The main findings of our study are as follows: (1) Olfr734 levels in the liver may serve as a sensor of nutrient and glucose availability; (2) Olfr734 knockdown in the liver exacerbates MASLD and increases hepatic glucose production in DIO mice; (3) the effects of Olfr734 knockdown in the liver inhibit the Sirt1/ER stress pathway; and (4) the hepatic levels of Olfr734 are upregulated in patients with T2DM in a sex-dependent manner. This evidence concerns the gene OR4M1 and metabolic dysfunction-associated steatotic liver disease.