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Circadian Regulation Of Brown Adipose Thermogenesis

Descripción del proyecto

Los ritmos circadianos y su relación con la termogénesis del tejido adiposo marrón

El tejido adiposo marrón (TAM) es una importante fuente de producción de calor con una significativa capacidad de disipación de energía, lo que representa un objetivo prometedor para combatir la obesidad y la diabetes. Un estudio reciente ha descubierto un nuevo vínculo entre el ritmo circadiano y el estrés termogénico en el control de la función de quema de calorías del TAM. Es importante destacar que la señalización circadiana y termogénica del TAM incorpora información hormonal y neuronal de nutrientes transmitida por la sangre. El objetivo del proyecto aCROBAT, financiado por el Consejo Europeo de Investigación, es investigar esta diafonía de señalización que permite a los mamíferos emplear eficazmente ritmos diarios en el metabolismo de los TAM al tiempo que se adaptan a los cambios en la demanda energética. Entender mejor estos mecanismos podría revelar dianas farmacológicas para aprovechar el potencial energético de los TAM a la hora de prevenir y trata la obesidad y la diabetes.

Objetivo

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.

Régimen de financiación

ERC-STG - Starting Grant

Institución de acogida

KOBENHAVNS UNIVERSITET
Aportación neta de la UEn
€ 1 497 007,51
Dirección
NORREGADE 10
1165 Kobenhavn
Dinamarca

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Región
Danmark Hovedstaden Byen København
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 1 497 007,51

Beneficiarios (1)