Adipose tissue in the body is classified as white adipose tissue (WAT); a fat-accumulating tissue, or brown adipose tissue (BAT); an energy-dissipating tissue. Transforming WAT-to-BAT (browning) is a promising strategy for the treatment of obesity, since it would lead to an increase in energy expenditure. Rosiglitazone (Rosi), an agonist of the peroxisome proliferator-activated receptor γ (PPARγ), is known to be a potent browning inducer in subcutaneous WAT. However, the effectiveness of Rosi has been quite limited because of several off-target effects. The objective of this study was to develop locally administered Rosi-loaded nanoparticles (Rs-NPs) with the ability to target adipocytes to achieve the adipose tissue-specific activation of PPARγ, thus causing the browning of WAT. We prepared dual targeted Rs-NPs that were modified with a specific peptide that targets prohibitin that are expressed in adipocytes, and a cell penetrating peptide for enhancing cellular uptake and controlling intracellular trafficking. The Rs-NPs modified with a single ligand were internalized into mature adipocytes and induced browning activity in vitro but they failed to significantly affect the body weight of the diet-induced obese mice model. The dual-targeted Rs-NPs induced a strong browning activity, both in vitro and in vivo, and successfully inhibited the progression of obesity, as evidenced by the shrinkage of hypertrophied adipocytes without any detectable systemic adverse effects. Meanwhile, free Rosi aggravated hepatic steatosis and did not cause adipose tissue browning nor the inhibition of body weight gain. We conclude that the increased energy expenditure via adipose tissue browning using dual-targeted Rs-NP is a promising strategy for the treatment of obesity and its related metabolic syndrome.