Department of Pathophysiology, Naval Medical University, Shanghai, China.
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
Int J Obes (Lond). 2022 May;46(5):1068-1075. doi: 10.1038/s41366-022-01082-7. Epub 2022 Feb 12.
Brown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis and represents an important therapeutic target for metabolic diseases. Carbohydrate response element-binding protein (ChREBP) is a key transcription factor regulating de novo lipogenesis, and its activity is associated with UCP1 expression and thermogenesis in BAT. However, the exact physiological role of endogenous ChREBP in BAT thermogenesis remains unclear.
We used the Cre/LoxP system to generate ChREBP BAT-specific knockout mice, and examined their BAT thermogenesis under acute cold exposure and long-term cold acclimation. Gene expression was analyzed at the mRNA and protein levels, and lipogenesis was examined by H-HO incorporation assay.
The mice lacking ChREBP specifically in BAT displayed a significant decrease in the expression levels of lipogenic genes and the activity of de novo lipogenesis in BAT after cold exposure, with UCP1 expression decreased under thermoneutral conditions or after acute cold exposure but not chronic cold acclimation. Unexpectedly, BAT-specific ChREBP deletion did not significantly affect body temperature as well as local temperature or morphology of BAT after acute cold exposure or chronic cold acclimation. Of note, ChREBP deletion mildly aggravated glucose intolerance induced by a high-fat diet.
Our work indicates that ChREBP regulates de novo lipogenesis in BAT and glucose tolerance, but is not required for non-shivering thermogenesis by BAT under acute or long-term cold exposure.
棕色脂肪组织 (BAT) 通过解偶联蛋白 1 (UCP1) 介导的产热发挥关键作用，能量消耗，并代表代谢疾病的重要治疗靶点。碳水化合物反应元件结合蛋白 (ChREBP) 是调节从头脂肪生成的关键转录因子，其活性与 BAT 中的 UCP1 表达和产热有关。然而，内源性 ChREBP 在 BAT 产热中的确切生理作用仍不清楚。
我们使用 Cre/LoxP 系统生成 ChREBP 特异性敲除 BAT 的小鼠，并在急性冷暴露和长期冷适应下检查其 BAT 产热。在 mRNA 和蛋白质水平上分析基因表达，并通过 H-HO 掺入测定法检查脂肪生成。
BAT 特异性缺乏 ChREBP 的小鼠在冷暴露后 BAT 中的脂肪生成基因表达水平和从头脂肪生成活性显著降低，UCP1 表达在体温正常条件下或急性冷暴露后降低，但在慢性冷适应后没有降低。出乎意料的是，BAT 特异性 ChREBP 缺失在急性冷暴露或慢性冷适应后并没有显著影响体温或 BAT 的局部温度或形态。值得注意的是，ChREBP 缺失轻度加重了高脂肪饮食引起的葡萄糖不耐受。
我们的工作表明，ChREBP 调节 BAT 中的从头脂肪生成和葡萄糖耐量，但在急性或长期冷暴露下 BAT 非颤抖产热不需要 ChREBP。
