Editors' ChoiceObesity

Anti-inflammatory drug formulations fight fat

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eabf7736
DOI: 10.1126/scitranslmed.abf7736

Abstract

Macrophage-targeted dexamethasone improves weight loss and glucose tolerance not possible with systemic administration of the free drug.

Obesity is a global health crisis, affecting more than one in ten adults worldwide. The impact of obesity on health is largely due to its role in the development of cardiovascular disease, type 2 diabetes, and other chronic conditions caused by metabolic and inflammatory dysfunction. Importantly, the accumulation of excessive adipose tissue (AT) is associated with a concurrent increase in inflammatory AT macrophages. The application of anti-inflammatory drug therapies, however, has been limited by detrimental effects on distant tissues, including overt immunosuppression, bone loss, and aberrant fat deposition. To overcome these challenges, Prabhu et al. developed an approach to target anti-inflammatory therapies to AT macrophages.

Here, the authors prepared a polymer-drug conjugate consisting of a potent anti-inflammatory drug (dexamethasone) chemically linked to dextran, a polymer recognized by macrophage cell surface receptors to induce internalization and thereby aid drug targeting. When injected directly into the abdominal cavity of obese mice, greater than 50% of the dose was distributed to visceral AT and associated macrophage populations. Following a single administration of the formulation, mice exhibited dose-dependent effects on lipid metabolism that included an increase in circulating non-esterified fatty acids, reflecting mobilization of lipids from AT. In addition, the macrophage-targeted therapy yielded a nearly 20-fold increase in the reduction of inflammatory gene expression within AT as compared to free drug. The effects of long-term treatment were investigated by repeated drug administration over a two-week time course that led to a steady reduction in body weight, contrasting with AT gains typically associated with systemic dexamethasone administration. Even two weeks after ceasing treatment, mice maintained reduced inflammatory gene expression and an improved insulin tolerance. The methods here are limited to mouse models but provide evidence that AT-target glucocorticoid therapy uniquely decouples immunosuppression and metabolic effects, representing a solution to combat obesity and its contribution to the development of comorbidities.

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