Silk Hydrogel-Mediated Delivery of Bone Morphogenetic Protein 7 Directly to Subcutaneous White Adipose Tissue Increases Browning and Energy Expenditure

Abstract

Objective: 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.Methods: 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 in vivo 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 in vitro brown adipocyte differentiation studies. Fluorescently-labeled silk hydrogel loaded with BMP7 was directly injected into WAT through the skin and monitored by non-invasive in vivo whole body imaging, including in UCP1-luciferase reporter mice, thereby enabling an approach that is translatable to humans.Results: 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).Conclusions: 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.

An insight into brown/beige adipose tissue whitening, a metabolic complication of obesity with the multifactorial origin

“…Recently, Townsend et al. ( 51 ) demonstrated that BMP7-loaded silk hydrogels into the subcutaneous WAT of mice induced brown adipogenesis in committed and uncommitted progenitor cells, which in turn increased energy expenditure and reduced weight gain in mice. In human-neck adipose-derived stromal cells, BMP7 enhanced mitochondrial DNA content, concomitant with increased gene expression of proliferator-activated receptor coactivator 1 alpha (PGC1α), a transcriptional co-regulator, responsible for mitochondrial biogenesis ( 52 ).…”

Therapeutic Potential of Engineered Beige Adipocytes in Metabolic Diseases

“…Silk hydrogels loaded with BMP7 were injected into the subcutaneous WAT of mice, resulting in 'browning', including the development of multihoused, uncoupling protein 1 (UCP1)-positive brown adipocytes, as well as an increase in whole-body energy expenditure and skin temperature. In diet-induced obese mice, the delivery of BMP7-loaded filaments to subcutaneous WAT resulted in reduced weight gain, lower circulating glucose, and lower respiratory exchange rate (RER) for metabolic treatment (Townsend et al, 2022). There is interest in the ability to produce beige fat as a potential treatment for metabolic disease and obesity, which has "good" metabolic function.…”

Potential of bone morphogenetic protein-7 in treatment of lupus nephritis: addressing the hurdles to implementation

“…Firstly, it has been known for some time that BMP-7 reduces appetite, increases weight loss and improves insulin sensitivity in a leptin-independent manner and likely via the mTOR pathway (Townsend et al 2012 ). Secondly, BMP-7 was demonstrated to promote differentiation of adipose derived mesenchymal stem cells (AD-MSCs) in brown adipose tissue rather than white adipose tissue both in vitro (Zheng et al 2014 ) and in vivo (Townsend et al 2022 ), which again confers a more desirable energy expenditure status. Since the majority of studies on BMP-7’s effect on adipose tissue and energy expenditure has been performed in the context of obesity and diabetes, some questions remain unanswered in the SLE context.…”

“…For example, a pre-clinical study reported improved osteogenic differentiation of human mesenchymal stem cells after exposure to MSNs laden with BMP-7-derived bone-forming peptide (Luo et al 2015 ). Also recently, an injectable silk hydrogel carrier for BMP-7 was described, which could be optimised for desired release kinetics (Townsend et al 2022 ), suggesting significant advances in terms of delivery and sustained release of BMP-7 in a more focal manner. These encouraging data warrant further exploration.…”