Brain IL-6—Where Amylin and GLP-1 Antiobesity Signaling Congregate

Jansson, John‐Olov; Pálsdóttir, Vilborg

doi:10.2337/db14-1910

Cited by 10 publications

(8 citation statements)

References 20 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These studies showed a combined effect of SCT and liraglutide on c-fos activation in the DVC, consistent with a combined suppression of food intake and gastric emptying (Liberini et al, 2019;. Furthermore, earlier work indicated that this effect may entail a local upregulation of brain IL-6 in the hypothalamus, by both amylin and GLP-1 (Jansson and Palsdottir, 2015). Hence, while the complete picture of how the combination works is still unclear, there is evidence supporting that it entails common signaling pathways.…”

Section: Discussionsupporting

confidence: 54%

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile 

Larsen

Gydesen

Sonne

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Weight loss therapy is becoming more and more important, and two classes of molecules, namely amylin receptor and GLP-1 receptor agonists, have shown promise in this regard. Interestingly, these molecules have several overlapping pharmacological effects, such as suppression of gastric emptying, reduction of glucagon secretion and weight loss in common; however, they also have distinct effects on prandial insulin secretion. Hence, a combination of these two mechanisms is of significant interest. Methods: In this study, we investigated the add-on potential of the dual amylin and calcitonin receptor agonist (DACRA) KBP-089 in combination with the GLP-1 receptor agonist liraglutide as obesity treatment in high-fat diet (HFD) fed rats. Results: Increasing doses of KBP-089 and liraglutide alone and in combination were studied with respect to their effects on body weight, food intake and glucose metabolism during a 9-week intervention study conducted in HFD rats. Further, the gastric emptying rate during an oral glucose tolerance was assessed. Treatment with KBP-089 and liraglutide dose-dependently lowered body weight 15% (at 2.5 µg/kg/day) and 7% (at 400 µg/kg/day) in HFD rats, respectively, while the combination resulted in a 21% body weight reduction, which was mirrored by reduction in fat depot sizes. Gastric emptying and glucose metabolism were improved, primarily by KBP-089, although liraglutide led to a reduction in fasting plasma glucagon. Conclusion: DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

show abstract

Section: Discussionsupporting

confidence: 54%

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile 

Larsen

Gydesen

Sonne

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that deficiency of IL‐6 is causing mature onset obesity, and the results of several studies involving central IL‐6 administration indicate that this anti‐obesity effect is exerted at the level of the brain . In addition, there is evidence that brain IL‐6 is crucial in the anti‐obesity signalling of both GLP‐1 analogues and amylin analogues . These functions of IL‐6 are of clinical relevance, given that both GLP‐1‐ and amylin analogues are widely used for treatment of diabetes and obesity …”

Section: Discussionmentioning

confidence: 99%

Functional interleukin‐6 receptor‐α is located in tanycytes at the base of the third ventricle

Anesten

Santos

Gidestrand

et al. 2017

J Neuroendocrinology

View full text Add to dashboard Cite

Interleukin (IL)‐6−/− mice develop mature onset obesity, whereas i.c.v. injection of IL‐6 decreases obesity in rodents. Moreover, levels of IL‐6 in cerebrospinal fluid (CSF) were reported to be inversely correlated with obesity in humans. Tanycytes lining the base of the third ventricle (3V) in the hypothalamus have recently been reported to be of importance for metabolism. In the present study, we investigated whether tanycytes could respond to IL‐6 in the CSF. With immunohistochemistry using a well characterised antibody directed against the ligand binding receptor for IL‐6, IL‐6 receptor α (IL‐6Rα), it was found that tanycytes, identified by the two markers, vimentin and dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa, contained IL‐6Rα. There were fewer IL‐6Rα on another type of ventricle‐lining cells, ependymal cells, as identified by the marker glucose transporter‐1. To demonstrate that the immunoreactive IL‐6Rα were responsive to IL‐6, we injected IL‐6 i.c.v. This treatment increased immunoreactive phosphorylated signal transducer and activator of transcription‐3 (pSTAT3) in tanycytes after 5 minutes and in cells in the medial part of the arcuate nucleus after 5 and 15 minutes. Intracerebroventricular injection of leptin exerted similar effects. As expected, i.p. injection of leptin also induced pSTAT3 staining in the hypothalamus, whereas i.p. IL‐6 injection had little effect on this parameter. Intracerebroventricular or i.p. injection of vehicle only had no effect on pSTAT3‐immunoreactivity. In summary, there are functional IL‐6Rα on tanycytes at the bottom of the 3V, in agreement with the possibility that ventricular administration of IL‐6 decreases obesity in mice via an effect on this cell type.

show abstract

“…Peptides with known anorectic effects, such as amylin and GLP-1 analogs, are associated with GI tolerability problems (3,13), and we speculate that the massive suppression of food intake following initial dosing is indicative of adverse effects on the GI tract, as also supported by kaolin intake at high doses of KBP-042 (11). To investigate whether a similar weight loss, albeit with a less pronounced suppression of appetite, could be obtained, we mimicked the clinical situation for pramlintide and GLP-1 analogs and used dose escalation (3,17).…”

Section: Discussionmentioning

confidence: 99%

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

Gydesen

Andreassen

Hjuler

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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 ( < 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 ( < 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.

show abstract

Brain IL-6—Where Amylin and GLP-1 Antiobesity Signaling Congregate

Cited by 10 publications

References 20 publications

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile

Functional interleukin‐6 receptor‐α is located in tanycytes at the base of the third ventricle

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

Contact Info

Product

Resources

About

Brain IL-6—Where Amylin and GLP-1 Antiobesity Signaling Congregate

Cited by 10 publications

References 20 publications

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile&nbsp;

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile&nbsp;

Functional interleukin‐6 receptor‐α is located in tanycytes at the base of the third ventricle

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

Contact Info

Product

Resources

About

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile