Effects of 6‐ OHDA ‐Mediated Chemical Denervation of Sympathetic Axons in Inguinal Subcutaneous White Adipose Tissue

AIMS: White adipose tissue (WAT) innervation by sensory and sympathetic axons contributes to tissue functions, but the consequences of selectively disrupting sympathetic input to WAT remain incompletely defined. MATERIALS AND METHODS: We utilised 6-hydroxydopamine (6-OHDA) as a validated approach to achieve bilateral sympathetic denervation of mouse inguinal subcutaneous WAT (ing-scWAT) and investigated impacts on adipose and whole-body metabolism. RESULTS: Sympathetic denervation did not impact body weight or adipose mass by 16 days post-denervation but significantly altered energy expenditure. Sympathetic denervation increased both sensory neuropeptide levels and sensory innervation at 7 days, which may explain the minimal whole-body impacts, since sensory nerves can contribute to many of the same metabolic processes as sympathetic nerves in adipose. In acute studies, intra-ing-scWAT norepinephrine delivery increased calcitonin gene related peptide (CGRP) levels in the depot, while CGRP administration reduced norepinephrine levels, underscoring previous reports of nerve cross talk at the tissue level. Multi-omics profiling of sympathetically denervated ing-scWAT revealed selective remodelling of lipid signalling pathways, including accumulation of polyunsaturated fatty acid-derived oxylipins from the cytochrome P450 pathway, alongside perturbations in tricarboxylic acid cycle metabolism. These changes were distinct from CL316,243 treatment. Single-nuclei transcriptomics identified cell-type-specific re-programming, including altered oxidative phosphorylation and lipid metabolic pathways in adipocytes and increased immune cell representation with sympathetic denervation. CONCLUSIONS: Together, these data demonstrate that sympathetic denervation of scWAT induces coordinated metabolic, lipidomic, and transcriptional changes in the tissue as well as alterations to energy balance. Nerve crosstalk and potential compensation by sensory axons may help explain the findings.