Adiponectin modulates the diurnal hepatic transcriptome and energy metabolism in male mice

Adiponectin is an adipocyte-derived hormone with insulin-sensitizing and lipid-lowering effects. Its expression and circulating levels show pronounced variation across the day, which opens the possibility that adiponectin influences metabolic programs in target tissues, such as the liver in a time-of-day dependent manner. To test this, we compared liver circadian transcriptome profiles (with sampling at 4-h intervals) between adiponectin-deficient (ADQ-KO) and wild-type (ADQ-WT) mice. Adiponectin loss led to tonic (i.e. time-independent) transcriptional changes in the liver with 1,393 differentially expressed genes (518 up- and 875 downregulated). These included upregulation of chromatin and RNA processing pathways and downregulation of immune and mitochondrial metabolic genes. At the same time, circadian analysis identified a marked reprogramming of transcriptome rhythms in ADQ-KO livers with changes in MESOR (n = 3,369 transcripts), amplitude (n = 386), and phase of gene expression (n = 603). Genes associated with mitochondrial respiration and fatty acid metabolism showed reduced rhythm amplitude and MESOR, whereas glycolytic genes exhibited increased MESOR. One of the identified adiponectin candidate targets and a regulator of hepatic metabolism, Hif1a, was further studied by functional assays in murine hepatocytes. Pharmacological adiponectin receptor activation promoted glycolysis and mitochondrial respiration under normoxia, but these effects were attenuated under hypoxia mimicry, consistent with HIF1a-dependent interference. These findings suggest adiponectin as a regulator of liver circadian metabolism, modulating both the timing and magnitude of energy-related gene expression programs, potentially in part through a HIF1a-mediated mechanism.