Bmal2 is a biological clock gene. In an article published in
Metabolism, scientists show that mice with the
Bmal2 gene inactivated exhibit significant weight gain and increased inflammation in the liver and adipose tissue. Fat accumulation in the liver is associated with a loss of storage in white adipose tissue. These results show that the BMAL2 protein acts as a protector of metabolism against obesity.
Obesity is often associated with a disruption of circadian rhythms, particularly those of sleep and eating. This disturbance promotes metabolic complications such as type 2 diabetes.
Among the players in the circadian system, BMAL2, a transcription factor, is already known to be associated with obesity and diabetes in humans. However, its precise role in adipose tissue remained poorly understood.
The objective of the work, published in the journal
Metabolism, was to study the influence of the
Bmal2 gene on inflammation and the metabolic adaptation of white adipose tissue during obesity, using mice lacking this gene (
Bmal2-/-).
For this purpose, the scientists used
Bmal2-/- mice and wild-type (WT) controls fed either a normal diet or a high-fat diet.
The key results are as follows:
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Weight gain and fat distribution: Under a high-fat diet,
Bmal2-/- mice show increased weight gain with fat accumulation in the liver (hepatic steatosis). A decrease in storage in visceral adipose tissue is observed, but an increase in subcutaneous tissue.
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Insulin resistance: These same mice develop glucose intolerance and insulin resistance, associated with decreased activation of the PI3K/AKT/mTOR signaling pathway, which is an important intracellular signaling pathway in the regulation of the cell cycle in the liver and adipose tissue.
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Inflammation: They show a strong increase in pro-inflammatory cytokines (TNF-α, IL-6) in the liver, mature adipocytes, and adipose progenitors. The liver also shows increased infiltration of CD8
+ T lymphocytes.
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Alteration of adipose progenitors: Adipose tissue progenitor cells lose their cellular identity, show a decrease in their proliferation capacity, and activate pro-inflammatory and pro-apoptotic transcriptional programs.
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Circadian rhythm: The rhythmic expression of the TNF-α gene is altered in adipose tissue, illustrating a direct link between the biological clock and inflammation.
BMAL2 appears as a key regulator of the immuno-metabolic balance and is an essential regulator of the immuno-metabolic balance of adipose tissue. Its loss leads to chronic inflammation, a reduction in the lipid storage capacity of visceral adipose tissue, and ectopic fat accumulation in the liver, promoting insulin resistance.
This work reveals the importance of circadian clock genes in the pathophysiology of obesity and suggests that targeting BMAL2 could constitute a new therapeutic target to prevent or treat metabolic complications related to obesity.