In adolescents with PCOS and without obesity, a low-dose combination of one mixed antiandrogen and anti-mineralocorticoid (spironolactone) which increases brown adipose tissue activity (23, 28), and two insulin sensitizers (pioglitazone plus metformin) (spiomet) results in a better improvement in the metabolic condition as compared to OCs, including increased insulin sensitivity, reduced inflammation and liver fat accumulation, and more normalization of circulating hepatokines (20–23, 29). The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.