Adipocyte glutamine production and lactation

脂肪细胞谷氨酰胺的产生和泌乳

• 批准号: 10650377
• 负责人: MALCOLM WATFORD
• 金额: $ 23.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10650377
• 关键词: Ablation; Adipocytes; Adipose tissue; Amino Acids; Binding Proteins; Branched-Chain Amino Acids; Breast Epithelial Cells; Carbon; Cells; Circulation; Data; Development; Dietary Supplementation; Enterocytes; Epithelial Cell Proliferation; Epithelium; Family suidae; Fatty acid glycerol esters; Genes; Gland; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Goals; Health; Human; Hypersensitivity; Immune; Impairment; Infant formula; Infection; Intestines; Lactation; Liver; Mammary gland; Measurement; Metabolic; Metabolism; Milk; Milk Proteins; Mouse Strains; Mus; Neonatal; Nitrogen; Obese Mice; Obesity; Overweight; Performance; Play; Pregnancy; Production; Proliferating; Proteins; Role; Site; Skeletal Muscle; Source; Supplementation; Testing; Thinking; Tissues; Woman; Work; absorption; amino acid metabolism; attenuation; diet-induced obesity; dietary; environmental change; immune function; immunoregulation; improved; mammary; mammary epithelium; maternal obesity; milk production; mother nutrition; neonatal health; response; stable isotope; suckling

Glutamine (together with glutamate) make up 20% of the amino acids in protein and are 50% of the non-protein amino acids in milk. As lactation progresses the concentration of most free amino acids in milk stay relatively constant but the concentrations of free glutamate and glutamine increase by 40% and 350% respectively. These free amino acids are thought to function by an immunomodulating mechanism to protect against neonatal allergies and infections. Supplementation of glutamine to lactating pigs increases the free glutamine in milk and supplementation to suckling piglets improves immune and intestinal function. Thus, the levels of free glutamine and glutamate in milk may not be optimal and free glutamine may play important roles in neonatal immune function and intestinal health. The lactating mammary gland takes up large amounts of glutamine from the circulation but up to 50% of the glutamine in milk is synthesized with the gland through the action of glutamine synthetase. Preliminary data suggest that adipocytes within the mammary gland are the source of this glutamine production. We developed a mouse strain where glutamine synthetase was ablated in adipocytes (AT Glul-/-). Arterio-venous difference measurements and stable isotope tracing will be used in these mice to determine the contribution of glutamine production by adipocytes to glutamine metabolism during lactation. Similar studies will be carried out to determine how adipocyte glutamine synthesis responds to dietary and environmental changes. Glutamine synthetase in adipose tissue is decreased during obesity which may impair mammary epithelial proliferation. Using the AT Glul-/- mice the role of glutamine production in adipose tissue will be determined in diet-induced obese mice. The work will be the first application of the ablation of a key metabolic gene to the study of amino acid metabolism in lactation. The long-term goals are to understand the function of large amounts of glutamine and glutamate in milk which may lead to changes both in maternal diet and the composition of infant formula.

谷氨酰胺（与谷氨酸一起）占蛋白质氨基酸的 20%，占牛奶中非蛋白质氨基酸的 50%。随着哺乳期的进行，牛奶中大多数游离氨基酸的浓度保持相对恒定，但游离谷氨酸和谷氨酰胺的浓度分别增加 40% 和 350%。这些游离氨基酸被认为通过免疫调节机制起作用，以防止新生儿过敏和感染。给哺乳猪补充谷氨酰胺可以增加牛奶中的游离谷氨酰胺，给哺乳仔猪补充可以改善免疫和肠道功能。因此，牛奶中游离谷氨酰胺和谷氨酸的水平可能不是最佳的，游离谷氨酰胺可能在新生儿免疫功能和肠道健康中发挥重要作用。哺乳期乳腺从循环中吸收大量谷氨酰胺，但牛奶中高达 50% 的谷氨酰胺是通过谷氨酰胺合成酶的作用由腺体合成的。初步数据表明，乳腺内的脂肪细胞是谷氨酰胺产生的来源。我们开发了一种小鼠品系，其中脂肪细胞中的谷氨酰胺合成酶被消除（AT Glul-/-）。将在这些小鼠中使用动静脉差异测量和稳定同位素示踪来确定脂肪细胞产生的谷氨酰胺对哺乳期间谷氨酰胺代谢的贡献。将进行类似的研究以确定脂肪细胞谷氨酰胺合成如何响应饮食和环境变化。肥胖期间脂肪组织中的谷氨酰胺合成酶减少，这可能损害乳腺上皮增殖。使用 AT Glul-/- 小鼠，将在饮食诱导的肥胖小鼠中确定脂肪组织中谷氨酰胺产生的作用。这项工作将是首次将关键代谢基因的消融应用于哺乳期氨基酸代谢的研究。长期目标是了解牛奶中大量谷氨酰胺和谷氨酸盐的功能，这可能会导致母亲饮食和婴儿配方奶粉成分的变化。