Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice

Shah, Rachana; O’Neill, Sean M.; Hinkle, Christine; Caughey, Jennifer; Stephan, Stephen; Lynch, Emma; Bermingham, Kate; Lynch, Gina; Ahima, Rexford S.; Reilly, Muredach P.

doi:10.1371/journal.pone.0138317

Cited by 28 publications

(26 citation statements)

References 27 publications

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“…Interestingly, one of the strongest correlations we observed were between fractalkine receptor Cx3cr1 and fat mass response (p = 9.62E–10). Fractalkine (Cx3cl1) is a chemokine, that was recently implicated in diet induced obesity, insulin regulation and promotion of hypothalamic inflammatory response to fatty acids ( Shah et al, 2015 ). However, different models of Cx3cr1 knockout mice resulted in variable results on diet induced obesity.…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Hasin-Brumshtein

Hormozdiari

et al. 2016

eLife

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Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.DOI: http://dx.doi.org/10.7554/eLife.15614.001

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Section: Resultsmentioning

confidence: 99%

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Hasin-Brumshtein

Hormozdiari

et al. 2016

eLife

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“…A study indicated that O 2 consumption peaks in C57BL/6 mice around 7 pm (Shah et al. ), so the time period we selected at night (8–11 pm ) may also contribute to the observation.…”

Section: Discussionmentioning

confidence: 99%

Reduced body weight gain in ubiquilin-1 transgenic mice is associated with increased expression of energy-sensing proteins

et al. 2017

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Ubiquilin‐1 (Ubqln1), a ubiquitin‐like protein, is implicated in a variety of pathophysiological processes, but its role in mediating body weight gain or metabolism has not been determined. Here, we demonstrate that global overexpression of Ubqln1 in a transgenic (Tg) mouse reduces the animal's body weight gain. The decreased body weight gain in Tg mice is associated with lower visceral fat content and higher metabolic rate. The Ubqln1 Tg mice exhibited reduced leptin and insulin levels as well as increased insulin sensitivity manifested by homeostatic model assessment of insulin resistance. Additionally, the reduced body weight in Tg mice was associated with the upregulation of two energy‐sensing proteins, sirtuin1 (SIRT1) in the hypothalamus and AMP‐activated protein kinase (AMPK) in the skeletal muscle. Consistent with the in vivo results, overexpression of Ubqln1 significantly increased SIRT1 and AMPK levels in the mouse embryonic fibroblast cell culture. Thus, our results not only establish the link between Ubqln1 and body weight regulation but also indicate that the metabolic function of Ubqln1 on body weight may be through regulating energy‐sensing proteins.

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“…Consistent with our hypothesis, these pathways, which are interrelated, have been described to play important roles in weight gain and in the appearance of T2D‐associated obesity. Explicitly, CDKN1A and MYC have been related to obesity , while CX3CL1, ECE1, STAT3, TNF, GLUL, and IL1β have been reported to be related to both obesity and T2D‐associated inflammation . Other studies have shown that HIF1A, KDR, VEGFA, GPI, and NOS3 were mainly associated with IR and obesity‐associated angiogenesis and that ZNF274 was related to obesity and IR .…”

Section: Discussionmentioning

confidence: 99%

miR‐20b, miR‐296, and Let‐7f Expression in Human Adipose Tissue is Related to Obesity and Type 2 Diabetes

Gentile

Lhamyani

Coín‐Aragüez

et al. 2018

Obesity

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Objective: This study aimed to analyze the potential association of different microRNA (miRNA) molecules with both type 2 diabetes (T2D) and obesity and determine their target genes. Methods: Quantitative PCR was used to analyze the miR-20b, miR-296, and Let-7f levels in human visceral and subcutaneous adipose tissues (ATs) in relation to obesity and T2D, miRTarBase 4.0 was used for validation of target genes, and the Protein Analysis Through Evolutionary Relationships (PANTHER) Classification System and the Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to annotate the biological processes of the predicted targets. Results: In AT, miR-20b, miR-296, and Let-7f levels were significantly different between normoglycemic subjects and those with T2D. In visceral adipose tissue, miRNA levels were higher in normoglycemic/obesity samples than in T2D/obesity samples. miR-20b, miR-296, and Let-7f target genes that showed significant differences in both ATs in relation to obesity and T2D were CDKN1A, CX3CL1, HIF1A, PPP2R1B, STAT3, and VEGFA. These genes are known to be principally involved in the vascular endothelial growth factor (VEGF) and WNT pathways. Conclusions: This study provides experimental evidence of the possible correlation between AT miR-20b, miR-296, and Let-7f with obesity and T2D, which might involve vascular endothelial growth factor and WNTdependent pathways that are regulated by six different genes, suggesting a novel signaling pathway that could be important for understanding the mechanisms underlying the AT dysfunction associated with obesity and T2D.

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Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice

Cited by 28 publications

References 27 publications

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Reduced body weight gain in ubiquilin-1 transgenic mice is associated with increased expression of energy-sensing proteins

miR‐20b, miR‐296, and Let‐7f Expression in Human Adipose Tissue is Related to Obesity and Type 2 Diabetes

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