Maternal Overweight: Consequences for Insulin Signaling in the Offspring

母亲超重：对后代胰岛素信号传导的影响

• 批准号: 8489288
• 负责人: Kartik Shankar
• 金额: $ 30.24万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489288
• 关键词: Address; Adipose tissue; Affect; Age-Months; Anabolism; Birth Weight; Body Composition; Body Weight; Chronic; Clinical Research; Conceptions; Consumption; Development; Diet; Effectiveness; Elderly; Endocrine; Energy Intake; Energy Metabolism; Ensure; Enteral Nutrition; Environment; Euglycemic Clamping; Exposure to; Fatty acid glycerol esters; Gene Expression; Glucose; Glucose Clamp; Health; Hyperglycemia; Hyperinsulinism; Hypertrophy; Incidence; Indirect Calorimetry; Individual; Infant; Insulin; Insulin Resistance; Intervention; Label; Life Style; Lipids; Liver; Long-Term Effects; Mediating; Metabolic; Modeling; Monitor; Nutrient; Obesity; Overweight; Pancreas; Physical activity; Predisposition; Pregnancy; Preventive Intervention; Rattus; Relative (related person); Research; Risk; Role; Running; Signal Transduction; Skeletal Muscle; System; Testing; Time; Tissues; Tracer; Water; Weaning; Weight Gain; Woman; abstracting; base; energy balance; feeding; glucose uptake; human subject; improved; in utero; insulin secretion; insulin sensitivity; insulin signaling; lipid biosynthesis; muscle form; novel; obesity prevention; offspring; postnatal; prevent; prospective; research study; response

Abstract: The major reasons underlying the remarkable global rise in obesity remain unclear. While, diet composition and life-style factors such as physical activity undoubtedly have important roles in determining body composition, maternal overweight (OW) status ( BMI > 25) at conception may be a critical synergizing factor. In clinical studies, we found that maternal OW status significantly increased risk of OW (i.e. the % above the 95th percentile) at 6 months of age, in infants born with normal body weights. Our overall objective is to investigate interactions in the offspring, between an obesegenic environment (consumption of a high-fat diet, HFD) and prior exposure to maternal OW during gestation. To this end, we have developed a rat model in which metabolic and endocrine abnormalities akin to obesity in human subjects were reproduced prior to conception. Exposure to maternal OW did not influence birth weight/size of offspring. However, offspring from OW dams when fed a HFD became obese to much greater extent compared to offspring from lean dams on the same diet, without changes in caloric intake. Offspring of OW rats also developed hyperinsulinemia, adipose tissue hypertrophy and showed lipogenic gene expression. Based on our preliminary studies, we hypothesize that increased glucose flux into adipose tissue and accelerated lipogenesis causes obesity in the offspring of OW dams when fed a HFD. The proposed studies are aimed at understanding the underlying differences in energy balance and insulin signaling prior to the development of obesity in the offspring. In Specific Aim 1, indirect calorimetry will be utilized to examine if gestational OW decreases energy expenditure in the offspring. In Specific Aim 2, we will test the hypothesis that maternal OW leads to skeletal muscle insulin resistance in the offspring, consequently increasing glucose partitioning into adipose tissue, lipogenesis and fat mass accretion. This will be addressed via hyperinsulinemic-euglycemic clamp experiments using labeled tracers, and will reveal the status of insulin sensitivity in the individual tissues (skeletal muscle, adipose and liver) and whole-body glucose flux. Studies examining responsiveness of adipose tissue to insulin signaling via IR-PI3K-Akt to increase lipogenic gene expression and de novo lipid synthesis and will be performed in Specific Aim 3. Finally, Specific Aim 4 will employ physical activity prior to conception as an intervention and will test the hypothesis that increased physical activity (treadmill running) in the OW dams prior to conception will improve offspring insulin sensitivity and mitigate increased adipose tissue anabolism. Overall, these studies will elucidate important metabolic mechanisms in the offspring altered by maternal OW and high-fat diets, which may contribute to increased susceptibility to obesity.

摘要：全球肥胖率显著上升的主要原因尚不清楚。同时,饮食

项目成果

Distinct adipogenic differentiation phenotypes of human umbilical cord mesenchymal cells dependent on adipogenic conditions.

人脐带间充质细胞的独特脂肪生成分化表型取决于成脂条件。

• DOI: 10.1177/1535370214539225
• 发表时间: 2014-10
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Saben J;Thakali KM;Lindsey FE;Zhong Y;Badger TM;Andres A;Shankar K
• 通讯作者: Shankar K

Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning.

• DOI: 10.1371/journal.pone.0024068
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Borengasser SJ;Lau F;Kang P;Blackburn ML;Ronis MJ;Badger TM;Shankar K
• 通讯作者: Shankar K

Maternal obesity is associated with a lipotoxic placental environment.

• DOI: 10.1016/j.placenta.2014.01.003
• 发表时间: 2014-03
• 期刊: PLACENTA
• 影响因子: 3.8
• 作者: Saben, J.;Lindsey, F.;Zhong, Y.;Thakali, K.;Badger, T. M.;Andres, A.;Gomez-Acevedo, H.;Shankar, K.
• 通讯作者: Shankar, K.

High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring.

• DOI: 10.1371/journal.pone.0084209
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Borengasser SJ;Kang P;Faske J;Gomez-Acevedo H;Blackburn ML;Badger TM;Shankar K
• 通讯作者: Shankar K

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations.

• DOI: 10.1371/journal.pone.0175675
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wankhade UD;Zhong Y;Kang P;Alfaro M;Chintapalli SV;Thakali KM;Shankar K
• 通讯作者: Shankar K