Thromb Haemost 2019; 119(03): 384-396
DOI: 10.1055/s-0038-1677033
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway

Ziane Elaïb*
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Jose Javier Lopez*
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
2  Departamento de Fisiología, Catedrático de Universidad, Universidad de Extremadura, Cáceres, Spain
,
Muriel Coupaye
3  Service des Explorations Fonctionnelles, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
4  Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Paris, France
,
Kevin Zuber
5  Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France
,
Yann Becker
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Aurélie Kondratieff
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Christelle Repérant
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Marion Pépin
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Laurence Salomon
5  Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France
6  Département de Santé Publique, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
,
France Teillet
7  Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
8  Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Simon Msika
8  Université Paris Diderot, Sorbonne Paris Cité, Paris, France
9  Service de Chirurgie Digestive, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
,
Cécile V. Denis
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Dominique de Prost
7  Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
8  Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Jean-Philippe Rosa
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Régis Bobe**
1  INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Alain Stépanian**
8  Université Paris Diderot, Sorbonne Paris Cité, Paris, France
10  Service d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France
11  EA3515 Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris-Diderot, Paris, France
› Author Affiliations
Funding This work was supported by Grant CRC 10018 (Contrat de Recherche Clinique) from Assistance Publique–Hôpitaux de Paris. J.J.L. is supported by contract Juan de la Cierva (Ministerio Economia y Competitividad, Spain) JCI-2012–12934, MINECO (Grants BFU2013–45564-C2–1-P/2-P and BFU2016–74932-C2–1-P/2-P) and Junta de Extremadura-FEDER (Fondo Europeo de Desarrollo Regional Grants IB16046 and GR15029).
Further Information

Publication History

22 August 2018

29 November 2018

Publication Date:
16 January 2019 (eFirst)

Abstract

In obesity, platelets are described as hyperactive, mainly based on increased platelet size and presence of pro-thrombotic plasmatic molecules. We explored platelet functions, including calcium signalling in obesity, and the effect of weight loss. We included 40 obese patients (women with body mass index [BMI] of ≥ 35 kg/m2) who were to undergo gastric bypass surgery and 40 healthy lean subjects (women with BMI of < 25 kg/m2) as a control group. Approximately 1 year after surgery, the obese patients lost weight (75% had a BMI < 35 kg/m2). They were explored a second time with the same healthy control for the same platelet experiments. Compared with controls, obese patients' platelets displayed reduced sensitivity to thrombin (aggregation EC50 increased by 1.9 ± 0.3-fold, p = 0.005) and a lower Ca2+ response (70 ± 7% decrease, p < 10−4). In 17 pairs of patients, we performed additional experiments: in obese patients' platelets, thrombin-induced αIIbβ3 activation was significantly lower (p = 0.003) and sarco-endoplasmic reticulum Ca2+ATPase (SERCA3) expression was decreased (48 ± 6% decrease, p < 10−4). These differences were abolished after weight loss. Interestingly, pharmacological inhibition of SERCA3 activity in control group's platelets mimicked similar alterations than in obese patients' platelets and was associated with defective adenosine diphosphate (ADP) secretion. Addition of ADP to agonist restored platelet functions in obese patients and in SERCA3-inhibited control platelets (five experiments) confirming the direct involvement of the SERCA3-dependent ADP secretion pathway. This is the first study demonstrating that platelets from obese patients are hypo-reactive, due to a deficiency of SERCA3-dependent ADP secretion. Weight loss restores SERCA3 activity and subsequent calcium signalling, αIIbβ3 activation, platelet aggregation and ADP secretion.

* These authors contributed equally to this work.


** These authors are joint senior authors on this work.


Supplementary Material