Heart‐Specific Disruption of Bmal1 Leads to Hepatic Insulin Resistance in Mice

Abstract

Daily balance of glucose metabolism is closely coupled with the function of the circadian clock in mammals. The molecular clock composed of a series of circadian clock genes resides in nearly all cells throughout the body, including cells in both metabolic and non‐metabolic tissues. Disruption of the molecular clock in metabolic tissues such as pancreas was shown to induce glucose intolerance. However, it remains unknown whether the clock in non‐metabolic tissues also plays an important role in maintaining systemic glucose metabolism. By studying mice with heart‐specific deletion of Bmal1, a core circadian clock gene, we demonstrate that clock function in the heart has a great influence on glucose tolerance. Heart‐specific disruption of Bmal1 not only results in a reduction in cardiac function but induces a significant increase in the blood glucose level in an age‐dependent manner. In addition, the insulin tolerance test reveals a decrease in insulin sensitivity in heart‐specific Bmal1 deficient mice, indicating that the increase in the blood glucose level observed in these mice is at least in part due to systemic insulin resistance. Importantly, the levels of mRNA expression of gluconeogenic genes in the liver of heart‐specific Bmal1 deficient animals are not suppressed by systemic administration of insulin, indicating that disruption of the molecular clock in the heart can induce hepatic insulin resistance. Taken together, our results suggest that, in addition to the clock function in major metabolic tissues, the function of the heart clock also has an impact on systemic glucose metabolism by altering hepatic insulin sensitivity.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Number 25460316 and the Takeda Science Foundation.