Hypothalamic AgRP‐mediated energy metabolism in skeletal muscle is a critical regulatory system in feeding rhythm‐induced insulin resistance

Abstract

Hypothalamic control of peripheral energy metabolism is an important regulatory system in whole body energy homeostasis, although whether feeding rhythm affect the hypothalamic regulation system of energy metabolism has not elucidated. In this study C57BL/6J mice were separated for 3 feeding scheduled groups; given lab chows freely during dark phase (ZT12‐24; Control group), first 4‐hour in dark phase (ZT12‐16; Morning group), and last 4‐hour in dark phase (ZT20‐24; Evening group) for 8weeks. Mice in Evening group showed impaired whole body insulin sensitivity while mice in Morning group showed normal insulin sensitivity compared to Control group. We observed that higher lipid accumulation and impaired insulin signals in skeletal muscle in Evening group compared to other group. On the other hand, mRNA expression of agouti‐related protein (AgRP) was increased in hypothalamus in Evening group. We found that intracerebroventricular injection of AgRP increased gene expression of lipid accumulation in skeletal muscle of mice in Control group. Inhibition of central AgRP expression by antisense oligo improved insulin resistance in skeletal muscle of Evening group. These results indicate that usual energy ingestion mainly after the evening impairs insulin sensitivity in skeletal muscle mediated by hypothalamic AgRP.