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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE347045 | GEO | 2026/09/16

REPOSITORIES: GEO

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Project description:This study aimed to quantify the regulation of transcripts in the hairy skin of the back of adult rats in the condition of loss of sensory and autonomic (sympathetic) innervation (i.e., denervated). Denervated skin has reduced wound healing capacity, reduced proliferation of epidermal progenitor cells, and also expresses factors that regulate ingrowth of sensory and sympathetic axons from neighboring regions of innervated skin. It was expected that this quantification f transcript regulation would offer insight into the general and specific mechanisms that may contribute to these important biological processes. All animals were adult (200-250g) Sprague-Dawley female rats. Three conditions were examined. Groups were naive (n=6), 7-day denervated skin (n=5), and 14-day (n=5) denervated skin. Denervation preparations: Full-thickness incision along long-axis of the body 1cm to right of midline (to avoid injuring skin to be sampled). Incision was centered rostro-caudally on the T13 (thoracic 13) costo-vertebral angle so as to allow access to the T9-L2 (lumbar 2) cutaneous nerves. Skin was reflected to the left and the left T9, T10, L1, and L2 dorsal and lateral cutaneous nerves were isolated, ligated with 7-0 monofilament suture close to their exit from the body wall, and transected. Approximately 5mm of the distal portion of the nerve was resected. The T11 nerves were left unperturbed and were not isolated from the surrounding fascia. This generated two strips of skin that were devoid of sensory and autonomic innervation (those strips served by the T9 and T10 nerves, and by the L1 and L2 nerves). Between these denervated strips of skin was a strip of skin that retained the sensory and autonomic axons supplied by T11 nerves. The denervated zones were identified by mapping the cutaneous trunk muscle (CTM) reflex (see Petruska-JC et al. (2013) Journal of Comparative Neurology; Diamond-J et al., (1992) J Neuroscience), and the border marked with pen and remarked every few days. The samples were taken from the rostral (T9/10) denervated zone. Samples from naive animals (no denervation) were taken from the same region, using the dorsal cutaneous nerves as registration landmarks. Animals displayed no signs of overgrooming of the denervated skin. Because the CTM inserts onto the dermis of this region of skin, samples necessarily include both skin and underlying CTM (which is innervated from another source so was not denervated in the experiment).

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

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