title: Adipose-specific inactivation of JNK alleviates atherosclerosis in apoE-deficient mice.
abstract: Both atherosclerosis and obesity, an independent atherosclerotic risk factor, are associated with enhanced systemic inflammation. Obesity is also characterized by increased adipose tissue inflammation. However, the molecular mechanism underlying the accelerated atherosclerosis in obesity remains unclear. In obesity, activation of c-Jun N-terminal kinase (JNK) contributes to adipose tissue inflammation. The present study investigated whether the suppression of fat inflammation through adipose-specific JNK inactivation could protect against atherosclerosis in mice. ApoE-/-mice were cross-bred with transgenic mice with adipose-specific expression of a dominant negative form of JNK (dnJNK) to generate apoE-/-/dnJNK (ADJ) mice. ADJ mice treated with a high-fat-high-cholesterol diet exhibited significant attenuations of visceral fat and systemic inflammation without changes in lipid or glucose metabolism, and were protected against atherosclerosis, when compared with apoE-/-mice. Lean apoE-/-mice that received transplantation of visceral fat from obese wild-type donor mice for 4 weeks showed exacerbated systemic inflammation and atherosclerotic plaque formation. Conversely, apoE-/-recipients carrying a visceral fat graft from obese dnJNK donors were protected against enhanced systemic inflammation and atherogenesis. The beneficial effects of adipose-specific JNK inactivation on atherogenesis in apoE-/-recipients were significantly compromised by continuous infusion of recombinant adipocyte-fatty acid-binding protein (A-FABP), previously shown to interact with JNK via a positive feedback loop to modulate inflammatory responses. Together these data suggested that enhanced atherosclerosis in obesity can be attributed, at least in part, to a distant cross-talk between visceral fat and the vasculature, mediated by the release of proinflammatory cytokines, such as A-FABP, from the inflamed visceral adipose tissue with JNK activation.
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China.
authors: Kelvin H M
authors: KHM
authors: Kwok
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China.
authors: Kenneth K Y
authors: KKY
authors: Cheng
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China.
authors: Ruby L C
authors: RLC
authors: Hoo
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China.
authors: Dewei
authors: D
authors: Ye
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China Research Centre for Heart, Brain, Hormones and Healthy Aging, University of Hong Kong, 999077 Hong Kong Department of Pharmacology and Pharmacy, University of Hong Kong, 999077 Hong Kong ksllam@hku.hk amxu@hku.hk.
authors: Aimin
authors: A
authors: Xu
authors: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 999077 Hong Kong Department of Medicine, University of Hong Kong, 999077 Hong Kong, China Research Centre for Heart, Brain, Hormones and Healthy Aging, University of Hong Kong, 999077 Hong Kong ksllam@hku.hk amxu@hku.hk.
authors: Karen S L
authors: KSL
authors: Lam
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology* / Q000276:immunology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000276:immunology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D048670:MAP Kinase Kinase 4
keywords: JNK; adipose tissue; atherosclerosis; inflammation; obesity