Mammary Adipocyte Remodeling in Health and Disease

母乳喂养降低了母亲患2型糖尿病的风险，并保护孩子免受肥胖、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。乳房组织的哺乳是通过一系列复杂的细胞重塑完成的，断奶后会发生“反向”重塑，使乳房组织恢复到非授乳状态(退化)。我们对乳房组织在断奶期间和断奶后如何重塑的了解有限，这阻碍了我们解决哺乳并发症的能力。人的乳腺由腺体、导管、结缔组织和脂肪组织组成；在非哺乳期的乳腺中，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，乳腺脂肪细胞经历了一个脱分化过程，成为脂肪细胞前体细胞；在退化过程中，这些去分化的细胞可以增殖，并重新分化为脂肪细胞。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，并重新获得自我更新的能力。本研究的目的是确定在哺乳期是什么调控乳腺脂肪细胞的脱分化，并确定乳腺脂肪细胞脱分化和再生在哺乳期和退化期的作用。我们新的初步数据表明，乳腺脂肪细胞的去分化是由旁分泌刺激引起的，而Wnt信号是调节这一过程的首选信号。我们还发现，短期高脂饲料喂养会导致乳腺脂肪细胞脱分化不完全，乳泡结构变小。此外，抑制乳腺脂肪细胞的再生会导致严重延迟乳腺退缩、持续性肺泡生成、导管周围纤维化和乳汁滞留。我们推测乳腺脂肪细胞的脱分化受乳腺上皮细胞旁分泌因子的调控，尤其是Wnt信号，而成功的乳腺脂肪细胞脱分化和再生对于乳腺的哺乳和退化是必不可少的。我们将在三个具体目标上检验我们的假设。在目标1中，我们将确定在哺乳期调节脂肪细胞去分化的机制，重点是Wnt信号，以及识别新的旁分泌因子。在目标2中，我们将明确乳腺脂肪细胞去分化在乳泡发生和乳汁发生中的作用。具体地说，我们将确定不完全脂肪细胞去分化是否与乳泡形成和乳汁生成受损直接相关。在目标3中，我们将明确乳腺脂肪细胞再生在乳腺退行性变中的作用。我们的发现将为脂肪和乳腺生物学领域提供基础知识。我们还将提供对患有代谢紊乱的妇女的哺乳期和退缩并发症的新见解。此外，成熟脂肪细胞去分化的潜在机制将为肥胖症的治疗带来新的策略。

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.