Intermittent fasting promotes remodeling of neural and vascular networks in visceral white adipose tissue.

Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional imaging, we find that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals the upregulation of neurotrophic factors, including neuregulin 4 (Nrg4), and browning-associated gene programs. WAT explants from IF-treated mice promote neurite branching in SH-SY5Y neuron-like cells, an effect blunted by ErbB inhibition. In vivo ErbB inhibition further attenuates IF-induced sympathetic remodeling. Human visceral adipose RNA-seq analysis shows a strong positive correlation between NRG4 expression and browning gene signatures. These findings support NRG4-ErbB signaling as a contributor to sympathetic remodeling, linking adipose neurotrophic signaling to metabolic benefits and therapeutic potential in obesity-related disorders.