Abstract <p>Metabolic dysfunction, including insulin resistance and dyslipidemia,is a hallmark of diet-induced health impairments. The efficacy oftraditional oral pharmacotherapy is often limited by pharmacokineticconstraints such as first-pass metabolism and absorption variability.Microneedle-based transdermal delivery systems represent a promisingalternative, circumventing the gastrointestinal tract and facilitatinglocalized delivery to specific anatomical regions, such as the interscapular arearich in brown adipose tissue (BAT). The aim of this study was evaluationof the metabolic effects of metformin, sibutramine, tesofensine,and a metformin–sibutramine combination delivered transdermallyto the interscapular region in a Wistar rat model of diet-inducedmetabolic impairment.Metabolic dysfunction was induced in 132 maleWistar rats using a high-fat diet combined with a 20% fructose solution.Animals received the pharmacological agents either transdermallyvia microneedle patches affixed to the interscapular region or viadaily intragastric gavage at comparable cumulative doses for fiveweeks. We assessed body weight trajectories as area under the curve(AUC), feed and fluid intake, glucose tolerance, and serum biochemicalparameters. Transdermal delivery was associated with significantlylower body weight AUC values compared to the intragastric route.Transdermal administration provided distinct improvements in carbohydrate metabolism,characterized by a significant reduction in postprandial glycemiaand a distinct “flattening” of the glycemic curve in the sibutramineand tesofensine groups. Biochemical analysis confirmed significantimprovements in lipid profiles (cholesterol and triglycerides) followingtransdermal treatment compared to the intragastric comparator groups.Theseresults highlight the potential of localized transdermal deliveryto BAT-rich regions as an effective strategy for managing metabolicdisturbances associated with diet-induced dysfunction.</p>