(PTFS08-05-24) Browning White Adipose Tissue via Microneedle-Based Transdermal Delivery of Forskolin in Obese Mice

Objectives: Obesity is a serious health concern that leads to a higher risk for developing chronic diseases. Browning subcutaneous (subQ) white adipose tissue (WAT) to induce thermogenesis is a promising concept to combat obesity. The objectives of this study are to deliver forskolin (FSK), a natural and potent browning compound, directly to subQ WAT and induce its browning via microneedle (MN)-assisted approach, and to determine its anti-obesity effects and underlying mechanisms.

Methods: A dye was incorporated into the dissolvable PLGA-based microneedles (MNs) to determine the release profile in agarose gel (in vitro) and in mice (in vivo). FSK-loaded MNs were prepared using a micro-mold, and FSK content was determined using HPLC. Two groups of male obese C57BL6J mice were given the following two treatments: control MN and FSK loaded MNs three times per week for three weeks. In order to drive FSK into subQ WAT, iontophoresis at 0.6 mA for 5 minutes was applied on the MN-treated skin areas two times per week. Body weight and body composition of mice were measured weekly. Glucose tolerance test (GTT) was conducted at week 3. The energy expenditure of mice was determined using CLAMS.

Results: The MN dissolution rate was 7 days in agarose gel. After applying the MN on the mice skin above the inguinal WAT, the MN back layer was able to be easily separated from the MN needles. The dye-loaded MN released dye in the inguinal area for 7 days. HPLC confirmed there was 6.02 µg/mL FSK per MN, ~12 µg FSK per treatment, and ~0.3 µg FSK per 1 g body weight. Body weight significantly decreased by approximately 3.87 g in FSK mice when compared to HFT mice which remained within the same range (P=0.0045). Body fat % significantly decreased by approximately 5.23% in FSK mice when compared to HFT mice which increased 0.51% (P = 0.002). Lean mass of two groups of mice remained the same (P = 0.29). FSK-treated mice had lower area under the curve during GTT. FSK-treated mice had higher O2 consumption and CO2 out. The inguinal WAT of FSK-treated mice showed beige color during sacrifice.

Conclusions: Local FSK-loaded transdermal MN treatments combat obesity by significantly decreasing body weight and fat %, improving glucose tolerance and O2/CO2 exchange, and potentially turning WAT into BAT.

Funding Sources: Arizona State University