Endocrine Abstracts

Brain lipid sensing and adaptive response to modern food environment: a culprit in obesogenic environment? While the over-consumption of energy-dense foods is now clearly identified as one of the main causes of obesity, there is a large body of evidence supporting that the development of obesity and related disorders is also the result of an interaction between specific genetic polymorphisms and the modern food environment. High circulating triglyceride (TG) and reward-dysfunction re common hallmark of obesity and obesogenic environment. In the reward dopaminergic circuit, neurons specifically express the lipoprotein lipase (LPL), an enzyme able to hydrolyze TG, suggesting that circulating TG might modulate the activity of dopaminergic and dopaminoceptive neurons. W 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. 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. 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.