Serge Luquet
Unité "Biologie Fonctionnelle &
Adaptative"
- Université Paris Cité, CNRS UMR 8251DR1 CNRS
Group leader "Central
COntrol oF Feeding behaviour and Energy Expenditure" (C2OFFEE)
Title
Brain lipid sensing and adaptive response to modern food environment?
Abstract
In the brain, neurons and glial cells are equipped with the necessary machinery to transport and metabolize nutritional lipids. Since neurons only uses glucose as energy substrate it has been postulated that lipids might act as signaling molecule. Lipid sensing was initially described in hypothalamus, and alter described in various brain structures including the reward dopaminergic system which is is instrumental to encode the reinforcing/rewarding aspects of feeding. In the reward circuit, DA-producing and dopaminoceptive neurons specifically express the lipoprotein lipase (LPL), an enzyme able to hydrolyze the dietary form of lipids, namely the triglycerides (TG), suggesting that circulating TG might modulate the activity of dopaminergic and dopaminoceptive neurons. By using in vivo central TG delivery, which mimics post-prandial increase of TG specifically in the brain, we have discovered that circulating TG act directly onto DA-D2 (DR2) receptors expressing neurons modulating the reinforcing and motivational values of feeding. In humans, we discovered that the neural responses to food cues show a significant correlation between postprandial increases in TG and the presence of Drd2/Taq1A genetic polymorphism. Taq1A polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) near the dopamine D2 dopamine receptor (DR2) gene. It affects 30 to 80% of the population and its homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal DR2, a typical feature of addiction, over-eating and other psychiatric pathologies. Using genetic approaches, we revealed that Ankk1 loss-of-function in dorsal and ventral striatum leads to alteration in learning, impulsive, and flexible behaviors resembling the endophenotypes described in A1 carriers. We also observed an unsuspected role of ANKK1 in striatal DR2-expressing neurons in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with versus without the A1 allele. We are now investigating the consequences of an engineered point mutation in mice to produce humanized TaqIA mutation. Altogether, our data indicates that genetic variant of TaqIA greatly influence how the reward system response to modern food environment and particularly nutritional lipids to control behavior and metabolism.
Biosketch
Serge Luquet received his undergraduate degree in Biology &Biochemistry from the University of Nice Sophia Antipolis, France in 2003. During his PhD training he was interested in the role of the fatty-activated transcription factor PPAR delta in adipose and muscle cell differentiation. He published seminal paper showing the role of PPAR delta in the controls of muscle development and oxidative capability. In 2003 he joined the laboratory of Pr Richard Palmiter (Howard Hughes Medical Institute & Department of Biochemistry) at the University of Washington, Seattle for his post-doctoral training. He studied the role of hypothalamic neurons that produce Agouti related protein in the control of feeding behavior. He was recruited at researcher by the French CNRS in 2006 and was awarded a young investigator research program that led him to conduct an independent research. His group is established at the University Paris Cité. The core approach of his team (https://bfa.u-paris.fr/equipe-5/) is to leverage the power of modern molecular genetic tools and mouse models using integrated approaches in order to dissect out the role of discrete neural circuit elements in the control of different aspect of energy balance including feeding behavior & energy expenditure.