Ret finger protein (RFP, also known as TRIM27) is a multifunctional E3 ubiquitin ligase implicated in transcriptional regulation. While previously reported to repress myogenesis, its role in adipose tissue metabolism remains unclear. Here, using both global and adipocyte-specific RFP-knockout male mice subjected to high-fat diet feeding, we found that RFP deficiency markedly attenuated body weight gain, adipose tissue expansion and adipocyte hypertrophy, while improving glucose tolerance, insulin sensitivity and circulating lipid profiles. Indirect calorimetry demonstrated significantly increased whole-body energy expenditure, independent of food intake or physical activity. Consistent with these murine findings, RFP expression was elevated in omental adipose tissue from obese human subjects, underscoring the translational relevance. Mechanistic studies revealed that RFP physically interacts with PPAR-γ and enhances its transcriptional activity, thereby promoting expression of adipogenic target genes such as AP2 and adiponectin. Loss of RFP suppressed adipocyte differentiation both in vivo and in vitro. Collectively, our findings identify RFP as a positive regulator of adipogenesis and systemic metabolism via PPAR-γ activation. Genetic ablation of RFP confers resistance to high-fat diet-induced obesity, suggesting that targeting RFP may represent a potential therapeutic strategy for obesity and related metabolic disorders.