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Sesamol found in sesame oil has been shown to ameliorate obesity by regulating lipid metabolism. However, its effects on energy expenditure and the underlying molecular mechanism have not been clearly elucidated. In this study, we show that sesamol increased the uncoupling protein 1 (<i>Ucp1</i>) expression in adipocytes. The administration of sesamol in high-fat diet (HFD)-fed mice prevented weight gain and improved metabolic derangements. The three-week sesamol treatment of HFD-fed mice, when the body weights were not different between the sesamol and control groups, increased energy expenditure, suggesting that an induced energy expenditure is a primary contributing factor for sesamol’s anti-obese effects. Consistently, sesamol induced the expression of energy-dissipating thermogenic genes, including <i>Ucp1</i>, in white adipose tissues. The microarray analysis showed that sesamol dramatically increased the Nrf2 target genes such as <i>Hmox1</i> and <i>Atf3</i> in adipocytes. Moreover, 76% (60/79 genes) of the sesamol-induced genes were also regulated by tert-butylhydroquinone (tBHQ), a known Nrf2 activator. We further verified that sesamol directly activated the Nrf2-mediated transcription. In addition, the <i>Hmox1</i> and <i>Ucp1</i> induction by sesamol was compromised in Nrf2-deleted cells, indicating the necessity of Nrf2 in the sesamol-mediated <i>Ucp1</i> induction. Together, these findings demonstrate the effects of sesamol in inducing <i>Ucp1</i> and in increasing energy expenditure, further highlighting the use of the Nrf2 activation in stimulating thermogenic adipocytes and in increasing energy expenditure in obesity and its related metabolic diseases.