CV Science

ISABELLE MOTHE-SATNEY PhD Life Sciences

Course and current status

Education

1988 : Two-year university degree in Biological Sciences (DEUG)

University of Nice-Sophia Antipolis, France          

1989: One-year university degree in Biochemistry (Licence)        

University of Nice-Sophia Antipolis, France          

1991 : Master’s degree in Biochemistry                  

University of Nice-Sophia Antipolis, France

1992 : Postgraduate degree (1 year) in Pharmacology

University of Nice-Sophia Antipolis, France                                  

1997 : Ph.D in Life Sciences

Biochemistry, Molecular Biology, Endocrinology

University of Nice-Sophia Antipolis, France      

Work and research experience

September 1991-September 1992

One-year postgraduate student after my master, in the laboratory of Pr. E. Van Obberghen, INSERM (French National Institute for Health and Medical Research) Unit 145, Nice, France.

“Study of the desensitization of EGF binding to its receptor, in response to NGF and bFGF in a rat phechromocytoma cell line, PC12”.

September 1992 – December 1997  

Ph.D student in the laboratory of Pr. E. Van Obberghen INSERM Unit 145, Nice, France.

“Signal transduction through tyrosine kinase receptors: modulation at receptor and post-receptor levels”.

January 1998 – December 2000

Research associate in the laboratory of Pr John C. Lawrence, Jr. Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.

Research: “Role of the phosphorylation sites of the translational repressor PHAS-I in the regulation of insulin-stimulated protein synthesis”.

January 2001-September 2001

Research associate in the laboratory of Pr. E. Van Obberghen, INSERM Unit 145, Nice, France.

“Regulation of mTOR (mammalian Target of Rapamycin) kinase activity and phosphorylation at serine residue 2448 by insulin and amino acids in freshly isolated rat adipocytes and in primary cultures of rat hepatocytes”.

Current position

Senior Research Scientist (CR1) at INSERM

- In the laboratory of Pr E. Van Obberghen, INSERM Unit 145, Nice France (October 2001- December 2007)

- Since January 2008 in the laboratory of Paul Grimaldi, , INSERM Unit 907, Nice, France.

Research:        - Role and regulation of mTOR in response to insulin and amino acids; study in physiological and pathophysiological states associated with insulin-resistance (obesity and type 2 Diabetes)

                        - Role of the mTOR pathways in skeletal muscle protein synthesis in sarcopenia: study in animal models of old rats and in the elderly

Awards

1998 : Postdoctoral fellowship from “ARC” (French Association for Research against Cancer).

1999-2000 : Postdoctoral fellowship from JDRF (American Juvenile Diabetes Research Foundation)

2001 : Postdoctoral fellowship from FRM (French Foundation for Medical Research)

Fundings

- Partner of PNRA: “Food lipids and inflammatory status: implication in the development of sarcopenic obesity” (LIP-AGE- ANR-07-PNRA-021); length:  3 years and a half (2008-2011). Coordinator: Stéphane WALRAND, UMR1019 Human Nutrition Unit, INRA, Clermont-Ferrand, France. Obtention of 55,000 euros for a one-year technician salary and for analyses expenses.

- Funding from the Conseil Général of Alpes Maritimes for one year (july 2009- july 2010) « Defining the role of mTOR protein in sarcopenia » (n° 2009-00990). Obtention of 30,000 euros for analyses expenses.

Translational research activities

- Contrat Interface INSERM-Hospital: obtained in april 2006 for 5 years with Stéphane Schneider, Professor of Nutrition, Pôle Digestif, CHU of Nice. “Role of the mTOR pathways in protein synthesis in skeletal muscle of healthy and malnourished humans”.

Scientific summary

Role and regulation of the mTOR pathway in response to insulin and amino acids and study of its possible involvement in pathologies associated to insulin (obesity, diabetes) or to protein synthesis deficiency (sarcopenia) (Isabelle Mothe-Satney)

1. Role of mTOR and amino acids in insulin signaling and in adipocyte functions. We have studied the effect of amino acids (aas) on two insulin-induced metabolic responses in freshly isolated rat adipocytes. We have shown that aas negatively regulate insulin-stimulated lipogenesis, but this effect is not reversed by rapamycin. Moreover, aas do not modulate basal or insulin-stimulated glucose transport. Surprisingly, aas, notably leucine, are able to partially restore PKB activity when the PI 3-kinase (PI3-K) is inhibited. In these conditions, aas and leucine also restore the mTOR pathway as well as glucose transport and metabolism. In addition, leucine is able to potentiate the activating effect of insulin on PKB in the adipose tissue of the diabetic db/db mouse model. (Hinault et al. FASEB J. 2004, vol.18, p.1894-1896). Next, we have tried to determine the molecular mechanisms underlying this combined action of insulin and aas when PI3-K is inhibited and found it occurs only in “physiological” adipocytes (i.e. that come from rat or mouse adipose tissue) and requires the presence of glucose. Moreover, this PI3-K-independent pathway activated in response to insulin and aas requires the PDK1, is rapamycin-insensitive (thus mTORC1-independent), but is inhibited with high concentrations of wortmannin, suggesting a possible role of mTORC2. Finally, aas are able to increase insulin-induced glucose transport in adipocytes from high-fat-fed rats (who are obese and insulin-resistant), but not in adipocytes from lean rats. In conclusion, aas appear to be physiological molecules with particular properties allowing them to act positively on insulin signalling in situations where the PI3-K is deficient, at least in adipocytes (Hinault et al. Diabetologia, 2006). Our work has also been published in the form of an invited review (Hinault et al. J. Nutr. Biochem., 2006).

2. Role of the mTOR pathway in age-related sarcopenia (Contrat Interface INSERM with CHU of Nice 2006-2011). Loss of muscle mass and function is known to occur with age in the healthy elderly. So far, this process called sarcopenia was considered as physiological. But its consequences in terms of functional impairments, increased risk of handicap and failure to adapt to denutrition, have lead to the conclusion that sarcopenia must be considered as a disease situation, i.e. it must be diagnosed and treated. The causes of this syndrome are multiple (modifications in protein substrate availability and hormones such as GH, DHEA and testosterone, sub-inflammatory chronic state due to IL-6, etc). Resistance to the anabolic effect of amino acids and insulin has also been described. Indeed, amino acids (especially leucine) play an important role in the postprandial stimulation of protein synthesis. Therefore, this resistance could implicate a defect in the mTOR pathway, since this cascade plays a major role in the stimulation of protein synthesis. In this project, we are using a model of aged rats with sarcopenia. Our hypothesis is that the mTOR pathway is impaired in sarcopenia, participating in the decreased muscle mass observed. Our analyses show that, compared to adult rats, sarcopenic aged rats display increased levels of PKB, mTOR and RAPTOR, indicating the existence of a possible compensatory mechanism during aging (manuscript in preparation). We are collaborating with Dominique Dardevet from INRA (Human Nutrition Unit, Clermont-Ferrand, France) in order to evaluate the effects of an oral leucine supplementation in adult and aged rats. In a first study, adult rats were given a leucine-supplemented diet for five weeks. We showed that leucine induced a delay in the postprandial stimulation in the early steps of muscle insulin signaling without muscle resistance on insulin-induced glucose uptake. However, it resulted in overall glucose intolerance linked to increased local adiposity (Balage et al. J. Nutr. Biochem., 2010). In a second study performed on aged sarcopenic rats, supplemented or not wwith leucine for 5 months, we found a marked increase in adipose tissue mass, correlated with increased activation of the mTOR pathway and increased PPARg. Thus, leucine could induce adipose tissue hypertrophy and hyperplasia without improvement in muscle mass (Zeanandin et al. AGE, 2011). Finally, I am currently participating in a PNRA (National Research Program in Human Nutrition) entitled “Food lipids and inflammatory status: implication in the development of sarcopenic obesity”, conducted by S. Walrand (Human Nutrition Unit, INRA, Clermont-Ferrand, France). The aim of the project is to characterize and compare the effects of different high-fat diets (enriched with oleate or palmitate) on the inflammatory response, insulin-resistance, and their consequences on the anabolic muscular response in old and aged individuals (animal models and in human). My main role in this project is to investigate the protein levels as well as activation of the insulin and mTOR pathways (paper under revision in Clinical Nutrition).