Metabolic Effects of Transdermally Delivered Pharmacological Agents in a Rat Model of Diet-Induced Metabolic Dysfunction

Metabolic dysfunction, including insulin resistance and dyslipidemia, is a hallmark of diet-induced health impairments. The efficacy of traditional oral pharmacotherapy is often limited by pharmacokinetic constraints such as first-pass metabolism and absorption variability. Microneedle-based transdermal delivery systems represent a promising alternative, circumventing the gastrointestinal tract and facilitating localized delivery to specific anatomical regions, such as the interscapular area rich in brown adipose tissue (BAT). The aim of this study was evaluation of the metabolic effects of metformin, sibutramine, tesofensine, and a metformin–sibutramine combination delivered transdermally to the interscapular region in a Wistar rat model of diet-induced metabolic impairment.Metabolic dysfunction was induced in 132 male Wistar rats using a high-fat diet combined with a 20% fructose solution. Animals received the pharmacological agents either transdermally via microneedle patches affixed to the interscapular region or via daily intragastric gavage at comparable cumulative doses for five weeks. We assessed body weight trajectories as area under the curve (AUC), feed and fluid intake, glucose tolerance, and serum biochemical parameters. Transdermal delivery was associated with significantly lower body weight AUC values compared to the intragastric route. Transdermal administration provided distinct improvements in carbohydrate metabolism, characterized by a significant reduction in postprandial glycemia and a distinct “flattening” of the glycemic curve in the sibutramine and tesofensine groups. Biochemical analysis confirmed significant improvements in lipid profiles (cholesterol and triglycerides) following transdermal treatment compared to the intragastric comparator groups.These results highlight the potential of localized transdermal delivery to BAT-rich regions as an effective strategy for managing metabolic disturbances associated with diet-induced dysfunction.