Brown adipose tissue involution associated with progressive restriction in progenitor competence

Area of Science:

• Adipose tissue biology
• Cellular and molecular mechanisms
• Developmental biology

Background:

• Human brown adipose tissue (BAT) undergoes involution, a process not recapitulated in rodents, leaving its mechanisms poorly understood.
• Understanding BAT involution is crucial for metabolic health research.

Purpose of the Study:

• To investigate the mechanisms underlying BAT involution, focusing on progenitor cell function.
• To identify key molecular regulators involved in BAT homeostasis and involution.

Main Methods:

• Comparative transcriptomic analysis of interscapular BAT (iBAT) in rabbits, humans, and mice.
• Single-cell RNA sequencing of iBAT progenitors.
• Genetic manipulation in mice to assess the role of FSTL1 in BAT involution.

Main Results:

• Rabbit iBAT exhibits rapid whitening during early adulthood, mirroring human involution.
• FSTL1 is highly expressed in rabbit and human iBAT progenitors but downregulated during involution.
• Reduced FSTL1 expression leads to progenitor functional incompetence and prevents brown adipocyte recruitment.
• Constitutive FSTL1 expression in mouse iBAT sustains WNT signaling and prevents involution.
• Fstl1 gene deletion or progenitor ablation in mice induces iBAT paucity and progenitor incompetence.

Conclusions:

• The study highlights the critical role of FSTL1 in maintaining BAT progenitor function and preventing involution.
• Functional incompetence of FSTL1-expressing progenitors is implicated as a key driver of BAT involution.
• Findings reveal insights into the hierarchy and dynamics of the BAT progenitor compartment.