title: Programmed cell death-4 deficiency prevents diet-induced obesity, adipose tissue inflammation, and insulin resistance.
abstract: Programmed cell death-4 (PDCD4), a selective protein translation inhibitor, has shown proinflammatory effect in some inflammatory diseases, but its roles in obesity remain unestablished. This study aims to investigate the effects of PDCD4 on obesity, inflammation, and insulin resistance. Surprisingly, high-fat diet (HFD)-fed PDCD4-deficient (PDCD4(-/-)) mice exhibited an absolutely lean phenotype together with improved insulin sensitivity. Compared with wild-type obese mice, HFD-fed PDCD4(-/-) mice showed higher energy expenditure, lower epididymal fat weight, and reduced macrophage infiltration inflammatory cytokine secretion in white adipose tissue (WAT). Alleviated hepatic steatosis along with decreased plasma levels of triglyceride and cholesterol was also observed in these mice. Importantly, PDCD4 appeared to disturb lipid metabolism via inhibiting the expression of liver X receptor (LXR)-α, a master modulator of lipid homeostasis, which was elevated in HFD-fed PDCD4(-/-) mice accompanied by upregulation of its target genes and relieved endoplasmic reticulum stress in WAT. These data demonstrate that PDCD4 deficiency protects mice against diet-induced obesity, WAT inflammation, and insulin resistance through restoring the expression of LXR-α, thereby proposing PDCD4 as a potential target for treating obesity-associated diseases.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shangdong, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Dong
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.forename: Xingguo
authors.initials: X
authors.lastname: Song
authors.forename: Qiang
authors.initials: Q
authors.lastname: Song
authors.forename: Qianwen
authors.initials: Q
authors.lastname: Shang
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D014280:Triglycerides; D002784:Cholesterol