The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO mice fed a chow diet exhibited decreased mRNA expression of ratelimiting enzymes in several important glucose and lipid metabolic pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid activation and synthesis, triglyceride synthesis, and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weight compared with WT mice. When fed a high-fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the liver. These lipogenic defects are consistent with the down-regulation of lipogenic genes in the KO mice.hepatic metabolism | lipogenesis | transcriptional regulation A dipose tissue regulates energy homeostasis by secreting cytokines known as adipokines. Adiponectin, the most abundant adipokine in the serum, modulates lipid and glucose metabolism, including promotion of fatty acid oxidation and glucose utilization and repression of hepatic gluconeogenesis (1, 2). Several lines of adiponectin knockout (KO) or transgenic (Tg) mice have been generated in different laboratories (3, 4). Although the phenotypes reported are variable in some aspects, these mouse models all demonstrate that adiponectin deficiency predisposed mice to high-fat-diet (HFD)-induced insulin resistance (3-5). It was proposed that adiponectin is required to maintain a basal tone of insulin responsiveness (5). However, the way in which the basal tone of insulin responsiveness is established and how adiponectin maintains insulin sensitivity remain largely unknown.Adiponectin is present in plasma at extremely high concentrations (2-10 μg/mL), in contrast to that of insulin, glucagon, and leptin, which are found at orders-of-magnitude smaller concentrations. Moreover, most metabolic hormones are released into the blood in a regulated pulsatile fashion (6); this process allows the insulin's actions to respond to nutritional signals following meals or for glucagon to increase hepatic glucose output during hypoglycemia. In contrast, the blood levels of adiponectin are strikingly constant, making adiponectin a less-sensitive regulator in response to the acute changes in glucose and lipid levels following food intake or deprivation. We therefore hypothesize that adiponectin primarily regulates glucose and lipid metabolism at transcriptional levels besides its well described role that involves AMP-activated protein kinase (AMPK).To test this hypothesis, we profiled hepatic gene expression in both wild-type (WT) and adiponectin KO mice fed a standard chow diet by high-throughput RNA sequencing (RNA-Seq). ...