The major findings are as follows: (i) RGS5 deletion increases dyslipidemia, obesity, adipose tissue deposition, hepatic steatosis and circulating inflammation; (ii) RGS5 deletion exacerbates inflammation and activates the JNK and NF-κB inflammatory signaling pathways in the adipose tissue, liver and skeletal muscle when mice are fed an HF; (iii) RGS5 deficiency results in decreased systemic insulin sensitivity accompanied by weakened Akt/GSK3β signaling in the adipose tissue, liver and skeletal muscle when mice are fed an HF. Here, RGS5 is linked to fatty liver disease.