Aim <p>To evaluate the short-term effects of metformin treatment on serum zinc (Zn), zinc-α2-glycoprotein (ZAG), peroxisome proliferator-activated receptor gamma (PPARγ), leptin (LEP), and adiponectin (ADIPO) levels in obese and insulin-resistant children compared with healthy controls.</p> Methods <p>Fifty-two children with obesity and insulin resistance (IR) and 33 age-matched healthy controls were included. The patient group received metformin for three months alongside lifestyle advice. Anthropometric data and the serum levels of Zn, ZAG, PPARγ, LEP, and ADIPO were measured before and after treatment. The outcomes were also analyzed on the basis of weight change.</p> Results <p>At baseline, the obesity group presented lower ZAG and ADIPO and higher LEP and IR indices than the control group did (<i>p</i> &lt; 0.001). After treatment, BMI, insulin, HOMA-IR, and HDL-C improved. The serum Zn, ZAG, ADIPO, and LEP levels increased significantly (<i>p</i> &lt; 0.05), whereas the PPARγ level remained unchanged. Although 73% had lost weight, 27% had gained weight. In the weight-gain group, both LEP and ADIPO increased, suggesting a weight-independent adipokine response to metformin.</p> Conclusion <p>Metformin led to short-term improvements in metabolic and adipokine profiles in children with obesity and IR. The increase in ADIPO, even among those who gained weight, may reflect the potential weight-independent effect of metformin on insulin sensitivity.</p> Clinical trial registration <p>ClinicalTrials.gov, NCT06266598. Registration date: February 11, 2024.</p>