Abstract：
Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.
摘要：
烟酰胺腺嘌呤二核苷酸（NAD）作为调节多种生物过程的必需辅因子。本研究的目的是确定核NAD+生物合成的作用，由烟酰胺单核苷酸腺苷酰转移酶1（NMNAT1）介导，产热和全身能量代谢。我们首先评估了棕色脂肪组织（BAT）中NMNAT1表达与产热活性之间的关系，非颤抖产热的关键器官。我们发现BATNMNAT1表达降低与肥胖和热中性诱导的产热基因程序失活有关。接下来,我们产生并表征了脂联素-Cre驱动的脂肪细胞特异性Nmnat1敲除（ANMT1KO）小鼠。NMNAT1的缺失显著降低BAT中核NAD+浓度约70%。尽管如此，脂肪细胞特异性Nmnat1缺失对产热没有影响(直肠温度，BAT温度和全身耗氧量）对β-肾上腺素能配体去甲肾上腺素给药和急性冷暴露的反应，肾上腺素能介导的脂解活性，和对肥胖高脂肪饮食喂养的代谢反应。此外,NMNAT1缺失不影响BAT中核赖氨酸乙酰化或产热基因程序。这些结果表明，脂肪细胞NMNAT1表达是维持核NAD+浓度所必需的，但不是为了调节BAT产热或全身能量稳态。
