RESUMEN
Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.
Asunto(s)
Adipogénesis/genética , Tejido Adiposo Beige/metabolismo , Metabolismo Energético/genética , Quinasa 1 de Adhesión Focal/metabolismo , Transducción de Señal/genética , Células Madre/metabolismo , Tetraspanina 28/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Beige/citología , Tejido Adiposo Beige/crecimiento & desarrollo , Tejido Adiposo Blanco/metabolismo , Adulto , Animales , Ataxina-1/metabolismo , Femenino , Fibronectinas/farmacología , Quinasa 1 de Adhesión Focal/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Resistencia a la Insulina/genética , Integrinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Obesidad/genética , Obesidad/metabolismo , RNA-Seq , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de la Célula Individual , Células Madre/citología , Tetraspanina 28/genéticaRESUMEN
Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Metabolismo Energético , Homeostasis , Proteínas Mitocondriales/metabolismo , Proteínas Transportadoras de Solutos/metabolismo , Termogénesis , Tejido Adiposo Pardo/citología , Animales , Frío , Intolerancia a la Glucosa/metabolismo , Humanos , Masculino , Ratones , Mitocondrias/metabolismo , Obesidad/metabolismoRESUMEN
Body temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of anterior hypothalamus (POA), with â¼30% of its neurons sensitive to brain temperature change. It is still unknown whether and how these temperature-sensitive neurons are involved in thermoregulation, because for eight decades they have only been identified via electrophysiological recording. By combining single-cell RNA-seq with whole-cell patch-clamp recordings, we identified Ptgds as a genetic marker for temperature-sensitive POA neurons. Then, we demonstrated these neurons' role in thermoregulation via chemogenetics. Given that Ptgds encodes the enzyme that synthesizes prostaglandin D2 (PGD2), we further explored its role in thermoregulation. Our study revealed that rising temperature of POA alters the activity of Ptgds-expressing neurons so as to increase PGD2 production. PGD2 activates its receptor DP1 and excites downstream neurons in the ventral medial preoptic area (vMPO) that mediates body temperature decrease, a negative feedback loop for thermoregulation.