Updated project metadata. Both epidemiological data and scientific reports corroborate the higher incidence of neuropathy and chronic pain in female gender not only in patients with metabolic disorders but also in normometabolic subjects and in murine models. Our previous results showed different immune and neuroimmune response to neuropathic pain (NeP) between male and female mice as well as a different metabolic pattern in proteins expressed in sciatic nerve. Here, we provide evidence that adipose tissue (AT) plays a contributing role in sex-dependent differences before and after peripheral nerve injury-induced NeP in mice. The metabolic parameters assessed, the metabolic profile signature (metabolomics), the energy expenditure evaluation, the AT proteomic analysis and the adipokines mobilization reveal a sex-specific AT response to peripheral nerve damage. Of interest, an alteration of lipolysis and fatty acids oxidation (FAO) emerges in females as well as an enhancement of whole-body energy expenditure and higher secretion of sex hormones from AT, affecting glucose and insulin metabolism. On the contrary, neuropathy in males induced an engagement of glycolysis pathway, a decrease of systemic energy expenditure and unsaturated fattyacids levels. In males, AT responds favoring molecules useful in regenerative processes and in the oxidative stress, as well as stimulating peroxisome proliferator activated receptors (PPARs) gamma subtype (PPAR-γ) and adiponectin. This study discloses new factors underlying the higher susceptibility of female sex to NeP, indicating in AT a crucial player for the regulation of sex-dependent inflammatory and metabolic response to nerve lesion.