The cholesterol transporter Abcg1, a candidate gene for obesity: deletion of Abcg1 in mice corrects diet-induced insulin resistance

Metabolic diseases affecting the energy homeostasis such as obesity, the metabolic syndrome and type-2 diabetes are determined by genetic and environmental factors. Genomic approaches, e.g. large scale gene expression analysis and human genome scans for susceptibility genes have led to the identification of several candidate genes and candidate drug targets for the metabolic syndrome. For the identification of additional obesity genes we compared results of two genome wide screenings performed in Drosophila melanogaster and in a polygenic obesity mouse model, the New Zealand obese (NZO) mouse. By correlation of both screenings, we identified the ATP-binding cassette transporter G1 (ABCG1) which catalyzes export of cellular cholesterol. An insertion of EP-elements upstream of CG17646, the Drosophila ortholog of the mammalian Abcg1 led to an increased triglyceride content in the flies. NZO mice carry an Abcg1 variant with an altered sequence in a regulative intron which might be responsible for a higher expression in white adipose tissue of the NZO mouse compared to that of lean mouse strains. Targeted disruption of the Abcg1 gene in mice reduced gain in body weight over a period of 12 weeks (wild type, 13.1±1.1g; knockout, 8.42±0.6g) and in adipose tissue depots (wild type, 9.39±1.6g; knockout, 3.78±1.3g) under high-fat diet conditions due to decreased size of adipocytes. Abcg1^-/- mice are protected against high-fat diet-induced impairment of glucose tolerance and fatty liver. Decreased food intake and elevated total energy expenditure (Abcg1^+/+ mice: 684.3±5.0; Abcg1^-/- mice 748.1±5.4 kJ/kg metabolic body mass; p=0.011), body temperature (Abcg1^-/- mice, 33.9±0.1°C; Abcg1^-/- mice, 34.6±0.3°C; p<0.05), and locomotor activity (Abcg1^+/+ mice: 2445±235; Abcg1^-/- mice, 3655±189 counts/12h during dark phase; p<0.01) appear to cause decreased adiposity in Abcg1^-/- mice. Increased expression of hormone sensitive lipase, perilipin and several fat-specific genes (e.g. PPARgamma, adiponectin) and decreased plasma levels of free fatty acids after fasting suggest an enhanced lipolysis. Our data indicate a previously unrecognized role of ABCG1 in the regulation of energy balance and triglyceride storage.