Dynamic interplay between Afadin<sup>S1795</sup> phosphorylation and diet regulates glucose homeostasis in obese mice

Tozzi, Marco; Brown, Erin L.; Petersen, Patricia S S; Lundh, Morten; Isidor, Marie S.; Plucińska, Kaja; Nielsen, Thomas S.; Agueda-Oyarzabal, Marina; Small, Lewin; Treebak, Jonas T.; Emanuelli, Brice

doi:10.1113/jp281657

Cited by 4 publications

(6 citation statements)

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“…As recently discussed [ 28 ], a large part of the stress response likely comes from manipulating the tail to collect blood, and therefore GTT procedures in which smaller blood samples are taken may reduce stress-induced rises in blood glucose. We report that insulin can be reliably measured from small (as low as 5 μl) samples of blood by ELISA (as measured in previous publications [ 35 , 36 ]). Whole blood insulin shows a strong linear correlation with plasma insulin ( Figure 4 A) at both low and high concentrations ( Figure 4 B) with whole-blood insulin values recorded as ∼70% of plasma values ( Figure 4 C) likely due to dilution of insulin in whole-blood by the non-plasma fraction.…”

Section: Resultsmentioning

confidence: 55%

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Small

Ehrlich

Iversen

et al. 2022

Molecular Metabolism

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Objective The glucose tolerance test (GTT) is widely used in preclinical research to investigate glucose metabolism, but there is no standardised way to administer glucose. The aim of this study was to directly compare the effect of the route of glucose administration on glucose and insulin kinetics during a GTT in mice. Methods A GTT was performed in lean male and female mice and obese male mice and glucose was administered via the oral or intraperitoneal (I.P.) route. Samples were collected frequently during the GTT to provide a full time-course of the insulin and glucose excursions. In another cohort of lean male mice, plasma concentrations of insulin, c-peptide, and incretin hormones were measured at early time points after glucose administration. A stable-isotope labelled GTT (SiGTT) was then performed to delineate the contribution of exogenous and endogenous glucose to glycemia during the GTT, comparing both methods of glucose administration. Finally, we present a method to easily measure insulin from small volumes of blood during a GTT by directly assaying whole-blood insulin using ELISA and show a good concordance between whole-blood and plasma insulin measurements. Results We report that I.P. glucose administration results in an elevated blood glucose excursion and a largely absent elevation in blood insulin and plasma incretin hormones when compared to oral administration. Utilising stable-isotope labelled glucose, we demonstrate that the difference in glucose excursion between the two routes of administration is mainly due to the lack of suppression of glucose production in I.P. injected mice. Additionally, rates of exogenous glucose appearance into circulation were different between lean and obese mice after I.P., but not after oral glucose administration. Conclusion Reflecting on these data, we suggest that careful consideration be given to the route of glucose administration when planning a GTT procedure in mice and that in most circumstances the oral route of glucose administration should be preferred over the I.P. route to avoid possible artifacts originating from a non-physiological route.

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Section: Resultsmentioning

confidence: 55%

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Small

Ehrlich

Iversen

et al. 2022

Molecular Metabolism

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“… 133 Phosphorylation of Afadin at S1795 also promotes insulin resistance in the early stages of diet‐induced obesity. 134 …”

Section: Phosphorylationmentioning

confidence: 99%

“…In addition, phosphorylation of obesity‐associated PPARγ at S273 induces insulin resistance by upregulating Gdf3 expression and inhibiting the BMP signaling pathway1 133 . Phosphorylation of Afadin at S1795 also promotes insulin resistance in the early stages of diet‐induced obesity 134 …”

Section: Phosphorylationmentioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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“…Afadin phosphorylation alters Adherens Junctions in kidney epithelial cells and favours cell migration of breast cancer cells (Elloul et al, 2014;Gao et al, 2017). Of note, it has been suggested that Afadin phosphorylation may also be involved in the negative feed-back regulation of insulin action in adipocytes (Lundh et al, 2019), and Afadin phospho-mutant mice display a mild amelioration of glucose homeostasis at the early stages of high fat diet (Tozzi et al, 2022). Consistent with an important role of the mTOR/S6K1 pathway on cell adhesion, S6K1 phosphorylation down-regulates PI 4 phosphate 5 kinase type I g (PIPKIg90), which mediates together with talin the assembly of focal adhesion (Jafari et al, 2016).…”

Section: Cytoskeleton Dynamicsmentioning

confidence: 99%

S6 kinase 1 at the central node of cell size and ageing

Fumagalli

Pende

2022

Front. Cell Dev. Biol.

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Genetic evidence in living organisms from yeast to plants and animals, including humans, unquestionably identifies the Target Of Rapamycin kinase (TOR or mTOR for mammalian/mechanistic) signal transduction pathway as a master regulator of growth through the control of cell size and cell number. Among the mTOR targets, the activation of p70 S6 kinase 1 (S6K1) is exquisitely sensitive to nutrient availability and rapamycin inhibition. Of note, in vivo analysis of mutant flies and mice reveals that S6K1 predominantly regulates cell size versus cell proliferation. Here we review the putative mechanisms of S6K1 action on cell size by considering the main functional categories of S6K1 targets: substrates involved in nucleic acid and protein synthesis, fat mass accumulation, retrograde control of insulin action, senescence program and cytoskeleton organization. We discuss how S6K1 may be involved in the observed interconnection between cell size, regenerative and ageing responses.

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Dynamic interplay between Afadin^S1795 phosphorylation and diet regulates glucose homeostasis in obese mice

Abstract: support-information-section).

Cited by 4 publications

References 47 publications

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

S6 kinase 1 at the central node of cell size and ageing

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Dynamic interplay between AfadinS1795 phosphorylation and diet regulates glucose homeostasis in obese mice

Abstract: support-information-section).

Cited by 4 publications

References 47 publications

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

S6 kinase 1 at the central node of cell size and ageing

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Dynamic interplay between Afadin^S1795 phosphorylation and diet regulates glucose homeostasis in obese mice