis; anthocyanins, flavonoids, polyvenols and free radical scavenging properties in H. sabdariffa enabled a hypolipidemic effect on the animals by lowering the levels of serum TG, VLDL-c, LDL-c despite challenge on the liver. However, it was unable to produce significant effect on HDL concentration -very important cholesterol required in high level to maintain homeostasis inside the body. This may be due to the challenge on the liver as a result of the paracetamol abuse.

PYY(3–36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity

2006 ◽  
Vol 291 (2) ◽  
pp. R367-R375 ◽  
Author(s):  
Niels Vrang ◽  
Andreas Nygaard Madsen ◽  
Mads Tang-Christensen ◽  
Gitte Hansen ◽  
Philip Just Larsen
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Peptide Yy ◽  
Body Weight Gain ◽  
Subcutaneous Administration ◽  
Treated Group ◽  
Metabolic Effects ◽  
Male Rats ◽  
Reduced Body ◽  
Gut Hormone

The gut hormone peptide YY (PYY) was recently proposed to comprise an endogenous satiety factor. We have studied acute anorectic functions of PYY(3–36) in mice and rats, as well as metabolic effects of chronic PYY(3–36) administration to diet-induced obese (DIO) mice and rats. A single intraperitoneal injection of PYY(3–36) inhibited food intake in mice, but not in rats. We next investigated the effects of increasing doses (100, 300, and 1,000 μg·kg−1·day−1) of PYY(3–36) administered subcutaneously via osmotic minipumps on food intake and body weight in DIO C57BL/6J mice. Whereas only the highest dose (1,000 μg·kg−1·day−1) of PYY(3–36) significantly reduced food intake over the first 3 days, body weight gain was dose dependently reduced, and on day 28 the group treated with 1,000 μg·kg−1·day−1 PYY(3–36) weighed ∼10% less than the vehicle-treated group. Mesenteric, epididymal, retroperitoneal, and inguinal fat pad weight was dose dependently reduced. Subcutaneous administration of PYY(3–36) (250 and 1,000 μg·kg−1·day−1) for 28 days reduced body weight and improved glycemic control in glucose-intolerant DIO rats. Neither 250 nor 1,000 μg/kg PYY(3–36) elicited a conditioned taste aversion in male rats.

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 Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility

2005 ◽  
Vol 186 (1) ◽  
pp. 203-211 ◽  
Author(s):  
Simon Klebanov ◽  
Clinton M Astle ◽  
Olga DeSimone ◽  
Vitaly Ablamunits ◽  
David E Harrison
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Hormone Replacement ◽  
Tolerance Test ◽  
Reduced Body ◽  
Insulin Tolerance

Adipose tissue affects metabolism by secreting various adipokines. Lipodystropic mice benefit both from leptin replacement therapy and from transplantation of normal fat. Leptin-deficient Lepob/Lepob (ob/ob) mice can also be treated with leptin. Surprisingly, there have been no reports of successful treatment of obese ob/ob mice by transplantation of normal white adipose tissue (WAT). If WAT transplantation is ineffective in treating insulin resistance and diabetes in obese individuals, its applicability may be limited in humans as such abnormalities are usually associated with obesity. In the current study, we tested whether WAT transplantation might prevent, and even reverse, abnormalities characteristic of ob/ob mice. To assess the preventive potential, 6-week-old ob/ob mice were transplanted, subcutaneously, with gonadal fat pads from normal mice. Profound effects on multiple physiological phenotypes were achieved despite leptin levels below 25% of those in control mice. WAT from one donor reduced body weight gain, and WAT from 4 or 8 donors prevented obesity in ob/ob mice. Nonfasting insulin levels and insulin tolerance test were normalized. Corticosterone elevation was also prevented. Finally, WAT from 4 donors restored fertility in ob/ob females. The effects of WAT transplantation were long-lasting, with body weight gain suppressed for at least 40 weeks. To assess the therapeutic potential, obese 13-month-old ob/ob mice with a long history of leptin deficiency were used. Their body weight decreased by approximately 50% when transplanted with WAT from 8 donors. As in young recipients, transplantation greatly reduced nonfasting insulin, suggesting normalized insulin sensitivity. Thus, WAT transplantation was effective for both prevention and therapy. In the future, WAT transplantation may become a useful alternative to hormone replacement in treating not only lipodystropy, but also certain types of obesity.

scholarly journals Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

2010 ◽  
Vol 299 (3) ◽  
pp. G751-G760 ◽  
Author(s):  
Derek M. Culnan ◽  
Vance Albaugh ◽  
Mingjie Sun ◽  
Christopher J. Lynch ◽  
Charles H. Lang ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Zucker Rats ◽  
Ileal Interposition ◽  
Obese Zucker Rat ◽  
Obese Zucker Rats ◽  
Glucagon Like Peptide 1

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group ( P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[14C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt ( P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

The Effect of Beef Flavor on the Fat Metabolism in Mice

2013 ◽  
Vol 781-784 ◽  
pp. 1574-1581
Author(s):  
Jing Jing Ouyang ◽  
Yu Qiang Wang ◽  
Wen Tang ◽  
Xiao Li Zhou ◽  
Yi Ming Zhou ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Low Density Lipoprotein ◽  
Fat Metabolism ◽  
Density Lipoprotein ◽  
Whole Body ◽  
Control Group ◽  
Lung Weight ◽  
Blood Biochemical ◽  
Beef Flavor

The beef flavor was selected to carry out toxicological analysis regarding food intake, body weight, organs weight and blood biochemical indexes in mice. The results show that beef flavor could suppress food intake but promote mice weight compared with the control group. Flavor intake has significant effect on the ratio of liver and lung weight to the whole body weight, but it has no difference in the ratio of heart, spleen and kidney weight. Some biochemical indexes about fat metabolism in blood such as the total protein, total bile acid and alkaline phosphatase are respectively 4 g/L, 0.7μmol/L and 23 IU/L more than the control group. These factors and cholesterol, triglyceride, low density lipoprotein, high-density lipoprotein cholesterol in the mice blood all have extremely significant differences (P<0.01) in different conditions. The results suggest that the beef flavor has significant impact on fat metabolism in mice.

scholarly journals Ameliorative Effect of Pleurotus ostreatus on Lipid Levels and Atherogenic Indices in Hyperlipidemic Rats

2019 ◽  
pp. 1-6
Author(s):  
N. L. Nwobi ◽  
O. S. Usiobeigbe ◽  
R. O. Osaro ◽  
J. C. Nwobi
Keyword(s):  
Body Weight ◽  
Pleurotus Ostreatus ◽  
Wistar Rats ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Levels ◽  
Reduced Body ◽  
Atherogenic Indices ◽  
Male Wistar Rats

Aim: To evaluate the effects of Pleurotus ostreatus on the lipid profile and atherogenic indices in Hyperlipidemic rats. Study Design, Place and Duration of Study: This case-control study was done for 60 days between March and April, 2017 at the department of Medical Laboratory Science and Department of Chemical Pathology, Babcock University, Ogun State, Nigeria. Methodology: Thirty male wistar rats weighing 117-130 g were divided randomly into 3 groups: Normolipidemic (NL) rats (fed with standard rodent chow), Hyperlipidemic (HL) rats (fed with standard rodent chow + duck yolk and reused oil), Hyperlipidemic Treated (HL+T) rats (fed with standard rodent chow + duck yolk and reused oil + 5% Pleurotus ostreatus powder).  Changes in the animal body weights were measured in this study. Serum was obtained from fasting blood samples for the standard biochemical analyses of total cholesterol (TC), triglycerides (TG), High density lipoprotein cholesterol (HDL-C), creatinine, urea, Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST). Low density lipoprotein (LDL), very low density lipoprotein (VLDL), TC/HDL, LDL/HDL and Log (TG/HDL) ratios were calculated. Results: The HL+T rats compared to HL rats had significantly reduced body weight, TC, TG, LDL, VLDL, TC/HDL, LDL/HDL and Log(TG/HDL) by 19.59%, 14.38%, 15.82%, 25.52%, 15.83%, 28.89%, 20.24% and 27.27% respectively (p ≤ 0.05) but recorded no significant change in HDL-C (p > 0.05). Creatinine, urea, AST and ALT did not show any significant change in HL rats and HL+T rats (p > 0.05). Conclusion: Treatment of hyperlipidemic male wistar rats with Pleurotus ostreatus reduced body weight, lipid levels (TC, TG, LDL, VLDL) and atherogenic indices (TC/HDL, LDL/HDL, Log (TG/HDL)) and appeared to have no detrimental effects on the liver and kidneys. These findings may provide insights and scientific basis for the promotion of the use of Pleurotus ostreatus in controlling hyperlipidemia and associated complications.

Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor

2014 ◽  
Vol 306 (7) ◽  
pp. R490-R498 ◽  
Author(s):  
Krystyna Tatarkiewicz ◽  
Emmanuel J. Sablan ◽  
Clara J. Polizzi ◽  
Christiane Villescaz ◽  
David G. Parkes
Keyword(s):  
Body Weight ◽  
Gastric Emptying ◽  
Food Intake ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Oral Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP-1R (Glp1r−/−). Exenatide (30 nmol·kg−1·day−1) was infused subcutaneously for 12 wk in Glp1r−/− and wild-type (Glp1r+/+) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r−/− mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r+/+ mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC0–2h, ALT, and HLC in Glp1r+/+ mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r−/− versus Glp1r+/+ mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel “GLP-1” receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r+/+ versus Glp1r−/− mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides.

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