This study determined if a perturbation in in utero adipogenesis leading to later-life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Het_db) had 2.4-fold higher pre-pregnancy fat mass and in late gestation had higher plasma insulin and triglycerides, compared to wild-type (Wt) females (p < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Het_db dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole-body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Het_db vs. Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all p < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR and ex vivo AT lipolytic responses to isoproterenol, were all higher in Wt offspring born to Het_db dams (p < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.

中文翻译：

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加速发育的脂肪生成程序会影响代谢功能障碍母猪所生后代的脂肪组织功能障碍和心脏代谢风险

这项研究确定了导致晚年脂肪组织 (AT) 功能障碍的子宫内脂肪生成的扰动是否是代谢功能障碍水坝所生后代心脏代谢风险编程的基础。与野生型 (Wt) 雌性相比，瘦素受体缺陷 (Het _db )杂合的雌性小鼠的孕前脂肪量高出 2.4 倍，并且在妊娠后期具有更高的血浆胰岛素和甘油三酯 (p < 0.05)。为了分离子宫内环境的作用，研究了每次怀孕的野生型 (Wt) 后代。分离祖细胞的分化潜能和细胞大小分布分析揭示了 Het _db出生的 Wt 幼崽的脂肪生成加速水坝，伴随着更高的新生儿脂肪量积累。在成年期，与 Wt 妊娠相比，Het _db与 Wt 妊娠所生的男性 (69%) 和女性 (20%) Wt 后代的 NMR 全身脂肪量更高，以及脂肪细胞肥大和高脂血症（所有 p < 0.05）。气相色谱法的脂质组学分析显示，高脂肪/果糖饮食 (HFFD) 后脂肪生成指数 (16:0/18:2n6) 增加。餐后胰岛素、ADIPO-IR 和对异丙肾上腺素的离体 AT 脂肪分解反应，在 Het _db母猪所生的 Wt 后代中都较高（p < 0.05）。宫内代谢刺激可能会将更大比例的祖细胞引导至终末分化，从而导致肥大诱导的脂肪细胞功能障碍。