Focusing on adipose tissue function, this review examines the neuroimmune mechanisms by which sympathetic neurons regulate body weight. Under healthy conditions, anti-inflammatory cues from perineurial barrier cells, mesenchymal cells, and immune cells support sympathetic-adipose communication, in part through the release of neurotrophic factors that sustain local neuronal production of fat-reducing neurotransmitters and neuropeptides such as noradrenaline and neuropeptide Y. In obesity, chronic hyperleptinemia leads to progressive weakening of the sympathetic perineurial barrier, thereby triggering neuroinflammation and sympathetic neuropathy. These effects disrupt local sympathetic signaling to adipose tissue and exacerbate weight gain. Notably, sympathetic neuronal release of neuropeptide Y and tachykinins is essential for brown adipose tissue thermogenesis. Finally, we critically examine shared neuroimmune and immunometabolic mechanisms in obesity and cancer, and we propose that impaired neuroimmunometabolic signaling may contribute to the well-established epidemiological link between these diseases.