Sulforaphene‐Enriched <i>Raphanus sativus L.</i> 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.