Luc Pellerin Laboratory

Presentation

Neuroenergetics and body energy homeostasis.

Energy production and utilization is a fundamental feature of all living organisms. Maintenance of energy homeostasis requires coordinated mechanisms between various tissues and organs in multicellular organisms such as vertebrates. The brain plays a central role in this coordination. Moreover, the brain itself requires an important energy supply to sustain its main functions. In our laboratory, we are interested in deciphering the molecular and cellular mechanisms involved in the intercellular generation and utilization of energy within the central nervous system (a field known as neuroenergetics) in relation with cognitive processes such as learning and memory. Detection of energy substrate utilization forms the basis of some functional brain imaging techniques (e.g. Positron Emission Tomography) and it is critical to understand the precise mechanisms at play in order to interpret the imaging signals appropriately. Moreover, failure to provide enough energy to neurons has been identified as a major factor involved in neurodegenerative diseases such as Alzheimer’s disease and clarifying the causes represents an important clinical interest.

Body energy homeostasis depends on the capacity of the brain to detect the energy status of the organism by deciphering peripheral signals such hormones, nutrients as well as afferent nerve activity. In return, the brain should be able to activate the appropriate responses, whether via nervous efferent signals or behavioral responses, to maintain homeostasis. Any imbalance can lead to metabolic diseases such as obesity. Our laboratory is also dedicated to investigate the mechanisms by which the brain senses some of these peripheral signals, in particular nutrients such as lactate and ketone bodies. In addition, it is also interested to explore how such nutrients (i.e. monocarboxylates) influence energy homeostasis in various peripheral organs and tissues.

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Research

Importance of monocarboxylate transporters (MCTs) in the central nervous system.

In our laboratory, we have identified the presence of three specific monocarboxylate transporter isoforms in the central nervous system. These are known as MCT1, MCT2 and MCT4. These transporters are responsible for the transport of pyruvate, lactate and the ketone bodies b-hydroxybutyrate and acetoacetate. They were found to have a cell-specifc distribution. MCT1 is expressed by endothelial cells forming brain microvessels, by olgodendrocytes, astrocytes and microglial cells, as well as by certain populations of neurons. MCT2 is the major neuronal monocarboxylate transporters. MCT4 is exclusively expressed by astrocytes. Our in vitro and in vivo studies have revealed that each transporter is subject to specific regulations.

Our aims for this topic are: 1) To further investigate the role of monocarboxylate transporters in the lactate transfer between astrocytes and neurons in vivo. For this purpose, we are using adenoviral associated vectors to downregulate their expression in the rat somatosensory cortex and subsequently evaluate the impact on metabolism and plasticity mechanisms 2) To determine the importance of monocarboxylate transporters in astrocytes and neurons for cognitive processes such as learning and memory. We are taking advantage of floxed mice for each monocarboxylate transporter and adenoviral associated vectors to knockdown the targeted transporter in specific brain regions (e.g. hippocampus) and then assess the impact on spatial learning and memory 3) to investigate in vitro in cultured astrocytes and neurons how monocarboxylate transporter expression/localization is regulated by various active signals and evaluate the effect of putative neuroprotective substances on their expression.

Role of circulating monocarboxylates and MCTs in regulating body energy homeostasis.

In order to understand the role of monocarboxylate transporters in the regulation of body energy homeostasis, we have produced a MCT1 haploinsufficient (MCT1+/-) mouse. This mouse exhibits a phenotype of resistance to the development of diet-induced obesity and hepatic steatosis. Among the different parameters that are affected and can explain this phenotype, food intake seems to play an important role. Indeed, the monocarboxylate transporter MCT1 is expressed by a subpopulation of NPY neurons in the hypothalamic arcuate nucleus which are involved the regulation of food intake and energy expenditure. This observation suggests that MCTs might be involved in the detection of circulating nutrients including lactate and ketone bodies, leading then to the appropriate adaptative responses to maintain body energy homeostasis.

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In this context,: 1) We investigate the effect of ketone bodies perfused directly to the brain or infused in the hypothalamus on various metabolic features including food intake, body weight gain and insulin resistance with the use of our transgenic mice to decipher the role of monocarboxylate transporters 2) We characterize the expression of monocarboxylate transporters in different areas of the hypothalamus and on different cell types including a particular glial cell type named tanycytes. It is postulated that tanycytes might play a particular role in sensing monocarboxylates in the hypothalamus and in return modulate the activity of neurons involved not only in the regulation of body energy homeostasis but also fertility.

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Members

Luc Pellerin - Group leader

Luc Pellerin graduated with a bachelor degree in biochemistry in 1985 from Laval University in Quebec city, Canada. He obtained a 1967 NSERC PhD fellowship to undertake graduated studies and completed his PhD degree in 1991 at the Biochemistry Department of McGill University in Montreal, Canada under the supervision of Leonhard S. Wolfe at the Montreal Neurological Institute. Dr. Pellerin obtained a postdoctoral fellowship from Quebec FCAR and joined the laboratory of Prof. Pierre Magistretti at the Institute of Physiology of the University of Lausanne. During several years, he worked on the role of astrocytes in brain energy metabolism and proposed the seminal concept of the Astrocyte-Neuron Lactate Shuttle to account for the tight relationship existing between neuronal activity and metabolic responses that forms the basis of functional brain imaging techniques. In 2000, he became maître d’enseignement et de recherche at the Institute of Physiology and created his own research group focusing on the regulation and roles of monocarboxylate transporters in the central nervous system. Since 2008, he was promoted as associate professor of the Department of Physiology at the University of Lausanne. His research interests concern various areas of neuroenergetics and body energy homeostasis with a focus on monocarboxylate transporters.

Cendrine Repond - Technician

Cendrine is laboratory technician associated to the group of Prof. Luc Pellerin since 2007. She obtained a CFC degree of medical technician from the Cantonal hospital in Fribourg and she also obtained a diploma of cytotechnician. During her professional career prior to join the department of Physiology, she worked in various laboratories and improved her knowledge in several areas including chemistry, cosmetic science and pathology.

She is involved in the management of the laboratory and has a good experience in molecular biology, cell cultures and microscopy. She helps all members of the group with various techniques and participate to different collaborations with external groups. She also carry her own independent research projects.

Cathy Gouelle – PhD student

I come from University of Rouen (in France) where I do my master degree in Neuroscience but I just began my experimental work in the laboratory of Pr. Pellerin. I had already the occasion to do an internship in this team during the summer 2015 as part of my bachelor degree and of the SUR (Summer Undergraduate Research) program of the University of Lausanne. During this internship I had started to study the role of lactate on the regulation of reproductive function. Then I completed my pre-master in 2016 for two months in team 2 of the INSERM U982 directed by Dr. David Vaudry and more specifically under the direction of Dr. Julien Chuquet with whom I worked on the role of ODN in post-ischemic synaptic plasticity. More particularly interested in energy homeostasis and its impact on the large physiological functions controlled by the hypothalamus, I decided to join again the team of Pr. Pellerin to continue the project on which I had worked one and a half year ago but now in the context of my master degree.

Anna Hadjichambi - Postdoctoral fellow

Anna Hadjichambi obtained her Bachelor degree in Biochemistry from the University of Warwick in the UK. Her final year project was focused on the fabrication and characterisation of biosensors for adenine. She then completed her Masters Degree in Neuroscience at UCL, where she worked with Prof. Gourine and Dr. Ackland on the real time measurement of glutamate release from phagocytes. Anna has completed her PhD in UCL, funded by the Grand Challenges UCL, which was a collaboration between the departments of Liver and Digestive health (Prof. Jalan) and Neuroscience, Physiology and Pharmacology (Prof. Gourine). Her thesis was entitled “The Neurochemistry of Hepatic Encephalopathy" and involvedexperimental studies conducted in animal (rat) models of hepatic encephalopathy, in vivoand in vitro, in combination with pharmacological approaches. The results obtained during her PhD provided the first evidence of a critical pathophysiologicalrole of ammonia in inducing neuronal energy deficit in hepatic encephalopathy due to impaired cerebraloxygenation, compromised hemichannel-mediated lactate transport betweenastrocytes and neurons and affected glymphatic clearance. In 2018 she joined the group of Prof. Pellerin, as a postdoctoral fellow, focusing her research on the role of cerebral lactate metabolism and transport (MCTs) on the development of cognitive deficits during non-alcoholic fatty liver disease.

Charlotte Jollé – PhD student

I completed a Bachelor degree at the University Paul Sabatier (Toulouse, France) in Cellular Biology and Physiology (2013). Then, I obtained my Master Degree in “Neuroscience, Behavior and Cognition” from the same university in 2015. As part of a specific agreement, I performed my experimental studies in the group of Prof. Luc Pellerin at the University of Lausanne, working on the involvement of astrocytes in the physiopathology of Huntington’s disease. Since February 2016, I started my PhD in the group of Prof. Pellerin at the Department of Physiology. The main aim of my PhD project is to further investigate the role of monocarboxylate transporters in the lactate shuttling between neurons and astrocytes. To achieve this goal, I use viral vectors to downregulate their expression in the rat brain and I analyze the consequences of this downregulation on different parameters such as cellular metabolism or synaptic plasticity.

Citlalli Netzahualcoyotzi Piedra – Postdoctoral fellow

Citlalli obtained her Bachelor degree in Biochemistry from the Autonomous University of Puebla in Mexico. Her thesis focused on studying the cognitive decline and recovery in a pharmacological-induced model of Alzheimer’s disease in rats. She then joined the lab of Prof. Ricardo Tapia in the National Autonomous University of Mexico (UNAM). During her Master’s thesis, she studied the neuroprotective effect of energy substrates in an in vivo model of excitotoxic-induced neurodegeneration in the hippocampus of rats. For her PhD, she studied neuroprotective strategies to prevent the death of spinal motor neurons in a model of amyotrophic lateral sclerosis in rats. In September 2016, Citlalli joined the group of Prof. Luc Pellerin as a Swiss Government Excellence postdoctoral fellow. She is currently investigating the involvement of neuronal MCT2 and astrocytic MCT4 energy substrate transporters in hippocampus-dependent learning and memory processes, as well as their implications in synaptic plasticity.