Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging

Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (= 4-month-old), middle aged (10 to 14-month-old), and old (= 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR?) in an age-dependent manner. In addition, administration of a PPAR? agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPAR? axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging. Overall design: We determined the effects of adipocyte-specific Nampt deletion on subcutaneous white adipose tissue gene expression profiling in young and old mice by analyzing control (flox/flox) and adipocyte-specific Nampt knockout (ANKO) mice.

烟酰胺腺嘌呤二核苷酸（Nicotinamide adenine dinucleotide, NAD+）是一类通用辅酶，可调控多种细胞类型中的细胞能量代谢。近期研究证实，NAD+代谢缺陷与衰老及衰老相关代谢疾病存在紧密关联。本研究的核心目的为验证下述假说：由限速酶烟酰胺磷酸核糖转移酶（nicotinamide phosphoribosyltransferase, NAMPT）介导的NAD+生物合成过程，在衰老进程中对维持正常脂肪组织功能与全身代谢健康至关重要。
为此，我们对衰老过程中的雌性脂肪细胞特异性Nampt基因敲除（ANKO）小鼠开展了深入且全面的代谢评估。我们首先分别评估了年轻（4月龄）、中年（10至14月龄）及老年（18月龄）小鼠的体脂质量。值得关注的是，脂肪细胞特异性Nampt缺失可抵抗衰老诱导的肥胖，且未改变机体能量平衡。然而，高胰岛素正常血糖钳夹实验获得的数据显示，尽管呈现瘦型表型，老年ANKO小鼠的骨骼肌、心脏与白色脂肪组织（white adipose tissue, WAT）均存在严重胰岛素抵抗。老年ANKO小鼠同时表现出高胰岛素血症与低脂联素血症。
机制层面，Nampt缺失会以年龄依赖的方式，显著降低过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma, PPARγ）的脂肪生成靶基因在白色脂肪组织中的表达水平。此外，给予过氧化物酶体增殖物激活受体γ激动剂罗格列酮（rosiglitazone）可恢复老年ANKO小鼠的体脂质量，并改善其代谢异常。
综上，本研究结果凸显了NAMPT-NAD+-PPARγ轴在维持雌性小鼠衰老过程中脂肪组织的功能完整性与数量，以及全身代谢功能方面的重要性。
整体实验设计：我们通过分析对照（flox/flox）小鼠与脂肪细胞特异性Nampt基因敲除（ANKO）小鼠，明确了脂肪细胞特异性Nampt缺失对年轻与老年小鼠皮下白色脂肪组织基因表达谱的影响。