Subcutaneous Administration of a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and Insulin Resistance in High-Fat Diet-Induced Obese Mice

Abstract

Nitric oxide (NO) is a gaseous signaling molecule, which plays crucial roles in various biological processes, including inflammatory responses, metabolism, cardiovascular functions, and cognitive function. NO bioavailability is reduced with aging and cardiometabolic disorders in humans and rodents. NO stimulates the metabolic rate by increasing the mitochondrial biogenesis and brown fat activation. Therefore, we propose a novel technology of providing exogenous NO to improve the metabolic rate and cognitive function by promoting the development of brown adipose tissue. In the present study, we demonstrate the effects of the peptide amphiphiles–NO-releasing nanomatrix gel (PANO gel) on high-fat diet-induced obesity, insulin resistance, and cognitive functions. Eight-week-old male C57BL/6 mice were subcutaneously injected in the brown fat area with the PANO gel or vehicle (PA gel) every 2 weeks for 12 weeks. The PANO gel-injected mice gained less body weight, improved glucose tolerance, and decreased fasting serum insulin and leptin levels compared with the PA gel-injected mice. Insulin signaling in the muscle, liver, and epididymal white adipose tissue was improved by the PANO gel injection. The PANO gel reduced inflammation, increased lipolysis in the epididymal white adipose tissue, and decreased serum lipids and liver triglycerides. Interestingly, the PANO gel stimulated uncoupled protein 1 gene expression in the brown and beige fat tissues. Furthermore, the PANO gel increased the cerebral blood flow and improved learning and memory abilities. Our results suggest that using the PANO gel to supply exogenous NO is a novel technology to treat metabolic disorders and cognitive dysfunctions.

Transdermal Delivery of Succinate Accelerates Energy Dissipation of Brown Adipocytes to Reduce Remote Fat Accumulation

“…Brown adipose tissue (BAT) is considered thermogenic adipocytes that burn calories to perform energy consumption and dissipation, whereas white adipose tissue (WAT) is regarded as fat depots to store the excess energy. , Even though the biological strategy has been found to transform the subcutaneous WAT to inducible thermogenic adipocytes (also called brown-like-in-white or beige adipocytes), , the energy expenditure of beige adipocytes is dominated by cold-inducible thermogenesis that is not commonly used to fight obesity. , Increasing thermogenesis of brown adipocytes through the energy dissipation process of calorie expenditure might be an efficient approach to fighting obesity. Still, it is unclear whether the fat storage of WAT can be decreased by BAT thermogenesis.…”