Brown adipose tissue (BAT)-dependent thermogenesis and its suggested augmenting hormone, FGF21, are potential therapeutic targets in current obesity and diabetes research. Here, we studied the role of UCP1 and FGF21 for metabolic homeostasis in the cold and dissected underlying molecular mechanisms using UCP1-FGF21 double-knockout mice. We report that neither UCP1 nor FGF21, nor even compensatory increases of FGF21 serum levels in UCP1 knockout mice, are required for defense of body temperature or for maintenance of energy metabolism and body weight. Remarkably, cold-induced browning of inguinal white adipose tissue (iWAT) is FGF21 independent. Global RNA sequencing reveals major changes in response to UCP1- but not FGF21-ablation in BAT, iWAT, and muscle. Markers of mitochondrial failure and inflammation are observed in BAT, but in particular the enhanced metabolic reprogramming in iWAT supports the thermogenic role of UCP1 and excludes an important thermogenic role of endogenous FGF21 in normal cold acclimation.

中文翻译：

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长期冷适应不需要FGF21或UCP1。

棕色脂肪组织（BAT）依赖的热生成及其建议的增强激素FGF21是当前肥胖症和糖尿病研究的潜在治疗靶标。在这里，我们研究了UCP1和FGF21在使用UCP1-FGF21双敲除小鼠的寒冷和解剖的潜在分子机制中代谢稳态的作用。我们报告，UCP1基因敲除小鼠既不需要UCP1也不FGF21，甚至补偿性增加FGF21血清水平，对于防御体温或维持能量代谢和体重都不需要。值得注意的是，腹股沟白色脂肪组织（iWAT）的冷诱导褐变与FGF21无关。全局RNA测序揭示了BAT，iWAT和肌肉中对UCP1响应的主要变化，但对FGF21消融没有响应。在BAT中观察到线粒体衰竭和炎症的标志，