Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study

Guo, Yan-Fang; Xiong, Dong Hai; Shen, Hui; Zhao, Liang; Xiao, Peng; Guo, Yan; Wang, W.; Yang, Tie‐Lin; Recker, Robert R.; Deng, Hong‐Wen

doi:10.1136/jmg.2006.041715

Cited by 96 publications

(66 citation statements)

References 49 publications

(26 reference statements)

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“…Our study did not find a significant association between LRP5 polymorphisms and obesity in young Chinese men. These results seem to agree with Guo et al [18] .…”

Section: Discussionsupporting

confidence: 81%

“…Fujino et al [7] found that LRP5 was required for cholesterol and glucose metabolism. Guo et al [18] reported a significant association between SNPs and haplotypes in the LRP5 gene and human obesity, but the associations observed were found mainly in women. We measured whole-body fat mass, lean mass and BMI as indices of the degree of obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have found that LRP5 polymorphisms are associated with complex diseases or traits that are related to obesity [16,17] . However, only one study has reported the relationship between LRP5 polymorphisms and obesity in Caucasian nuclear families [18] .…”

Section: Introductionmentioning

confidence: 99%

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No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families

et al. 2010

Acta Pharmacol Sin

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Aim:To investigate the effect of low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms on bone and obesity phenotypes in young Chinese men. Methods: A total of 1244 subjects from 411 Chinese nuclear families were genotyped by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique at the Q89R, N740N, and A1330V sites in the LRP5 gene. Bone mineral density (BMD) in the lumbar spine and the hip, total fat mass and total lean mass were measured using dual-energy X-ray absorptiometry. The association between LRP5 gene polymorphisms and peak BMD, body mass index (BMI), total fat mass, total lean mass and percentage of fat mass was assessed using a quantitative transmission disequilibrium test (QTDT). Results: No significant within-family associations were found between genotypes or haplotypes of the LRP5 gene and peak BMD, BMI, total fat mass, total lean mass and percentage of fat mass. The 1000 permutations that were subsequently simulated were in agreement with these within-family association results. Conclusion: Our results suggest that common polymorphic variations of the LRP5 gene do not influence peak bone mass acquisition and obesity phenotypes in young Chinese men.

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“…Our study did not find a significant association between LRP5 polymorphisms and obesity in young Chinese men. These results seem to agree with Guo et al [18] .…”

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families

et al. 2010

Acta Pharmacol Sin

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“…Wnt signaling inhibits adipogenesis (28,29), and polymorphisms in pathway components are associated with an increased risk for the development of diabetes (30,31), obesity (32), and hyperlipidemia (33,34). In addition, the Lrp5 coreceptor was originally identified as a candidate gene in the IDDM4 locus with linkage to insulin-dependent diabetes mellitus (35,36), and mice globally deficient for Lrp5 are glucose intolerant and exhibit increased plasma cholesterol levels when fed a high-fat diet (37,38).…”

mentioning

confidence: 99%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

120

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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“…Abnormalities in the Wnt signaling pathways, such as with transcription factor 7-like 2 gene, may impart increased risk for type 2 DM in some populations [188][189][190] as well as have increased association with obesity [191]. Additional work has described the expression of Wnt5b in adipose tissue, the pancreas, and the liver in diabetic patients, suggesting a potential regulation of adipose cell function [192].…”

Section: Cysteine-rich Glycosylated Wnt Proteinsmentioning

confidence: 99%

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Maiese

2008

Biomedicine & Pharmacotherapy

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SummaryOxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, non promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

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Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study

Cited by 96 publications

References 49 publications

No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families

No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

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