The study shows that mice lacking the SCD1 gene (stearoyl-CoA desaturase-1) are resistant to diet-induced obesity, have increased insulin sensitivity, and exhibit higher energy expenditure. SCD1 is a key enzyme in the synthesis of monounsaturated fatty acids, including oleate and palmitoleate, which are essential for lipid storage and membrane composition. In SCD1-deficient mice, lipid oxidation genes are up-regulated, while lipid synthesis genes are down-regulated, leading to reduced triglyceride synthesis and storage. These mice also show increased plasma ketone bodies and reduced insulin and leptin levels. Despite increased food intake, SCD1-deficient mice are leaner and accumulate less fat, suggesting that SCD1 deficiency enhances fat oxidation and reduces lipid storage. The increased metabolic rate and lipid oxidation in SCD1-deficient mice are associated with the activation of the PPARα pathway, which promotes fatty acid β-oxidation. Additionally, the reduced expression of SREBP-1, a key regulator of lipid synthesis, further contributes to the decreased lipid storage in these mice. The findings suggest that SCD1 is a critical regulator of lipid metabolism and that its deficiency can lead to improved insulin sensitivity and resistance to obesity. The study also indicates that SCD1 may act downstream of leptin signaling, as SCD1-deficient mice have lower leptin levels but still show increased insulin sensitivity. These results highlight the potential of SCD1 as a therapeutic target for metabolic disorders associated with the metabolic syndrome.The study shows that mice lacking the SCD1 gene (stearoyl-CoA desaturase-1) are resistant to diet-induced obesity, have increased insulin sensitivity, and exhibit higher energy expenditure. SCD1 is a key enzyme in the synthesis of monounsaturated fatty acids, including oleate and palmitoleate, which are essential for lipid storage and membrane composition. In SCD1-deficient mice, lipid oxidation genes are up-regulated, while lipid synthesis genes are down-regulated, leading to reduced triglyceride synthesis and storage. These mice also show increased plasma ketone bodies and reduced insulin and leptin levels. Despite increased food intake, SCD1-deficient mice are leaner and accumulate less fat, suggesting that SCD1 deficiency enhances fat oxidation and reduces lipid storage. The increased metabolic rate and lipid oxidation in SCD1-deficient mice are associated with the activation of the PPARα pathway, which promotes fatty acid β-oxidation. Additionally, the reduced expression of SREBP-1, a key regulator of lipid synthesis, further contributes to the decreased lipid storage in these mice. The findings suggest that SCD1 is a critical regulator of lipid metabolism and that its deficiency can lead to improved insulin sensitivity and resistance to obesity. The study also indicates that SCD1 may act downstream of leptin signaling, as SCD1-deficient mice have lower leptin levels but still show increased insulin sensitivity. These results highlight the potential of SCD1 as a therapeutic target for metabolic disorders associated with the metabolic syndrome.