Mechanisms for Sex Differences in Metabolic Programming

代谢编程中性别差异的机制

• 批准号: 10198910
• 负责人: Chellakkan Selvanesan Blesson
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198910
• 关键词: Adult; Adult Children; Affect; American; Americas; Animal Model; Animals; Chemicals; Data; Development; Diabetes Mellitus; Disease; Environmental Risk Factor; Epidemic; Epigenetic Process; Estradiol; Etiology; Exposure to; Female; Gender; Genes; Genetic; Gluconeogenesis; Glucose Intolerance; Glycogen; Gonadal Steroid Hormones; Growth; Health; Hepatic; Hormones; Human; Hypertension; Impairment; Insulin Resistance; Life; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Mitochondria; Modeling; Mothers; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Pathway interactions; Play; Predisposition; Pregnancy; Prevention strategy; Protein-Restricted Diet; Proteins; Rat Protein; Rattus; Regulation; Rodent Model; Role; Sex Differences; Skeletal Muscle; Steroid Resistance; Steroid biosynthesis; Steroids; Stress; Structure; Supplementation; Testing; Testosterone; Thinness; Variant; Weight; base; blood glucose regulation; diabetic; dietary; epidemiologic data; fetal programming; glucose production; glucose transport; glycogenolysis; in utero; insulin sensitivity; insulin signaling; male; nutrition; offspring; prenatal exposure; prevent; sex; steroid hormone

Increased susceptibility to metabolic diseases including diabetes and hypertension during adult life has been recognized for offspring born to mothers with nutritional stress during pregnancy. We recently developed a unique gestational low-protein (LP) rat model in which the offspring are not obese but have glucose intolerance (GI) and insulin resistance (IR), and are unable to regulate glucose production, similar to that seen in humans who are metabolically aberrant with normal weight. Based on our recent exciting resultant observations with metabolic syndrome, we are focusing on the role of sex steroid hormones (testosterone (T) and estradiol (E2)) in regulating the onset and progression of GI and IR in the offspring exposed in utero to LP diet, and mechanisms involved. The central hypothesis is that the offspring from maternal LP- programming are GI and IR and their onset and progression are sex- and sex steroid (T in males and E2 in females)-dependent, and involve regulatory mechanisms of glucose homeostasis, insulin signaling, and mitochondrial function. Three specific aims are proposed: Specific Aim 1: Establish the onset and progression of GI and IR, in maternal LP programmed offspring and determine if these are sex-and sex steroid hormone-dependent. Sub aim 1a: We hypothesize that onset and progression of GI and IR in maternal LP-programmed offspring are catch-up growth associated, sex dependent and sex steroid hormone-related. Sub aim 1b: We hypothesize that steroid supplementation (T for males and E2 for females) prior to the onset will prevent and after the onset will reverse GI and IR. Specific Aim 2: Assess changes in insulin sensitivity in skeletal muscles and liver, and hepatic glucose production in LP offspring, and their regulation by sex and sex steroids. Sub aim 2a: We hypothesize that insulin signaling for glucose transport and glycogen synthesis are defective in LP rats and these changes are sex-dependent and steroid hormone related. Sub Aim 2b: We hypothesize that the regulation of hepatic glucose production by gluconeogenesis (GNG) and glycogenolysis (GYG) is impaired in LP offspring and this impairment is sex dependent and regulated by sex steroids. Specific Aim 3: Identify the mechanistic relationship between in utero nutrition, sex steroids and insulin resistance. Sub aim 3a: We hypothesize that gestational LP diet affects the epigenetic profiles of key genes involved in steroidogenesis and decreases synthesis of T in males and E2 in females. Specific Aim 3b: We hypothesize that mitochondrial structure and function is compromised in LP offspring contributing to the development of IR. Sub aim 3c: We hypothesize that alterations in mitochondrial structure and function in LP offspring are sex steroid mediated. The outcomes of this project are expected to provide new information about the onset, progression and the development of metabolic disturbances in a lean animal model, and the involvement of sex and sex steroid hormone related mechanisms. Understanding of these mechanisms involved in this maternal LP-induced programming model could aid in developing sex-specific strategies for the prevention and treatment of metabolic disorders.

在成年期，对包括糖尿病和高血压在内的代谢性疾病的易感性增加， 母亲在怀孕期间有营养压力，我们最近开发了一个 一种独特的妊娠期低蛋白（LP）大鼠模型，其中后代不肥胖，但有葡萄糖耐受不良 (GI)和胰岛素抵抗（IR），并且不能调节葡萄糖的产生，类似于在人类中看到的 体重正常但代谢异常的人根据我们最近令人兴奋的观测结果， 在代谢综合征中，我们关注性类固醇激素（睾酮（T）和雌二醇（E2））在 调节子宫内暴露于LP饮食的后代中GI和IR的发生和进展，及其机制 涉案中心假设是母体LP编程的后代是GI和IR， 其发作和进展依赖于性别和性类固醇（男性T，女性E2）， 涉及葡萄糖稳态、胰岛素信号传导和线粒体功能的调节机制。 提出了三个具体目标：具体目标1：确定GI和IR的发病和进展， 母体LP编程的后代，并确定这些是否是性别和性类固醇激素依赖性。 子目标1a：我们假设母体LP编程后代GI和IR的发生和进展是由于 追赶性生长相关、性依赖性和性类固醇激素依赖性。子目标1b：我们假设 在发病前补充类固醇（男性为T，女性为E2）可预防，发病后补充类固醇可 具体目标2：评估骨骼肌和肝脏中胰岛素敏感性的变化， LP后代肝葡萄糖生成及其受性别和性类固醇的调节。次级目标2a：我们 假设LP大鼠中葡萄糖转运和糖原合成胰岛素信号传导缺陷， 这些变化与性别和类固醇激素有关。子目标2b：我们假设， 在LP后代中，通过糖原生成（GNG）和糖原分解（GYG）产生的肝葡萄糖受损， 这种损害是性别依赖性的，并受性类固醇调节。具体目标3：确定机制 子宫内营养、性类固醇与胰岛素抵抗的关系子目标3a：我们假设 妊娠期LP饮食会影响参与类固醇生成的关键基因的表观遗传特征， 雄性合成T，雌性合成E2。具体目标3b：我们假设线粒体结构和 LP后代的功能受损，导致IR的发展。子目标3c：我们假设， LP后代中线粒体结构和功能的改变是性类固醇介导的。这个结果 该项目有望提供有关代谢性疾病的发病、进展和发展的新信息。 在瘦动物模型中的紊乱，以及性和性类固醇激素相关机制的参与。 了解这种母体LP诱导的编程模型中涉及的这些机制有助于 制定针对性别的代谢紊乱预防和治疗策略。

项目成果

Hyperandrogenemia alters mitochondrial structure and function in the oocytes of obese mouse with polycystic ovary syndrome.

• DOI: 10.1016/j.xfss.2020.12.001
• 发表时间: 2021-03
• 期刊: F&S science
• 作者: Chappell NR;Zhou B;Hosseinzadeh P;Schutt A;Gibbons WE;Blesson CS
• 通讯作者: Blesson CS

Fetal programming of polycystic ovary syndrome: Effects of androgen exposure on prenatal ovarian development.

• DOI: 10.1016/j.jsbmb.2021.105830
• 发表时间: 2021-03
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Barsky M;Merkison J;Hosseinzadeh P;Yang L;Bruno-Gaston J;Dunn J;Gibbons W;Blesson CS
• 通讯作者: Blesson CS

Polycystic Ovary Syndrome and the Forgotten Uterus.

• DOI: 10.1016/j.xfnr.2020.12.001
• 发表时间: 2021-01
• 期刊: F&S reviews
• 作者: Hosseinzadeh P;Barsky M;Gibbons WE;Blesson CS
• 通讯作者: Blesson CS

Embryos from polycystic ovary syndrome patients with hyperandrogenemia reach morula stage faster than controls.

• DOI: 10.1016/j.xfre.2020.05.006
• 发表时间: 2020-09
• 期刊: F&S reports
• 作者: Chappell NR;Barsky M;Shah J;Peavey M;Yang L;Sangi-Haghpeykar H;Gibbons W;Blesson CS
• 通讯作者: Blesson CS

Pathology of hyperandrogenemia in the oocyte of polycystic ovary syndrome.

• DOI: 10.1016/j.steroids.2022.108989
• 发表时间: 2022-04
• 期刊: Steroids
• 影响因子: 2.7
• 作者: Chappell NR;Gibbons WE;Blesson CS
• 通讯作者: Blesson CS