Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia

Castellani, L; Peppler, Willem T.; Sutton, Charles D.; Whitfield, Jamie; Charron, Maureen J.; Wright, David C.

doi:10.1016/j.psyneuen.2017.05.005

Cited by 31 publications

(41 citation statements)

References 30 publications

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“…Reductions in the insulin response, while prevented by AICAR, may not be a causal event in OLZ-induced hyperglycaemia. In support of this, we have recently shown that glucagon receptor knockout mice are protected against OLZ-induced hyperglycaemia despite severe insulin resistance (Castellani et al, 2017). These mice showed reductions in hepatic glucose output secondary to decreases in the protein content of the gluconeogenic enzymes, PEPCK and G6Pase, suggesting an important role for the liver in OLZ-induced hyperglycaemia (Castellani et al, 2017).…”

Section: Discussionmentioning

confidence: 86%

“…Previous studies have shown that OLZ induces insulin resistance in mice (Castellani et al, 2017;Townsend et al, 2018) and that AICAR improves whole body insulin action in insulinresistant high-fat diet-fed rats (Iglesias et al, 2002). These effects of AICAR were attributed to improvements in skeletal muscle glucose uptake (Iglesias et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Bush

Townsend

Wright

2018

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Bush

Townsend

Wright

2018

J Pharmacol Exp Ther

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“…The cold tolerance of Gcgr −/− mice is particularly interesting because they were unable to maintain blood glucose after prolonged cold exposure. This is likely because hepatic Pck1 expression is reduced in Gcgr −/− mice, leading to reduced hepatic PEPCK protein content (21), and thus cold‐induced gluconeogenesis is likely reduced. This provides evidence that glucagon signaling is necessary for cold‐induced gluconeogenesis and the maintenance of blood glucose during prolonged cold exposure but not thermoregulation.…”

Section: Discussionmentioning

confidence: 99%

“…All procedures in this study were approved by the Animal Care Committee at the University of Guelph and are in accordance with the guidelines of the Canadian Council on Animal Care. Breeding pairs of Gcgr −/− mice (20) were used to establish a colony at the University of Guelph and have been used for past projects (21). All mice were housed in shoebox cages, 2–5 per cage, on a 12:12‐h light cycle (light cycle from 8:00 am to 8:00 pm ).…”

Section: Methodsmentioning

confidence: 99%

Loss of glucagon signaling alters white adipose tissue browning

et al. 2019

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Various endocrine factors contribute to cold‐induced white adipose tissue (WAT) browning, but glucagon has largely been ignored. The purpose of the current investigation was to determine if glucagon was required for the effects of cold on WAT browning. Utilizing whole‐body glucagon receptor knockout (Gcgr−/−) mice and their wild‐type (WT) littermate controls, we examined the response of inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) to an acute (48 h) cold stress or challenge with the β3‐adrenergic agonist CL316,243. The effects of glucagon alone on the induction of thermogenic genes in adipose tissue from C57BL6/J mice were also examined. Gcgr−/− mice displayed modest increases in indices of browning at room temperature while displaying a blunted induction of Ucp1, Cidea, and Ffg21 mRNA expression in iWAT following cold exposure. Similarly, cold induced increases in mitochondrial DNA copy number, and the protein content of mitochondrial respiratory chain complexes, UCP1, and PGC1α were attenuated in iWAT from Gcgr−/− mice. In BAT, the induction of thermogenic markers following cold exposure was reduced, but the effect was less pronounced than in iWAT. Glucagon treatment increased the expression of thermogenic genes in both iWAT and BAT of C57BL6/J mice. In response to CL316,243, circulating fatty acids, glycerol, and the phosphorylation of hormone‐sensitive lipase were attenuated in iWAT of Gcgr−/− mice. We provide evidence that glucagon is sufficient for the induction of thermogenic genes in iWAT, and the absence of intact glucagon signaling blunts the cold‐induced browning of WAT, possibly due, in part, to impaired adrenergic signaling.—Townsend, L. K., Medak, K. D., Knuth, C. M., Peppier, W. T., Charron, M. J., Wright, D. C. Loss of glucagon signaling alters white adipose tissue browning. FASEB J. 33, 4824–4835 (2019). http://www.f asebj.org

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“…To design a Predator system that can specifically degrade the glucagon receptor (GCGR), we replaced the GFP/ErbB3 targeting module with glucagon, which could bind to GCGR specifically. If our Predator system can degrade GCGR protein levels, then the cells would have decreased GCGR protein levels, resulting in decreased sensitivity to glucagon and a corresponding reduction in the activation of glycogenolysis and gluconeogenesis, and eventually glucose production under the stimulation of glucagon in the liver cells ( Fig 4A) (28,32).…”

Section: Gcgr Predator: From Antibody To Ligandsmentioning

confidence: 99%

Predator: A novel method for targeted protein degradation

Liu

Kuang

Lü

et al. 2020

Preprint

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Protein expression and degradation are fundamental to cell function and physiological status of organisms. Interfering with protein expression not only provides powerful strategies to analyze the function of proteins but also inspires effective treatment methods for diseases caused by protein dysfunction. Recently, harnessing the power of the ubiquitin-proteasome system for targeted protein degradation (TPD) has become the focus of researches. Over the past two decades, TPD technologies, such as E3 ligase modification, PROTACs, and the Trim-Away method, have successfully re-oriented the ubiquitin-proteasome pathway and thus degraded many pathogenic proteins and even "undruggable" targets. However, A low-cost, convenient, and modularized TPD method is currently not available. Herein, we proposed a synthetic biology TPD method, termed Predator, by integrating the classic function of E3 ligase Trim21 and the expression of a bifunctional fusion protein that links Trim21 and the target protein, which leads to the formation of a ternary complex inside mammalian cells and therefore induce the ubiquitination and subsequent proteasome-dependent degradation of the target protein. We first proved this concept by using nanobody and scFv as the targeting module for the Predator system to degrade free GFP and membrane protein ErbB3, respectively. Then, we give an example of how the engineered Predator system can be developed towards biomedical solutions in the context of diabetes mellitus. Ligands-receptor interaction and adenovirus-mediated gene delivery were introduced to the Predator system, and we found this bifunctional fusion protein, in which glucagon was selected to function as the targeting module, downregulated the endogenous glucagon receptor (GCGR) and attenuated glucagon-stimulated glucose production in primary hepatocytes. Although preliminarily, our results showed that this Predator system is a highly modularized and convenient TPD method with good potential for both fundamental researches and clinical usage.Graphic abstract

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Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia

Cited by 31 publications

References 30 publications

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

Loss of glucagon signaling alters white adipose tissue browning

Predator: A novel method for targeted protein degradation

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