MON-683 - Cold Exposure and Β3-Adrenergic Stimulation Activate Brown and White Adipose Tissues Yet Lead to Different Physiological Responses

Brown adipose tissue (BAT) is a key thermogenic organ that contributes to energy expenditure through mitochondrial uncoupling. Both cold exposure and β3-adrenergic receptor (β3-AR) agonists activate human BAT thermogenesis, yet the similarities and differences in the overall physiological responses are incompletely understood while having therapeutic implications. Here, we describe the acute lipidomic, immunologic, and metabolic effects of β3-AR activation compared with cold exposure in healthy adults.
Cohort 1 comprised 12 men (24.7 ± 4.0y; BMI 23.5 ± 1.9 kg*m-2) who received a one-time dose of placebo, 50 mg, or 200 mg mirabegron, and underwent cold exposure on separate days. Cohort 2 consisted of 14 women (27.5 ± 1.1y; BMI of 25.4 ± 1.2 kg*m-2) acutely treated with 100 mg mirabegron. Metabolomics, immunomics, and lipidomics were performed on plasma samples collected before and after each intervention using GC–MS, reversed-phase LC-MS, and HILIC-LC–MS/MS.
Mirabegron induced a broad lipolytic response in both cohorts. Total non-esterified fatty acids (NEFAs) and 6 individual NEFAs showed dose-dependent increases. In contrast, cold exposure produced smaller changes in NEFA but elicited a more extensive inflammatory and angiogenic response, increasing IL-6, Tie-2, ICAM-1, and TARC in a pattern similar to aerobic exercise. Mirabegron showed a more restricted immune profile, decreasing several cytokines while selectively increasing pro-inflammatory IL-23.
Carnitine profiling revealed treatment-induced shifts across acylcarnitines. Several odd-chain acylcarnitines such as tridecanoylcarnitine and glutarylcarnitine decreased in response to cold and in a dose-dependent manner to mirabegron, identifying them as shared markers of thermogenic substrate utilization. Conversely, both stimuli increased hydroxybutyrylcarnitine, consistent with enhanced fatty acid oxidation and increased production of β-hydroxybutyrate. Only mirabegron reduced branched-chain amino acids (BCAAs), and the BAT metabolic activity correlated inversely with plasma isoleucine.
Together, these findings show that β3-AR stimulation and cold exposure activate overlapping yet distinct physiological responses. Mirabegron displayed a more targeted catabolic activation of WAT and BAT, characterized by lipolytic, carnitine, and BCAA responses. In contrast, cold triggered a more extensive immune signaling. Therefore, both cold exposure and mirabegron treatment could be developed to treat obesity-related metabolic disease.

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