Semaphorin 7A regulates axon outgrowth in subcutaneous white adipose tissue

Adipose tissue innervation is critical for regulating lipolysis, adipogenesis, and thermogenesis, yet the mechanisms that establish and maintain these neural networks remain poorly understood. Semaphorin 7A (Sema7A), a well-characterized axon guidance and neuroimmune signaling molecule that is highly expressed in adipose tissue. Sema7A regulates adipocyte metabolic processes, including lipid accumulation and thermogenic gene expression, via Integrin β1 signaling. However, its potential role in shaping adipose tissue innervation and coordinating neural–metabolic communication has not been explored. In this study, we investigated a knockout of Sema7A in mice, and influences on adipose tissue innervation and metabolic regulation during postnatal development and in adulthood, both under baseline conditions and following cold exposure, a potent activator of sympathetic nerve activity and axonal remodeling in scWAT. Deletion of Sema7A increased adiposity at postnatal day 21, marked by enlarged subcutaneous and brown adipose depots and reduced lipolytic enzyme expression. Tyrosine hydroxylase-expressing (TH+), and calcitonin gene-related peptide-expressing (CGRP+) innervation was markedly reduced, indicating dysregulated neuro-adipose communication. Plexin C1, a receptor for Sema7A, was strongly expressed on subcutaneous adipose axons, suggesting direct signaling to support neuronal growth. In adulthood, Sema7A-deficient mice displayed normal metabolic responses to cold exposure but failed to mount the typical increase in sympathetic axon outgrowth within beige regions of scWAT. Together, these findings identify Sema7A as a critical mediator of adipose neural development and remodeling, required for establishing and maintaining proper innervation and metabolic function. • Sema7A KO increased adiposity and reduced lipolytic signaling at P21. • Sema7A KO reduced adipose tissue innervation at P21. • PLXNC1, a receptor for Sema7A, is expressed on axons within adipose tissue. • Cold-induced sympathetic axon outgrowth is blunted in Sema7A KO. • Sema7A is required for developmental and adaptive adipose innervation.