CCAAT/enhancer-binding proteins, C/EBPα and C/EBPβ, are required for fat cell differentiation and maturation. Previous studies showed that replacement of C/EBPα with C/EBPβ, generating the β/β alleles in the mouse genome, prevents lipid accumulation in white adipose tissue (WAT). In this study, β/β mice lived longer and had higher energy expenditure than their control littermates due to increased WAT energy oxidation. The WAT of β/β mice was enriched with metabolically active, thermogenic mitochondria known for energy burning. The β/β allele exerted its effect through the elevated expression of the G protein α stimulatory subunit (Gα_s) in WAT. Gα_s, when overexpressed in fat-laden 3T3-L1 cells, stimulated mitochondrial biogenesis similar to that seen in the WAT of β/β mice, and effectively diminished the stored lipid pool.