Objective

Aging and weight gain lead to a decline in brown and beige adipocyte functionality that exacerbates obesity and insulin resistance. We sought to determine whether sphingolipids, such as ceramides, a class of lipid metabolites that accumulate in aging and overnutrition, are sufficient or necessary for the metabolic impairment of these thermogenic adipocytes.

Methods

We generated new mouse models allowing for the conditional ablation of genes required for ceramide synthesis (i.e., serine palmitoyltransferase subunit 2, Sptlc2) or degradation (i.e., acid ceramidase 1, Asah1) from mature, thermogenic adipocytes (i.e., from cells expressing uncoupling protein-1). Mice underwent a comprehensive suite of phenotyping protocols to assess energy expenditure and glucose and lipid homeostasis. Complementary studies were conducted in primary brown adipocytes to dissect the mechanisms controlling ceramide synthesis or action.

Results

Depletion of Sptlc2 increased energy expenditure, improved glucose homeostasis, and prevented diet-induced obesity. Conversely, depletion of Asah1 led to ceramide accumulation, diminution of energy expenditure, and exacerbation of insulin resistance and obesity. Mechanistically, ceramides slowed lipolysis, inhibited glucose uptake, and decreased mitochondrial respiration. Moreover, β-adrenergic receptor agonists, which activate thermogenesis in brown adipocytes, decreased transcription of enzymes required for ceramide synthesis.

Conclusions

These studies support our hypothesis that ceramides are necessary and sufficient for the impairment in thermogenic adipocyte function that accompanies obesity. Moreover, they suggest that implementation of therapeutic strategies to block ceramide synthesis in thermogenic adipocytes may serve as a means of improving adipose health and combating obesity and cardiometabolic disease.

中文翻译：

---

神经酰胺对于饮食引起的产热脂肪细胞损伤是必要的和足够的

客观的

衰老和体重增加导致棕色和米色脂肪细胞功能下降，从而加剧肥胖和胰岛素抵抗。我们试图确定鞘脂，如神经酰胺，一类在衰老和营养过剩中积累的脂质代谢物，是否足以或必需这些产热脂肪细胞的代谢损伤。

方法

我们生成了新的小鼠模型，允许对成熟的产热脂肪细胞（即表达解偶联蛋白的细胞）进行神经酰胺合成（即丝氨酸棕榈酰转移酶亚基 2，Sptlc2）或降解（即酸性神经酰胺酶 1，Asah1）所需的基因进行条件消融-1). 小鼠接受了一套全面的表型分析方案，以评估能量消耗以及葡萄糖和脂质稳态。在初级棕色脂肪细胞中进行了补充研究，以剖析控制神经酰胺合成或作用的机制。

结果

Sptlc2 的消耗增加了能量消耗，改善了葡萄糖稳态，并防止了饮食引起的肥胖。相反，Asah1 的消耗导致神经酰胺积累、能量消耗减少以及胰岛素抵抗和肥胖症的恶化。从机制上讲，神经酰胺减缓脂肪分解、抑制葡萄糖摄取并减少线粒体呼吸。此外，激活棕色脂肪细胞产热的 β-肾上腺素能受体激动剂降低了神经酰胺合成所需酶的转录。

结论

这些研究支持我们的假设，即神经酰胺对于伴随肥胖的产热脂肪细胞功能的损害是必要和充分的。此外，他们建议实施阻断产热脂肪细胞中神经酰胺合成的治疗策略可以作为改善脂肪健康和对抗肥胖和心脏代谢疾病的一种手段。