Descrizione del progetto
Ritmi circadiani e legame con la termogenesi del tessuto adiposo bruno
Il tessuto adiposo bruno (TAB) è un’importante fonte di produzione di calore con una significativa capacità di dissipare energia, e per questo rappresenta un obiettivo promettente per combattere l’obesità e il diabete. Un recente studio ha scoperto un nuovo legame tra il ritmo circadiano e lo stress termogenico nel controllo della funzione brucia-calorie del TAB. È importante notare che la segnalazione circadiana e termogenica al TAB incorpora input ormonali e nutrizionali neuronali trasportati dal sangue. L’obiettivo del progetto aCROBAT, finanziato dal CER, è quello di studiare questo scambio di segnali che consente ai mammiferi di utilizzare efficacemente i ritmi giornalieri del metabolismo del TAB, adattandosi al contempo ai cambiamenti della domanda di energia. Una migliore comprensione di queste intuizioni meccanicistiche potrebbe svelare i bersagli farmacologici al fine di sfruttare il potenziale energetico del TAB per la prevenzione e il trattamento dell’obesità e del diabete.
Obiettivo
Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Campo scientifico
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- medical and health scienceshealth sciencesnutritionobesity
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1165 Kobenhavn
Danimarca