Impact of metabolic diseases on fetal programming of vascular/metabolic functions in offspring.

Céline Fassot, CR Inserm

celine.fassot@inserm.fr

Céline Fassot, PhD, INSERM researcher

Keywords : maternal obesity, bariatric surgery, fetal programming, cardiovascular system.

Obesity is a "worldwide epidemic". In 2016, more than 1.9 billion adults were classified as overweight. Of these, around 650 million were considered obese, 15% of them being women (WHO Obesity and overweight Fact sheet, updated April 2020). Obesity in women of childbearing age is of particular concern since there is overwhelming evidence that being born to an obese mother increases the risk for the child to develop metabolic disorders [1]. Up to 50% of women of reproductive age and 20-25% of pregnant women at first antenatal visits in Europe are overweight or obese [2]. Maternal obesity is associated with considerable maternal and fetal metabolic perturbations and is associated with considerable detrimental short-term outcomes for both mother and neonate [3].

The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that intra-uterine life is a very sensitive period during which any stress, including nutritional ones, can impact on the long-term health of the offspring. The effects of such developmental programming can manifest in further generations without further suboptimal exposure [4].

         Most of the human evidence for the programming of offspring disease has come from observational studies which have shown associations between maternal obesity and long-term detrimental consequences for the offspring including increased risk of obesity [1], insulin resistance and cardiovascular disease [5]. Several animal models of obese pregnancies have given us insight into mechanisms driving offspring metabolic [6], and cardiovascular [7] systems in an experimental setting. However, if the maternal, obstetric and fetal complications of obese women during pregnancy are well demonstrated, little is known about long-term effects of maternal metabolic disorders in adult offspring, in particular in term of cardiovascular pathologies.

         Moreover, with the increase of women suffering from morbid obesity and the failure of medical therapies, bariatric surgery has rapidly emerged : sleeve gastrectomy (restrictive procedure) or gastric bypass (malabsorptive combined with restrictive procedure).Recent sib-pair studies, which compared BMI, glucose metabolism and blood pressure in siblings born to the same mother, before and after bariatric surgery reported that surgically induced reduction in body weight reduced the risk of obesity, insulin resistance and hypertension in the offspring [8]. Recently, a monocentric, observational, non-interventional cohort named “SMOOTHIE” (Surgery MOrbid ObesiTy Health ImprovEment) is developed at the University Hospital of Angers, ongoing cohort study analysing potential improvement of cardiovascular and metabolic health of morbid obese women and their children through bariatric surgery before pregnancy. Control patients with or without obesity (n=120), BMI-paired with morbidly obese women before (N=60) and approximately 1 year after and bariatric surgery for morbid obesity are enrolled and followed up in terms of general health before (bariatric surgery group) and/or during pregnancy and up to 1 year after delivery. Children born after maternal bariatric surgery are followed up to 5 years old with standardized monitoring for possible adverse side effects of bariatric surgery (e.g. related to maternal vitamin deficiency or anaemia). Neurocognitive development, physical activity, eating behaviour and dietary patterns of all the children included in the SMOOTHIE cohort are assessed by questionnaires. We have developed a biocollection of placenta, maternal and cord blood from normal and pathological pregnancies including maternal obesity and bariatric surgery.

The project of our group focuses on the impact of maternal obesity on offspring in association with either postnatal diet modification or bariatric surgery. Our aims are to evaluate changes in vascular and metabolic properties of offspring through physiological responses and epigenetic modifications in experimental models of fetal programming.

We will thus combine, in the next 5 years, the expertise in both human and animal studies to advance our knowledge of the fundamental biological processes underpinning the detrimental effects of maternal obesity on the health of offspring.

Publications:

• Payen C, Guillot A, Paillat L, Fothi A, Dib A, Bourreau J, Schmitt F, Loufrani L, Aranyi T, Henrion D, Munier M, Fassot C. Pathophysiological adaptations of resistance arteries in rat offspring exposed in utero to maternal obesity is associated with sex-specific epigenetic alterations. International Journal of Obesity, 2021 ; 45:1074-1085.

• Dib A, Payen C, Bourreau J, Munier M, Grimaud L, Fajloun  Z, Loufrani L, Henrion D, Fassot C. In utero exposure to maternal diabetes is associated with early abnormal vascular structure in offspring. Frontiers in Physiology, 2018; 9:350.

• Begorre M.A., Dib A., Habchi K., Guihot A.L., Bourreau J., Vessieres E.,  Blondeau B., Loufrani L., Chabbert M., Henrion D., Fassot C. Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. Scientific Reports, 2017 ; 7:45625.

• Vessieres E., Dib A., Bourreau J., Lelièvre E., Custaud M.A., Lelievre-Pegorier M., Loufrani L., Henrion D., Fassot C. Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed in Utero to Maternal Hyperglycaemia. PLoS One, 2016 ; 11:e0146830.

• - Habbout A, Guenancia C, Lorin J, Rigal E, Fassot C, Rochette L, Vergely C. Postnatal overfeeding causes early shifts in gene expression in the heart and long-term alterations in cardiometabolic and oxidative parameters. PLoS One, 2013 ; 8:e56981.

Collaborations:

• Institute of Enzymology, Budapest (Hungary, Dr T. Aranyi)
• HiFiH Laboratory, Angers (Dr F. Schmitt)
• RMeS INSERM unit, REGOS team, Angers (Dr G. Mabilleau)
• Pr Géraldine Gascoin (Toulouse)