Sulforaphene-Enriched Raphanus sativus L. Seed Extract Promotes Norepinephrine-Induced Thermogenesis and Weight Loss by Modulating the Interplay Between Adipocytes and Immune Cells in Adipose Tissue.

Adipose tissue (AT) cells, including adipocytes, immune cells, and macrophages, interact in obesity-related metabolic syndromes. Understanding these interactions is important to develop therapeutic agents. Sulforaphene-enriched radish seed extract (RSE) has shown potent anti-obesity effects on adipocytes. We investigated RSE's potential in preventing metabolic diseases by exploring AT cell interactions at the transcriptomics level. We investigated RSE's effects on C57BL/6J mice fed a high-fat diet (HFD). Metabolic cage experiments evaluated thermogenesis and norepinephrine (NE) levels in AT were measured. Transcriptomic analysis by RNA-sequencing, gene ontology (GO) enrichment, and CIBERSORTx analysis were conducted to identify RSE's mechanisms, with validation via qRT-PCR and Western blot assays. RSE (2.0% (w/w)) significantly reduced body weight by 14.5% and fat mass by 35.8% compared to the HFD group, while increasing rectal temperatures, energy expenditure, and VO2 consumption. It increased NE levels and enhanced NE-induced thermogenic gene expressions in AT through β-adrenergic receptor signaling. GO enrichment analysis showed that RSE predominantly down-regulated immune-related pathways, including leukocyte migration, activation, proliferation, and cytokine production. CIBERSORTx analysis showed a 47.3% reduction in immune cell-related gene expression (Absolute score), particularly associated with macrophages, in the RSE group. Histological analysis further demonstrated a 52.4% decrease in crown-like structures, related to the recruitment of M1 and lipid-associated macrophages (LAMs). Moreover, RSE modulated genes involved in NE clearance that interact with sympathetic neuron-associated macrophages (SAMs), suggesting a role in regulating thermogenic signaling within AT. RSE mitigated HFD-induced obesity by attenuating AT dysfunction and increasing NE-induced thermogenesis. These effects were associated with changes in AT immune cell composition, particularly reduced LAMs and SAMs, down-regulating inflammation and NE clearance. These findings suggest that RSE exerts anti-obesity efficacy by modulating specific macrophage-adipocyte interactions in AT, highlighting its potential role as a natural anti-inflammatory and thermogenic agent.