Characterization of Visceral Adipose Tissue Browning: Driving Stimuli and Cellular Heterogeneity

Diplôme Thèse Characterization of Visceral Adipose Tissue Browning: Driving Stimuli and Cellular Heterogeneity eng 2025-09-30 2025-09-30 author Arsovic Aleksandar 0000-0002-3262-9757 942879 Département de physiologie cellulaire et métabolisme (PHYME) director Trajkovski Mirko 0000-0002-3152-9551 810468 Département de physiologie cellulaire et métabolisme (PHYME) 138 10.13097/archive-ouverte/unige:189567 urn:nbn:ch:unige-1895674 Sc. Vie - Bioméd. 367 Extensive visceral adipose tissue (VAT) accumulation increases the risk of developing metabolic and cardiovascular diseases. The ability of adipose tissue to combust energy through non-shivering thermogenesis is viewed as a beneficial mechanism to counteract these severe metabolic issues. Yet, efforts to activate a thermogenic program in VAT remain elusive and limited to transgenic interventions or drastic temperature alterations. Here, we report extensive activation of VAT thermogenesis by exposing microbiota-depleted mice to cold. These mice exhibited a drastic reduction in visceral and overall adiposity, accompanied by improved respiration capacity and insulin sensitivity. The VAT displayed a multilocular morphology with a thermogenic program that was independent of UCP1 and alternatively differentiated macrophages. Combining adipocyte lineage tracing with snRNA-seq and spatial transcriptomics revealed a subset of adipocytes originating from existing mature adipocytes, which use a distinct, noncanonical thermogenesis process based on futile cycles. The functional remodeling of the VAT is driven by an increased sympathetic tonus, evidenced by increased systemic and local norepinephrine (NE) levels, along with the denser sympathetic nerve network in the VAT. Mechanistically, VAT of Cax mice shows consistent upregulation of Elovl3, a gene involved in the production and degradation of long and very long chain fatty acids. Tissue-restricted pgVAT Elovl3 deletion led to an increase in pgVAT mass during Cax treatment, coupled to a decrease in some of the common browning markers. Systemic depletion of Ucp-1-expressing cells in brown and subcutaneous adipose tissue (BAT and SAT, respectively) during cold led to a profound increase in VAT browning, indicating that VAT acts as a third line of defense that ensures thermogenic homeostasis. These findings reveal previously underexplored aspects of VAT and uncover a unique plasticity of this type of fat, opening a window for new therapeutic solutions in preventing and treating obesity. Visceral adipose tissue Obesity Thermogenesis Browning Futile cycle Optical projection tomography snRNA-seq Spatial transcriptomics CRISPR Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 724 Laboratory of metabolic diseases 934 ad3ea103-becc-4412-9537-a5085fc04769 Thesis Public AArsovic_Thesis.pdf 8186398 application/pdf 7ad990f9c656979c088cacf61b66bc62a320f30b88718c4cd102bc783ced0c01 c0e0ee34-ed07-443d-866e-3123aace0e14 Imprimatur Public Imprimatur_Aleksandar_Arsovic.pdf 180068 application/pdf 8754d6ebebc4e3ca23d5ae7f1bab797896e7940f47878e58cbbe2084701b616f openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Characterization of Visceral Adipose Tissue Browning: Driving Stimuli and Cellular Heterogeneity				2025	163	39

Archive ouverte UNIGE

Arsovic, Aleksandar

account_balance Affiliation entities

Research groups

Affiliation entities