title: Down-regulation of PPARα in the spinal cord contributes to augmented peripheral inflammation and inflammatory hyperalgesia in diet-induced obese rats.
abstract: Obesity is associated with augmented peripheral inflammation and pain sensitivity in response to inflammatory stimulation, but the underlying mechanisms remain unclear. Emerging evidence has shown that activation of peroxisome proliferator-activated receptor-α (PPARα) in the central nervous system controls peripheral inflammation and pain. We hypothesized that obesity might down-regulate PPARα in the spinal cord, leading to enhanced peripheral inflammation and inflammatory hyperalgesia. Sprague-Dawley rats fed a high-fat diet (HF) for 12weeks developed metabolic disorder and displayed significantly decreased spinal PPARα expression and activity. Interestingly, intracerebroventricular (ICV) infusion of the PPARα activator palmitoylethanolamide (PEA) in HF-fed rats for 2weeks normalized spinal PPARα expression and activity without altering metabolic parameters. HF-fed rats were more sensitive to stimulation of the inflamed paw, and exhibited more severe paw edema following carrageenan injection, whereas HF-fed rats receiving ICV PEA had similar pain sensitivity and paw edema to LF-fed rats. No difference in the expression of inflammatory mediators or nuclear factor (NF)-κB activity was observed at baseline among groups. Carrageenan induced decreased PPARα expression and activity, increased spinal cord inflammatory mediator expression and NF-κB activity in both LF-and HF-fed rats. However, the increase was more pronounced in HF-fed rats and corrected by PEA. Intrathecal injection of small interfering RNA (siRNA) against PPARα in HF-fed rats completely abolished PEA effects on peripheral pain sensitivity and paw edema. These findings suggest that diet-induced obesity causes down-regulation of spinal PPARα, which facilitates the susceptibility to peripheral inflammatory challenge by increasing inflammatory response in the spinal cord, contributing to augmented peripheral inflammation and inflammatory hyperalgesia in obesity.
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province 250021, China; Department of Pain Management, Qilu Hospital, Shandong University, Jinan City, Shandong Province 250012, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan City, Shandong Province, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The 148th Hospital of People's Liberation Army, Zibo City, Shandong Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province 250021, China. Electronic address: fu-zj@hotmail.com.
authors.forename: Z
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Pain Management, Qilu Hospital, Shandong University, Jinan City, Shandong Province 250012, China. Electronic address: liang-l@hotmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Liang
mesh_terms: D000577:Amides; D000818:Animals; D059305:Diet, High-Fat; D015536:Down-Regulation; D004983:Ethanolamines / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010147:Pain Measurement; D010169:Palmitic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D000577:Amides; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; C005958:palmidrol
keywords: inflammation; nuclear factor-κB; obesity; pain; peroxisome proliferator-activated receptor-α