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Adipose tissue is a pro-active player in sex dependent response to neuropathy

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

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): White Adipose Tissue

DISEASE(S): Chronic Pain

SUBMITTER: Luisa Pieroni

LAB HEAD: Luisa Pieroni

PROVIDER: PXD030391 | Pride | 2023-10-05

REPOSITORIES: Pride

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			Action	DRS
	3_AdiposoFASP_141216.raw.zip	Raw
	3_AdiposoFASP_211216.raw.zip	Raw
	3_AdiposoFASP_211216_B.raw.zip	Raw
	3_AdiposoFASP_211216_C.raw.zip	Raw
	4_AdiposoFASP_141216.raw.zip	Raw

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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].

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Adipose tissue is a pro-active player in sex dependent response to neuropathy

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