Ablation of cholesterol transporter ABCG1 in mice reduces adipose cell size and corrects diet-induced insulin resistance

Introduction: The aim of our study was to identify obesity genes as targets for the treatment of the metabolic syndrome. We performed two genome wide screenings, a random mutagenesis in Drosophila melanogaster and a QTL analysis in a polygenic obesity mouse model, the New Zealand obese (NZO) mouse. By comparing the results of these two screenings we identified several putative candidates. Methods: EP-element-bearing Drosophila melanogaster flies were generated and screened for their triglyceride content. Via this technique we identified 200 candidate genes which alter fat accumulation in the flies. One of the identified candidates was ATP-binding cassette transporter G1 (ABCG1) which catalyzes export of cellular cholesterol. To analyze the in vivo-function of ABCG1 we deleted the Abcg1 gene in mice by targeted disruption. We analyzed the metabolic phenotype of this mouse by monitoring body composition, feeding behavior, locomotor activity, total energy expenditure, and body temperature under standard and high-fat diet conditions. Furthermore, we analyzed histology of different tissues, glucose tolerance, expression of different metabolic relevant genes, and blood plasma parameters under fed and fasted conditions. Results: In Drosophila melanogaster an insertion of EP-elements upstream of CG17646 leads to flies with increased triglyceride stores. CG17646 is a Drosophila ortholog of the mammalian ABCG1. NZO mice carry a variant with an altered sequence in a putative promoter region which might be responsible for a higher expression in white adipose tissue of the NZO mouse compared to that of lean mouse strains. Deletion of the Abcg1 gene in mice reduced body weight gain (wildtype, 13.07g±1.11g; knockout, 8.42g±0.62g) and fat mass gain (wildtype, 9.39g±1.59; knockout, 3.78g±1.31 g) over 12 weeks under high-fat diet conditions, due to increased energy expenditure, body temperature and locomotor activity. Abcg1 ^-/- mice are protected against high-fat diet-induced insulin resistance, fat accumulation in liver, and have markedly decreased size of adipocytes. 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. Conclusion: Reduced adipose mass of Abcg1 ^-/- mice appears to be due to an enhanced lipolysis which might be utilized for heat production and thus protect against obesity. Our data demonstrate that ABCG1 is involved in adipocyte function and a putative regulator of adipocity.