The HMGI family of proteins consists of three members 1, 2, HMGIC, HMGI and HMGI (Y), that function as architectural factors 3, 4, 5 and are essential components of the enhancesome 6, 7. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues 8, 9. It is disrupted and misexpressed in a number of mesenchymal tumour cell types 10, 11, 12, including fat-cell tumours 12 (lipomas). In addition Hmgic–/–mice have a deficiency in fat tissue 13. To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice. Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lep ob/Lep ob) in a gene-dose–dependent manner. Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity.