Metabolic-sensing of the skeletal muscle clock coordinates fuel oxidation

Hongshan Yin, Weini Li, Somik Chatterjee, Xuekai Xiong, Pradip Saha, Vijay Yechoor, Ke Ma

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Circadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose metabolic pathway, resulting in markedly attenuated glucose utilization and fasting hyperglycemia. Notably, the loss of Bmal1 response to feeding abolished fasting-to-feeding metabolic fuel switch from fatty acids to glucose in skeletal muscle, leading to the activation of energy-sensing pathways for fatty acid oxidation. These altered metabolic substrate oxidations in Bmal1-deficient muscle ultimately depleted circulating lipid levels that prevented hepatic steatosis. Collectively, our findings highlight the key role of the metabolic-sensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis.

Original languageEnglish (US)
Pages (from-to)6613-6627
Number of pages15
JournalFASEB Journal
Volume34
Issue number5
DOIs
StatePublished - Mar 24 2020

Keywords

  • circadian clock
  • fatty acid metabolism
  • glucose metabolism
  • hepatic steatosis
  • skeletal muscle

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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