Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mol Metab. 2017 May 31;6(8):781-796. doi: 10.1016/j.molmet.2017.05.012. eCollection 2017 Aug.
The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood.
METHODS & RESULTS: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT.
These results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.
脂肪酸合酶（FASN）从头合成脂肪酸（DNL）在小鼠和人类中受到营养物质、激素、禁食和肥胖的精细调节。然而，DNL 在脂肪细胞生物学和调节全身葡萄糖稳态中的功能尚未完全了解。
在这里，我们表明脂肪细胞 DNL 控制与局部交感神经元的串扰，介导腹股沟白色脂肪组织（iWAT）中米色/褐色脂肪细胞的扩张。成熟小鼠白色和棕色脂肪细胞中 FASN 的诱导性缺失（iAdFASNKO 小鼠）增强了葡萄糖耐量、iWAT 中的 UCP1 表达和 cAMP 信号传导。与诱导脂肪交感神经活动一致，iAdFASNKO 小鼠的 iWAT 中神经元酪氨酸羟化酶（TH）和神经肽 Y（NPY）含量明显增加。相比之下，iAdFASNKO 小鼠的棕色脂肪组织（BAT）中 TH 或 NPY 没有增加，棕色脂肪细胞中 FASN 的缺失（UCP1-FASNKO 小鼠）也没有在 iWAT 中引起这些效应。
这些结果表明，成熟小鼠白色脂肪细胞中 FASN 耗竭下调脂肪酸合成可以刺激神经元信号传导，控制 iWAT 中的产热编程。
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