We thank SCAHU staff of Angers University for taking care of animals, the SCIAM platform, especially Florence Manero, for technical assistance for electron microscopy imaging, and the staff of University Hospital Centre of Angers analysis of clinical data of NUMEVOX cohort. Also, we thank the Department of Pathology of University Hospital Centre of Angers for help on histological analysis.Peer reviewe

Ali, Sakina

Andriantsitohaina, Ramaroson

Delibegovic, Mirela

Dubois, Séverine

Ducluzeau, Pierre-Henri

Gagnadoux, Frédéric

Henni, Samir

Kamli-Salino, Sarah

Martinez, Carmen

Metabol study Group

Piquet, Megan

Pomiès, Pascal

Simard, Gilles

Vergori, Loiusa

Vidal-Gómez, Xavier

Diabetologia

English

Aberdeen University Research

Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance

456789)Aims/hypothesis Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications. Methods Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells. Results Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes. Conclusions/interpretation These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity. Graphical Abstrac

Vergori, Luisa

Delibégovic, Mirela

Martínez, M. Carmen

HAL: Hyper Article en Ligne

Vidal-Gomez, Xavier

Portail HAL Um  (Université de Montpellier)

https://aura.abdn.ac.uk/bitstream/2164/24553/1/Ali_etal_D_Circulating_Extracellular_Vesicle_AAM.pdf

Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance

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Aberdeen University Research

HAL: Hyper Article en Ligne

Portail HAL Um (Université de Montpellier)