Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue

Area of Science:

• Immunology
• Metabolic Physiology
• Neuroendocrinology

Background:

• White adipose tissue (WAT) beiging, a process of thermogenesis, is linked to M2-like macrophages.
• The precise mechanisms by which M2-like macrophages influence WAT beiging remain unclear.

Purpose of the Study:

• To elucidate the role of macrophage-secreted factors in mediating the effects of M2-like macrophages on WAT beiging and cold adaptation.
• To identify novel signaling pathways involved in thermogenesis and adipose tissue homeostasis.

Main Methods:

• Transcriptomic analysis of M2-like macrophages in murine inguinal WAT (iWAT) following cold exposure.
• Investigated the interaction of macrophage cytokine Slit3 with the ROBO1 receptor on sympathetic neurons.
• Assessed the impact of Slit3 on Ca2+/calmodulin-dependent protein kinase II signaling and norepinephrine release.
• Utilized adoptive transfer of Slit3-overexpressing M2 macrophages and CRISPR-Cas9 gene editing to study Slit3 function in vivo.

Main Results:

• Identified Slit3 as a key secreted cytokine from adipose tissue macrophages (ATMs) that promotes cold adaptation.
• Demonstrated that Slit3 binds to ROBO1 on sympathetic neurons, enhancing norepinephrine release and adipocyte thermogenesis.
• Showed that Slit3 overexpression in M2 macrophages promotes beiging and thermogenesis.
• Mice lacking Slit3 in myeloid cells exhibited cold intolerance and increased weight gain.

Conclusions:

• Uncovered a novel macrophage-Slit3-sympathetic neuron-adipocyte signaling axis regulating long-term cold adaptation.
• Established the integral role of M2-like macrophages and Slit3 in maintaining adipose tissue homeostasis and energy expenditure.
• Provides new therapeutic targets for metabolic disorders related to cold adaptation and obesity.