do Carmo Jussara M, Omoto Ana C M, Dai Xuemei, Moak Sydney P, Mega Gabriela S, Li Xuan, Wang Zhen, Mouton Alan J, Hall John E, da Silva Alexandre A
Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
Centro Universitário Barão de Mauá, Ribeirão Preto, São Paulo, Brazil.
Am J Physiol Heart Circ Physiol. 2021 Sep 1;321(3):H485-H495. doi: 10.1152/ajpheart.00176.2021. Epub 2021 Jul 23.
Previous studies suggest that parental obesity may adversely impact long-term metabolic health of the offspring. We tested the hypothesis that parental (paternal + maternal) obesity impairs cardiac function in the offspring early in life. Within 1-3 days after weaning, offspring from obese rats fed a high-fat diet (HFD-Offs) and age-matched offspring from lean rats (ND-Offs) were submitted to echocardiography and cardiac catheterization for assessment of pressure-volume relationships. Then, hearts were digested and isolated cardiomyocytes were used to determine contractile function, calcium transients, proteins related to calcium signaling, and mitochondrial bioenergetics. Female and male HFD-Offs were heavier (72 ± 2 and 61 ± 4 g vs. 57 ± 2 and 49 ± 1 g), hyperglycemic (112 ± 8 and 115 ± 12 mg/dL vs. 92 ± 10 and 96 ± 8 mg/dL) with higher plasma insulin and leptin concentrations compared with female and male ND-Offs. When compared with male controls, male HFD-Offs exhibited similar systolic function but impaired diastolic function as indicated by increased IVRT (22 ± 1 vs. 17 ± 1 ms), E/E' ratio (29 ± 2 vs. 23 ± 1), and tau (5.7 ± 0.2 vs. 4.8 ± 0.2). The impaired diastolic function was associated with reduced resting free Ca levels and phospholamban protein expression, increased activated matrix metalloproteinase 2, and reduced SIRT3 protein expression, mitochondrial ATP reserve, and ATP-linked respiration. These results indicate that male and female Offs from obese parents have multiple metabolic abnormalities early in life (1-3 days after weaning) and that male, but not female, Offs have impaired diastolic function as well as reductions in cardiac SIRT3, resting free Ca levels, and mitochondrial biogenesis. Parental obesity contributes to diastolic dysfunction in young offspring (1-3 days after weaning) in a sex-dependent manner, as well as reduced cardiac SIRT3 expression and altered mitochondrial bioenergetics, resting Ca levels, and reduced phospholamban protein levels.
先前的研究表明，父母肥胖可能会对后代的长期代谢健康产生不利影响。我们检验了这样一个假设，即父母（父亲 + 母亲）肥胖会在后代生命早期损害其心脏功能。在断奶后1 - 3天内，对高脂饮食喂养的肥胖大鼠的后代（HFD - Offs）和年龄匹配的瘦大鼠的后代（ND - Offs）进行超声心动图检查和心脏导管插入术，以评估压力 - 容积关系。然后，将心脏消化，分离出心肌细胞，用于测定收缩功能、钙瞬变、与钙信号相关的蛋白质以及线粒体生物能量学。与雌性和雄性ND - Offs相比，雌性和雄性HFD - Offs体重更重（分别为72 ± 2和61 ± 4 g，而ND - Offs为57 ± 2和49 ± 1 g），血糖更高（分别为112 ± 8和115 ± 12 mg/dL，而ND - Offs为92 ± 10和96 ± 8 mg/dL），血浆胰岛素和瘦素浓度更高。与雄性对照组相比，雄性HFD - Offs表现出相似的收缩功能，但舒张功能受损，表现为等容舒张时间增加（22 ± 1对17 ± 1 ms）、E/E'比值增加（29 ± 2对23 ± 1）和心肌松弛时间常数增加（5.7 ± 0.2对4.8 ± 0.2）。舒张功能受损与静息游离钙水平降低、受磷蛋白表达减少、活化的基质金属蛋白酶2增加以及沉默调节蛋白3（SIRT3）表达减少、线粒体ATP储备和ATP相关呼吸作用降低有关。这些结果表明，肥胖父母的雌性和雄性后代在生命早期（断奶后1 - 3天）存在多种代谢异常，并且雄性后代（而非雌性后代）存在舒张功能受损以及心脏SIRT3、静息游离钙水平和线粒体生物发生减少。父母肥胖以性别依赖的方式导致幼年后代（断奶后1 - 3天）舒张功能障碍，以及心脏SIRT3表达减少、线粒体生物能量学改变、静息钙水平降低和受磷蛋白水平降低。
