Mammary Adipocyte Remodeling in Health and Disease

健康和疾病中的乳腺脂肪细胞重塑

• 批准号: 10643697
• 负责人: Qiong Annabel Wang
• 金额: $ 37.08万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-14 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643697
• 关键词: Address; Adipocytes; Adipose tissue; Alveolar; Alveolus; Apoptosis; Back; Biology; Breast; Breast Epithelial Cells; Breast Feeding; Cell Communication; Cell Cycle; Cell Proliferation; Cells; Child; Connective Tissue; Data; Defect; Disease; Duct (organ) structure; Ensure; Epithelial Cells; Exhibits; Fatty acid glycerol esters; Fibrosis; Functional disorder; Health; High Fat Diet; Hormonal; Human; Impairment; In Vitro; Insulin Resistance; Knowledge; Lactation; Mammary Gland Parenchyma; Mammary gland; Metabolic Diseases; Metabolism; Milk; Modeling; Morphogenesis; Mothers; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Performance; Phenotype; Play; Pregnancy; Process; Proliferating; Publishing; Risk; Role; Series; Structure; Testing; Time; Tissues; WNT Signaling Pathway; Weaning; Woman; Work; alveolar epithelium; cell dedifferentiation; design; epithelium regeneration; feeding; in vivo; insight; lactogenesis; mammary; mammary epithelium; milk production; novel; novel therapeutic intervention; obesity in children; obesity treatment; paracrine; self-renewal

Breastfeeding reduces the mother’s risk of type 2 diabetes and protects the child from obesity, type 2 diabetes, and other metabolic disorders. Unfortunately, mothers with obesity and type 2 diabetes often have insufficient milk production. Lactation by the breast tissue is accomplished through a serious of complicated cellular remodeling, and a “reverse” remodeling post-weaning takes place to return the breast tissue to the non-lactating state (involution). Our understanding of how breast tissue remodels during and post-weaning is limited, which impedes our ability to address lactation complications. The human breast (mammary gland) is comprised of glandular, ductal, connective, and adipose tissue; in the non-lactating mammary gland, the majority of the mass is made up of adipose tissue. My lab recently showed that during lactation, mammary adipocytes undergo a process of dedifferentiation to become adipocyte precursor-like cells; during involution, these dedifferentiated cells can proliferate, and re-differentiate back into adipocytes. Thus, for the first time, we discovered that terminally differentiated mature adipocytes can dedifferentiate, go back to cell cycle, and regain the capacity of self-renewal. Our objective for this proposal is to determine what regulate mammary adipocytes dedifferentiation during lactation, and to define the role of mammary adipocyte dedifferentiation and regeneration during lactation and involution. Our new preliminary data indicate that mammary adipocytes dedifferentiation is due to paracrine stimulation, and Wnt signaling is the top candidate that regulate this process. We also showed that short-term high fat diet feeding leads to incomplete mammary adipocyte dedifferentiation and smaller mammary alveolar structure. Furthermore, inhibiting the regeneration of mammary adipocytes leads to severely delayed mammary gland involution, persistent alveologenesis, periductal fibrosis, and milk retention. We hypothesize that mammary adipocyte dedifferentiation is regulated by paracrine factors from the mammary epithelial cells, especially Wnt signaling, and successful mammary adipocyte dedifferentiation and regeneration are essential for mammary lactation and involution. We will test our hypothesis in three specific aims. In Aim 1, we will determine the mechanisms that regulate adipocyte dedifferentiation during lactation, focusing on Wnt signaling, as well as identifying new paracrine factors. In Aim 2, we will define the role of mammary adipocyte dedifferentiation in mammary alveologenesis and lactogenesis. Specifically, we will determine if incomplete adipocyte dedifferentiation is directly correlated with impaired mammary alveologenesis and lactogenesis. In Aim 3, we will define the role of mammary adipocyte regeneration in mammary gland involution. Our findings will provide fundamental knowledge to the fields of both adipose and mammary gland biology. We will also provide novel insights into lactation and involution complications in women with metabolic disorders. Moreover, the underlying mechanism of mature adipocyte dedifferentiation will bring new strategies for the treatment of obesity.

母乳喂养可以降低母亲患2型糖尿病的风险，并保护儿童免受肥胖、2型糖尿病和其他代谢紊乱的影响。不幸的是，患有肥胖症和2型糖尿病的母亲通常产奶量不足。乳房组织的泌乳是通过一系列复杂的细胞重塑完成的，断奶后发生“反向”重塑，使乳房组织恢复到非泌乳状态（复归）。我们对断奶期间和断奶后乳腺组织重塑的理解是有限的，这阻碍了我们解决哺乳并发症的能力。人的乳房（乳腺）由腺组织、导管组织、结缔组织和脂肪组织组成；在非泌乳乳腺中，大部分肿块由脂肪组织组成。我的实验室最近发现，在哺乳期间，乳腺脂肪细胞经历了一个去分化的过程，成为脂肪细胞前体细胞样细胞；在退化过程中，这些去分化的细胞可以增殖，并重新分化回脂肪细胞。因此，我们首次发现终末分化的成熟脂肪细胞可以去分化，回到细胞周期，重新获得自我更新的能力。我们的目标是确定哺乳期间乳腺脂肪细胞去分化的调控因素，并确定哺乳和复归期间乳腺脂肪细胞去分化和再生的作用。我们新的初步数据表明，乳腺脂肪细胞去分化是由于旁分泌刺激，而Wnt信号是调节这一过程的首选候选。我们还发现，短期高脂肪饮食喂养会导致乳腺脂肪细胞不完全去分化和乳腺肺泡结构变小。此外，抑制乳腺脂肪细胞的再生会导致严重延迟的乳腺复旧，持续的肺泡形成，导管周围纤维化和乳汁潴留。我们假设乳腺脂肪细胞的去分化是由乳腺上皮细胞的旁分泌因子调控的，尤其是Wnt信号，成功的乳腺脂肪细胞去分化和再生对乳腺泌乳和复归至关重要。我们将在三个具体目标中检验我们的假设。在Aim 1中，我们将确定哺乳期间调节脂肪细胞去分化的机制，重点关注Wnt信号，以及识别新的旁分泌因子。在目标2中，我们将定义乳腺脂肪细胞去分化在乳腺肺泡形成和乳发生中的作用。具体来说，我们将确定不完全脂肪细胞去分化是否与乳腺肺泡生成和乳生成受损直接相关。在Aim 3中，我们将定义乳腺脂肪细胞再生在乳腺退化中的作用。我们的发现将为脂肪和乳腺生物学领域提供基础知识。我们也将提供新的见解，哺乳期和更年期并发症的妇女代谢紊乱。此外，成熟脂肪细胞去分化的潜在机制将为肥胖的治疗带来新的策略。