Circulating Exosomal miRNAs Signal Circadian Misalignment to Peripheral Metabolic Tissues.

Area of Science:

• Chronobiology
• Metabolic Health
• Cellular Communication

Background:

• Night shift work is linked to increased risk of metabolic disorders like obesity and insulin resistance.
• The precise mechanisms driving these metabolic disturbances due to circadian misalignment are not fully understood.
• Exosome-mediated intercellular communication is a potential pathway for transmitting circadian misalignment signals.

Purpose of the Study:

• To investigate the role of exosomes and their cargo in mediating metabolic dysfunction caused by simulated night shift work.
• To identify specific molecular changes in exosomes and their impact on peripheral tissues, such as adipocytes.

Main Methods:

• Simulated day shift (DS) and night shift (NS) conditions for 14 volunteers.
• Plasma exosome isolation and subsequent treatment of naïve adipocytes.
• Assessment of insulin-induced Akt phosphorylation.
• ChIP-Seq for BMAL1, mRNA microarrays, and exosomal miRNA arrays.
• Bioinformatic analysis and functional validation using agomirs/antagomirs.

Main Results:

• Exosomes from NS conditions altered insulin-induced Akt phosphorylation in adipocytes compared to DS.
• BMAL1 binding sites were significantly reduced in adipocytes treated with NS exosomes, affecting metabolic regulator genes.
• A distinct exosomal microRNA signature was identified in the NS condition, with hsa-mir-3614-5p implicated in circadian misalignment signaling.
• NS exosomes altered core clock gene expression in adipocytes, myocytes, and hepatocytes.

Conclusions:

• Simulated night shift work alters circulating exosomal cargo.
• These exosomal changes reduce adipocyte insulin sensitivity in vitro and disrupt peripheral tissue clock gene expression.
• Circulating exosomal microRNAs serve as key messengers of circadian misalignment, contributing to metabolic dysfunction in night shift workers.