The anorexic effect of Ex4/Fc through GLP-1 receptor activation in high-fat diet fed mice

Liu, Rui; Ma, Duan; Li, Yiming; Hu, Renming; Peng, Yongde; Wang, Qinghua

doi:10.1093/abbs/gmu044

Cited by 3 publications

(2 citation statements)

References 33 publications

(39 reference statements)

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“…GLP-1 also exerts a variety of biological actions independent of islet β cells, including reduction in gastric emptying, suppression of glucagon secretion and body weight sparing effects. Although controversial, previous studies showed that GLP-1 can also improve peripheral insulin sensitivity ( Liu et al, 2014 , 2016 ). Here, we demonstrate that GLP-1 improves insulin sensitivity of ER-stressed adipocyte through modulation of UPR.…”

Section: Discussionmentioning

confidence: 99%

“…Following drug treatment as indicated, cells were lysed in RIPA buffer (1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% SDS in PBS) supplemented with protease and phosphatase inhibitor mixtures. Forty to fifty micrograms of cell lysate protein was resolved by SDS-PAGE and immunoblotted as described previously ( Liu et al, 2014 ). The proteins were transferred to PVDF membrane and immunoblotted with primary antibodies overnight.…”

Section: Methodsmentioning

confidence: 99%

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GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress

Jiang

Wang

et al. 2018

Front. Pharmacol.

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Glucagon-like peptide 1 (GLP-1) improves insulin resistance of adipose tissue in obese humans. However, the mechanism of this effect is unclear. Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin signaling. We hypothesized that GLP-1 could directly improve insulin signaling in ER-stressed adipocytes. Here, we examined the effects of GLP-1 on ER stress response in fat cells in an obese and insulin-resistant murine model. We found that GLP-1 analog liraglutide reduced ER stress related gene expression in visceral fat cells accompanied by improved systemic insulin tolerance. Consistently, GLP-1 decreased CHOP expression and increased insulin stimulated AKT phosphorylation (p-AKT) in thapsigargin, a ER stress inducer, treated white fat cells differentiated from visceral stromal vascular fraction. We further found blocking CHOP expression increased insulin stimulated p-AKT in ER-stressed fat cells. Of note, we found mTOR signaling pathway contributed to the expression of ATF4 and subsequently the CHOP expression in ER stress response, while GLP-1 inhibited mTOR activity as exemplified by elevated autophagosome formation and increased LC3II/LC3I ratio. These findings suggest that GLP-1 directly modulates the ER stress response partially via inhibiting mTOR signaling pathway, leading to increased insulin sensitivity in adipocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress

Jiang

Wang

et al. 2018

Front. Pharmacol.

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Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

et al. 2016

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Background GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. Basic Procedures Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17 days (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days) of treatment, we also studied changes in fMRI responses to food cues. Main Findings By design, to avoid any confounding by weight changes, subjects were studied for 17 days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. Principal Conclusions We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that would over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

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In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein

Wang

et al. 2017

RSC Adv.

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The anorexic effect of Ex4/Fc through GLP-1 receptor activation in high-fat diet fed mice

Cited by 3 publications

References 33 publications

GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress

GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein

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