scholarly journals Intact Leptin Receptor Signalling is not Required for the Sustained Weight Loss and Appetite Suppression Induced by Roux-en-Y Gastric Bypass Surgery

2021 ◽  
Author(s):  
Mohammed K. Hankir ◽  
Laura Rotzinger ◽  
Arno Nordbeck ◽  
Caroline Corteville ◽  
Annett Hoffmann ◽  
...  
Keyword(s):  
Weight Loss ◽  
Gastric Bypass ◽  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Leptin Receptor ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Sustained Weight Loss ◽  
Obese Rats

Leptin is the archetypal adipokine that promotes a negative whole-body energy balance largely through its action on brain leptin receptors. As such, the sustained weight loss and food intake suppression induced by Roux-en-Y gastric bypass (RYGB) surgery have been attributed to enhancement of endogenous leptin action. We formally revisited this idea in Zucker Fatty fa/fa rats, an established genetic model of leptin receptor deficiency, and carefully compared their body weight, food intake and oral glucose tolerance after RYGB with that of sham-operated fa/fa (obese) and sham-operated fa/+ (lean) rats. We found that RYGB rats sustainably lost body weight, which converged with that of lean rats and was 25.5 % lower than that of obese rats by the end of the 4 week study period. Correspondingly, daily food intake of RYGB rats was similar to that of lean rats from the second postoperative week, while it was always at least 33.9 % lower than that of obese rats. Further, oral glucose tolerance of RYGB rats was normalized at the forth postoperative week. These findings assert that leptin is not an essential mediator of the sustained weight loss and food intake suppression as well as the improved glycemic control induced by RYGB, and instead point to additional circulating and/or neural factors.

KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight

2016 ◽  
Vol 310 (10) ◽  
pp. E821-E827 ◽  
Author(s):  
Sofie Gydesen ◽  
Kim Vietz Andreassen ◽  
Sara Toftegaard Hjuler ◽  
Jane Marie Christensen ◽  
Morten Asser Karsdal ◽  
...  
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Receptor Activation ◽  
Oral Glucose ◽  
Calcitonin Receptor ◽  
Oral Glucose Tolerance ◽  
Significant Weight Loss ◽  
Adipocyte Hypertrophy ◽  
Calcitonin Receptors

This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 μg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control.

scholarly journals Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

2017 ◽  
Vol 313 (5) ◽  
pp. E598-E607 ◽  
Author(s):  
Sofie Gydesen ◽  
Kim Vietz Andreassen ◽  
Sara Toftegaard Hjuler ◽  
Lars I. Hellgren ◽  
Morten Asser Karsdal ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Dose Escalation ◽  
Receptor Agonist ◽  
Receptor Activation ◽  
Oral Glucose ◽  
Equal Weight ◽  
Calcitonin Receptor

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance ( P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance ( P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

scholarly journals Peptide-based GIP receptor inhibition exhibits modest metabolic changes in mice when administered either alone or combined with GLP-1 agonism

2019 ◽  
Author(s):  
Jason A. West ◽  
Soumitra S. Ghosh ◽  
David G. Parkes ◽  
Anastasia Tsakmaki ◽  
Rikke V. Grønlund ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Mouse Model ◽  
Metabolic Effects ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Gip Receptor

ABSTRACTObjectiveCombinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. To this end we investigated the metabolic effects of co-administration of previously reported peptide-based GIPR antagonists with the GLP-1 agonist liraglutide.MethodsTwo GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised in vitro in an assay measuring cAMP production in CHO-K1 cells overexpressing the mouse GIPR. These peptides were then characterised in vivo in lean mice for their effect on oral glucose tolerance, as well as their ability to antagonize exogenous GIP action. Finally, a mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of peptide-based GIPR antagonists, alone or in combination with liraglutide.ResultsIn vitro, both GIPR peptides exhibited potent antagonistic properties, with GIPA-2 being the more potent of the two. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and circulated insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels, with offsetting effects on glycemia noted with co-administration with exogenous mouse GIP, suggesting true antagonism via GIPA-2 at the GIP receptor. Chronic administration studies in a DIO mouse model showed expected effects of GLP-1 agonism (via liraglutide), lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy with the GIPR antagonists and GLP-1 showed separation from single intervention arms though augmented insulin sensitizing effects (modestly lowering insulin and HOMA-IR) and lowering plasmas triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2.ConclusionWe conclude that, in contrast to the well-documented effects of GLP-1R agonism, systemic administration of peptide-based GIPR antagonists demonstrate minimal benefit on metabolic parameters in DIO mice, exhibiting no major effects on body weight, food intake and glycaemic parameters. However, the co-administration of both a GIPR antagonist together with a GLP1 agonist uncovers interesting synergistic and beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

scholarly journals Oral Supplementation with Physiological Doses of Leptin During Lactation in Rats Improves Insulin Sensitivity and Affects Food Preferences Later in Life

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 733-740 ◽  
Author(s):  
Juana Sánchez ◽  
Teresa Priego ◽  
Mariona Palou ◽  
Aixa Tobaruela ◽  
Andreu Palou ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Oral Glucose Tolerance Test ◽  
Glucose Tolerance Test ◽  
Food Preferences ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

The effects of ileal transposition on food intake and body weight loss in VMH-obese rats

1982 ◽  
Vol 35 (2) ◽  
pp. 284-293 ◽  
Author(s):  
H S Koopmans ◽  
A Sclafani ◽  
C Fichtner ◽  
P F Aravich
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Body Weight Loss ◽  
Ileal Transposition ◽  
Obese Rats

Gastric Bypass Surgery Causes Body Weight Loss Without Reducing Food Intake in Rats

2008 ◽  
Vol 18 (4) ◽  
pp. 415-422 ◽  
Author(s):  
Marianne W. Furnes ◽  
Karin Tømmerås ◽  
Carl-Jørgen Arum ◽  
Chun-Mei Zhao ◽  
Duan Chen
Keyword(s):  
Weight Loss ◽  
Gastric Bypass ◽  
Body Weight ◽  
Food Intake ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Body Weight Loss

The addition of cactus flour (Opuntia ficus indica) to the Western-style diet attenuates the onset of metabolic disorders in rats

2019 ◽  
Vol 49 (4) ◽  
pp. 564-579 ◽  
Author(s):  
Graziele Fonseca Cysneiros ◽  
Judith Libertad Chavez Gonzalez ◽  
Amanda Alves Marcelino da Silva ◽  
Taisy Cinthia Ferro Cavalcante ◽  
Omar Guzman Quevedo ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Dietary Intake ◽  
Relative Weight ◽  
Metabolic Parameters ◽  
Oral Glucose ◽  
Opuntia Ficus Indica ◽  
Content Type ◽  
Cholesterol Levels

PurposeThe purpose of this study is to investigate the effect of a 15-week dietary intake of cactus flour on metabolic parameters, body weight and dietary intake of rats.Design/methodology/approachMale Wistar rats were divided into four experimental groups (n= 8-10): control or westernized diets added or not of cactus flour. The following parameters were evaluated during the period of dietary manipulation: body weight, food intake, glycemic and lipid profile (oral glucose tolerance test, metabolic parameters, hepatic and muscular glycogen dosage), visceral and body fat (relative weight to body weight). Data were analyzed using Graphpad Prism®5,p= 0.05.FindingsAnimals fed on a Western-style diet together with flour cactus presented lower weight gain (335.7 ± 20.0,p= 0.05) over the evaluated period, even when the volume of food intake was not different among the groups. The addition of cactus flour to a Western-style diet appears to lower glucose levels at 30 and 60 min (p= 0.05), as shown in the glucose tolerance curve. There was a downward trend does fat stores, cholesterol levels and triglycerides. Therefore, it was concluded that this addition cactus flour is effective even when the diet is hyperlipidic, demonstrating its ability to attenuate risk parameters for the occurrence of metabolic syndromes such as sub fraction high cholesterol levels and glucose tolerance.Originality/valueThe addition of functional foods to diets may work to improve the harmful effects of this type of diet.Opuntia ficus indicahas high nutritional value and has hypoglycemic and hypolipemic properties besides being antioxidant.

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