Abstract
Brown and beige adipocytes are potent therapeutic agents to increase energy expenditure and reduce risks of obesity and its affiliated metabolic symptoms. One strategy to increase beige adipocyte content is through inhibition of the evolutionarily conserved Notch signaling pathway. However, systemic delivery of Notch inhibitors is associated with off-target effects and multiple dosages of application further faces technical and translational challenges. Here, we report the development of a biodegradable polymeric microsphere-based drug delivery system for sustained, local release of a Notch inhibitor, DBZ. The microsphere-based delivery system was fabricated and optimized using an emulsion/solvent evaporation technique to encapsulate DBZ into poly(lactide-co-glycolide) (PLGA), a commonly used biodegradable polymer for controlled drug release. Release studies revealed the ability of PLGA microspheres to release DBZ in a sustained manner. Co-culture of white adipocytes with and without DBZ-loaded PLGA microspheres demonstrated that the released DBZ retained its bioactivity, and effectively inhibited Notch and promoted browning of white adipocytes. Injection of these DBZ-loaded PLGA microspheres into mouse inguinal white adipose tissue depots resulted in browning in vivo. Our results provide the encouraging proof-of-principle evidence for the application of biodegradable polymers as a controlled release platform for delivery of browning factors, and pave the way for development of new translational therapeutic strategies for treatment of obesity.
Highlights
The obesity epidemic has posed a major concern for public health in modern society due to its association with a spectrum of metabolic diseases, including type 2 diabetes (T2D), heart diseases, hyperglycemia, and multiple cancers [1, 2]
We have recently reported that inhibition of the Notch signaling pathway leads to browning of white adipose tissue (WAT), and ameliorates obesity [13]
We showed that genetic deletion of Notch1 receptor or the nuclear mediator of Notch signaling (Rbpj) in mice improved their glucose tolerance and insulin sensitivity through inducing browning of WAT
Summary
The obesity epidemic has posed a major concern for public health in modern society due to its association with a spectrum of metabolic diseases, including type 2 diabetes (T2D), heart diseases, hyperglycemia, and multiple cancers [1, 2]. There are few medications available for obesity treatment [3] Those therapies are dedicated to decreasing energy intake by either suppressing appetite through stimulating the central nervous system or reducing nutrient digestion and absorption within the gastrointestinal tract [4]. Those medications only produce modest effects and are usually accompanied with unpleasant, potentially harmful side effects [5]. Alternative approaches to overcoming obesity are under extensive exploration. One such approach is through boosting energy expenditure. This strategy through stimulating thermogenesis has been emerging as an appealing alternative
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