Glucagon Receptor Signaling and Lipid Metabolism

Galsgaard, Katrine D.; Pedersen, Jens; Knop, Filip K.; Holst, Jens J.; Albrechtsen, Nicolai J. Wewer

doi:10.3389/fphys.2019.00413

Cited by 137 publications

(113 citation statements)

References 149 publications

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“…GLP-1 signaling directly modulates the ER stress response, leading to the promotion of beta-cell survival [66]. Furthermore, GLP-1 production promotes fatty acid oxidation and inhibits fatty acid synthesis [67,68], which potentially explains our findings showing normalization of serum levels of TG, cholesterol, and FFA upon Acarbose feeding in benzene exposed mice.…”

Section: Discussionmentioning

confidence: 71%

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Debarba

Mulka

Lima

et al. 2020

Preprint

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Abbreviations:CNS, central nervous system; ARC, arcuate nucleus of the hypothalamus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamus; PVH, paraventricular hypothalamic nucleus; AbstractBenzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping and evaporation of benzene containing petrol processes. While carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure.We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1α-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.

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Section: Discussionmentioning

confidence: 71%

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Debarba

Mulka

Lima

et al. 2020

Preprint

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“…40 Elevated glucagon levels are observed as a result of GC treatment. 41,42 Increased glucagon in the presence of elevated insulin levels is often found in patients with type 2 diabetes (T2DM). 42 High glucagon levels stimulate gluconeogenesis and glycogenolysis while inhibiting glycolysis and glycogen synthesis.…”

Section: Glucocorticoid Stimulation Of Gluconeogenesis and The Role Omentioning

confidence: 99%

“…41,42 Increased glucagon in the presence of elevated insulin levels is often found in patients with type 2 diabetes (T2DM). 42 High glucagon levels stimulate gluconeogenesis and glycogenolysis while inhibiting glycolysis and glycogen synthesis. 27,42 The overall effect of glucocorticoid-and glucagoninduced stimulation of gluconeogenesis is to increase the delivery of glucose into the bloodstream for uptake and use by peripheral tissues, and importantly, the brain.…”

Section: Glucocorticoid Stimulation Of Gluconeogenesis and The Role Omentioning

confidence: 99%

“…42 High glucagon levels stimulate gluconeogenesis and glycogenolysis while inhibiting glycolysis and glycogen synthesis. 27,42 The overall effect of glucocorticoid-and glucagoninduced stimulation of gluconeogenesis is to increase the delivery of glucose into the bloodstream for uptake and use by peripheral tissues, and importantly, the brain. Of course, some of the released glucose is taken up by the liver itself and can be converted to fatty acids and deposited as TGs in lipid-containing vesicles.…”

Section: Glucocorticoid Stimulation Of Gluconeogenesis and The Role Omentioning

confidence: 99%

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<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Rahimi

Rajpal

Ismail‐Beigi

2020

DMSO

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Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of verylow-density lipoprotein synthesis and secretion into the circulation and inhibition of βoxidation of fatty acids. Role of 11β-hydroxysteroid dehydrogenases-1 and-2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.

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“…The glucagon receptor (GCGR) is a Class B1 GPCR involved in regulation of glucose homeostasis, amino acid and lipid metabolism (6)(7)(8) . Consequently the GCGR is a potential candidate for treatment of diseases associated with insulin resistance, such as metabolic syndrome or type 2 diabetes, the prevalence of which increased two-fold over the past 30 years (9).…”

Section: Introductionmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Preprint

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The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers.Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2 interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2 compared to Class A GPCRs.Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting. Statement of SignificanceThe role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain . We also identify a unique PIP2 interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.GCGR_main text v16 figs MS biorxiv.docx

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Glucagon Receptor Signaling and Lipid Metabolism

Cited by 137 publications

References 149 publications

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

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