Townsend Kristy L, Pritchard Eleanor, Coburn Jeannine M, Kwon Young Mi, Blaszkiewicz Magdalena, Lynes Matthew D, Kaplan David L, Tseng Yu-Hua
Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States.
Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, United States.
Front Bioeng Biotechnol. 2022 May 12;10:884601. doi: 10.3389/fbioe.2022.884601. eCollection 2022.
Increasing the mass and/or activity of brown adipose tissue (BAT) is one promising avenue for treating obesity and related metabolic conditions, given that BAT has a high potential for energy expenditure and is capable of improving glucose and lipid homeostasis. BAT occurs either in discrete "classical" depots, or interspersed in white adipose tissue (WAT), termed "inducible/recruitable" BAT, or 'beige/brite' adipocytes. We and others have demonstrated that bone morphogenetic protein 7 (BMP7) induces brown adipogenesis in committed and uncommitted progenitor cells, resulting in increased energy expenditure and reduced weight gain in mice. BMP7 is therefore a reliable growth factor to induce browning of WAT. In this study, we sought to deliver BMP7 specifically to subcutaneous (sc)WAT in order to induce tissue-resident progenitor cells to differentiate into energy-expending recruitable brown adipocytes, without off-target effects like bone formation, which can occur when BMPs are in the presence of bone progenitor cells (outside of WAT). BMP7 delivery directly to WAT may also promote tissue innervation, or directly activate mitochondrial activity in brown adipocytes, as we have demonstrated previously. We utilized silk protein in the form of an injectable hydrogel carrying BMP7. Silk scaffolds are useful for delivery of substances due to favorable material properties, including controlled release of therapeutic proteins in an active form, biocompatibility with minimal immunogenic response, and prior FDA approval for some medical materials. For this study, the silk was engineered to meet desirable release kinetics for BMP7 in order to mimic our prior brown adipocyte differentiation studies. Fluorescently-labeled silk hydrogel loaded with BMP7 was directly injected into WAT through the skin and monitored by non-invasive whole body imaging, including in UCP1-luciferase reporter mice, thereby enabling an approach that is translatable to humans. Injection of the BMP7-loaded silk hydrogels into the subcutaneous WAT of mice resulted in "browning", including the development of multilocular, uncoupling protein 1 (UCP1)-positive brown adipocytes, and an increase in whole-body energy expenditure and skin temperature. In diet-induced obese mice, BMP7-loaded silk delivery to subcutaneous WAT resulted in less weight gain, reduced circulating glucose and lower respiratory exchange ratio (RER). In summary, BMP7 delivery via silk scaffolds directly into scWAT is a novel translational approach to increase browning and energy expenditure, and represents a potential therapeutic avenue for delivering substances directly to adipose depots in pursuit of metabolic treatments.
鉴于褐色脂肪组织（BAT）具有很高的能量消耗潜力，并且能够改善葡萄糖和脂质稳态，增加其质量和/或活性是治疗肥胖症及相关代谢疾病的一个有前景的途径。BAT要么存在于离散的“经典”储存部位，要么散布于白色脂肪组织（WAT）中，即所谓的“诱导性/可招募性”BAT，或“米色/明亮型”脂肪细胞。我们和其他人已经证明，骨形态发生蛋白7（BMP7）可诱导定向和未定向祖细胞发生褐色脂肪生成，从而增加小鼠的能量消耗并减少体重增加。因此，BMP7是诱导WAT褐色化的可靠生长因子。在本研究中，我们试图将BMP7特异性递送至皮下（sc）WAT，以诱导组织驻留祖细胞分化为消耗能量的可招募褐色脂肪细胞，而不会产生诸如骨形成等脱靶效应，当骨形态发生蛋白存在于骨祖细胞（在WAT之外）时可能会出现这种效应。如我们之前所证明的，将BMP7直接递送至WAT还可能促进组织神经支配，或直接激活褐色脂肪细胞中的线粒体活性。我们利用了呈携带BMP7的可注射水凝胶形式的丝蛋白。丝支架由于具有良好的材料特性，可用于递送物质，这些特性包括以活性形式控释治疗性蛋白质、具有最小免疫原性反应的生物相容性以及先前已获得FDA对某些医疗材料的批准。在本研究中，对丝进行了工程改造，以满足BMP7所需的释放动力学，从而模拟我们之前的褐色脂肪细胞分化研究。将装载有BMP7的荧光标记丝水凝胶通过皮肤直接注射到WAT中，并通过非侵入性全身成像进行监测，包括在UCP1 - 荧光素酶报告基因小鼠中，从而实现一种可转化至人体的方法。将装载有BMP7的丝水凝胶注射到小鼠的皮下WAT中导致了“褐色化”，包括多泡、解偶联蛋白1（UCP1）阳性褐色脂肪细胞的形成，以及全身能量消耗和皮肤温度的增加。在饮食诱导的肥胖小鼠中，将装载有BMP7的丝递送至皮下WAT导致体重增加减少、循环葡萄糖降低以及呼吸交换率（RER）降低。总之，通过丝支架将BMP7直接递送至scWAT是一种增加褐色化和能量消耗的新型转化方法，并且代表了一种将物质直接递送至脂肪储存部位以寻求代谢治疗的潜在治疗途径。
