Dataset Information

Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.

ABSTRACT: AIM:The Wnt/?-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. METHODS:We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. RESULTS:SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/?-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. CONCLUSIONS:Our results suggest that SFRP1 is an endogenous modulator of Wnt/?-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.

SUBMITTER: Lagathu C

PROVIDER: S-EPMC4266104 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.

Lagathu C C Christodoulides C C Tan C Y CY Virtue S S Laudes M M Campbell M M Ishikawa K K Ortega F F Tinahones F J FJ Fernández-Real J-M JM Orešič M M Sethi J K JK Vidal-Puig A A

International journal of obesity (2005) 20100601 12

<h4>Aim</h4>The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo.<h4>Methods</h4>We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the ...[more]

PMID: 20514047

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Project description:PurposeAdipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI).MethodsThe study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI.ResultsHere, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition.ConclusionOur study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.

Project description:Obesity is associated with an increase in ?-cell mass in response to the rising demand for insulin. ?-cell plasticity is essential to maintaining glucose homeostasis, however, the cellular and molecular mechanisms by which ?-cell mass is regulated remain poorly understood. Recently, we described the existence of a crosstalk between the peripancreatic adipose tissue and ?-cells as a novel mechanism that participates in the regulation of ?-cell plasticity. Here, we identify the secreted frizzled-related protein (Sfrp) 5 as down-regulated in the pancreatic islets of obese rats as well as in the pancreatic islets of human obese patients. Our results demonstrate that the silencing of Sfrp5 induces an increase in ?-cell proliferation, which we correlate with the activation of Wnt signaling and of the MAPK and PI3 kinase pathways. Together, these findings expand our understanding of the mechanisms underlying ?-cell proliferation under conditions of obesity. Furthermore, this study opens new insights into the specific targeting of Sfrp5 as a novel therapeutic strategy for balancing ?-cell mass. Adult male Wistar rats (Charles River Laboratories, Wilmington, MA), 7 wk old (weighing 225–250 g), were caged individually in a 12-h light, 12-h dark cycle in a temperature- and humidity-controlled environment. Animals were divided into two dietary sets for 30 days. One group was fed with standard chow diet (supplying 8% of calories as fat; type AO4 from Panlab, Barcelona, Spain). The second group was fed with a cafeteria diet (66% of calories as fat), as previously described (Endocrinology 2012;153:177-87). Pancreatic islets were isolated through collagenase perfusion of the pancreas, Histopaque gradient and hand-picking under microscopic guidance. Ten micrograms of total RNA from islets were converted into cRNA, biotinylated, fragmented, and hybridized to GeneChip Rat Genome 230 2.0 (Affymetrix, Santa Clara, CA). Ten microarrays were hybridized, five with independent samples coming from rats fed with standard chow (lean group) and five with independent samples coming from rats fed with the cafeteria diet (obese group).

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Dataset Information

Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.

Publications

Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.

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