Periodic Reporting for period 4 - PRiSM (Programming Sensory regulation of Metabolism)
Reporting period: 2023-12-01 to 2025-05-31
The escalating burden of obesity and obesity-associated diseases triggers an urge to further delineate the exact mechanisms underlying the regulation of feeding behaviour and maintenance of steady body weight and glycemia. Particularly troublesome for our society, metabolic disorders are increasingly diagnosed in childhood and have recognized roots in very early life. Indeed, compelling evidence from animals and epidemiological studies in humans reveal that abnormal changes in the maternal, fetal, and neonatal environment substantially contribute to the onset of these metabolic diseases. Notably, changes in the nutritional and/or hormonal environment during gestation and/or lactation (e.g. maternal obesity/malnutrition or diabetes) can permanently alter the development of “brain-metabolic” pathways, which directly impinges on their life-long functions and predisposes individuals to develop metabolic diseases later in life. Importantly, a better understanding of the mechanisms underlying this developmental origin of obesity is required to refine interventional and/or therapeutical approaches. Hence, the overarching aim of PRiSM is to unravel novel brain circuits controlling feeding behaviour in adults mice as well as to uncover new mechanisms underlying the developmental programming of metabolism. In particular, our projects focus on the emerging role of sensory perception in feeding and whole-body metabolism regulation. Our projects notably build on a recent paradigm-shifting discovery in the neurobiology of feeding revealing that key hunger neurons are switched off within a few seconds upon detection of food cues that signal to the brain food vicinity, i.e. sight, smell, or food-associated cues. This ERC grant aims to further our knowledge of the sensory regulation of feeding-regulatory circuits by providing new insights into the precise regulatory processes of sensory metabolic regulation and to shed light on critical basic mechanisms underlying the developmental programming of metabolic diseases.
Our ERC projects rely on a technology framework of physiological, behavioural, and developmental analyses in mice combined with various systems neuroscience approaches, including optogenetics, chemogenetics, and in vivo calcium imaging. We have successfully developed and established the tools required for the first objectives of our projects and already gathered exciting data. Among the obtained results we have generated, we achieved three main results: (1) we successfully mapped brain regions activated by sensory food detection, (2) we pinpointed critical candidate circuits mediating the sensory regulation of metabolism that are currently under examination, (3) we uncovered a novel mechanism by which maternal diet influences the metabolism of the offspring.
Our work already provided promising data on mechanisms by which maternal diet can predispose offspring to develop obesity and metabolic diseases. Hence, we expect that our work will further our knowledge on the developmental origin of obesity and open novel interventional approaches aiming at lowering obesity susceptibility in children and adults. Studies currently in progress aim at defining the exact associated mechanisms and the brain neurocircuits involved. Moreover, our significant progress on understanding further how the organisms integrate sensory cues to control metabolism and feeding accordingly will further expand our understanding of the critical pathways required to govern appetite and hence, open novel avenues towards the understanding of obesity and associated diseases.