The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

Hörbelt, Tina; Knebel, Birgit; Fahlbusch, Pia; Barbosa, David; Wiza, Daniella Herzfeld de; Velde, Frederique Van de; Nieuwenhove, Yves Van; Lapauw, Bruno; Thoresen, G. Hege; Al-Hasani, Hadi; Müller‐Wieland, Dirk; Ouwens, D.M.; Kotzka, Jörg

doi:10.1016/j.bbadis.2019.07.008

Cited by 33 publications

(31 citation statements)

References 38 publications

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“…Then, ECAR and OCR were recorded using the Seahorse XF24e analyzer, six times at 6 min intervals at baseline, and following injections with 4 µM Rot/AA and 50 mM 2-deoxyglucose (2-DG) (XF Cell Mito Stress Test Kit), respectively. PER, glycoPER, basal glycolysis, basal proton efflux rate, compensatory glycolysis, and post 2-DOG acidification were calculated as previously described [17,18].…”

Section: Methodsmentioning

confidence: 99%

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Lund

Ouwens

Wettergreen

et al. 2019

Cells

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Previous studies have shown that chronic hyperglycemia impairs glucose and fatty acid oxidation in cultured human myotubes. To further study the hyperglycemia-induced suppression of oxidation, lactate oxidation, mitochondrial function and glycolytic rate were evaluated. Further, we examined the intracellular content of reactive oxygen species (ROS), production of lactate and conducted pathway-ANOVA analysis on microarray data. In addition, the roles of the pentose phosphate pathway (PPP) and the hexosamine pathway were evaluated. Lactic acid oxidation was suppressed in hyperglycemic versus normoglycaemic myotubes. No changes in mitochondrial function or ROS concentration were observed. Pathway-ANOVA analysis indicated several upregulated pathways in hyperglycemic cells, including glycolysis and PPP. Functional studies showed that glycolysis and lactate production were higher in hyperglycemic than normoglycaemic cells. However, there were no indications of involvement of PPP or the hexosamine pathway. In conclusion, hyperglycemia reduced substrate oxidation while increasing glycolysis and lactate production in cultured human myotubes.

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Section: Methodsmentioning

confidence: 99%

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Lund

Ouwens

Wettergreen

et al. 2019

Cells

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“…adipogenic transcription factors (C/EBPα and Pparγ) [22]. Horbelt et al reported that Sfrp4 mRNA levels were high in the visceral adipose tissue of obese or type 2 diabetes patients and that Sfrp4 promotes de novo lipogenesis in mice hepatocytes [23]. These results suggest that a decrease in adipokine Sfrp4 levels in the epididymal fat of KO_A12 mice activates the Wnt signaling pathway and leads to inhibition of lipid synthesis in the liver.…”

Section: Plos Onementioning

confidence: 98%

Ablation of Iah1, a candidate gene for diet-induced fatty liver, does not affect liver lipid accumulation in mice

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD) is a pathological condition caused by excess triglyceride deposition in the liver. The SMXA-5 severe fatty liver mouse model has been established from the SM/J and A/J strains. To explore the genetic factors involved in fatty liver development in SMXA-5 mice, we had previously performed quantitative trait locus (QTL) analysis, using (SM/J×SMXA-5)F2 intercross mice, and identified Fl1sa on chromosome 12 (centromere-53.06 Mb) as a significant QTL for fatty liver. Furthermore, isoamyl acetate-hydrolyzing esterase 1 homolog (Iah1) was selected as the most likely candidate gene for Fl1sa. Iah1 gene expression in fatty liver-resistant A/J-12 SM mice was significantly higher than in fatty liver-susceptible A/J mice. These data indicated that the Iah1 gene might be associated with fatty liver development. However, the function of murine Iah1 remains unknown. Therefore, in this study, we created Iah1 knockout (KO) mice with two different backgrounds [C57BL/6N (B6) and A/J-12 SM (A12)] to investigate the relationship between Iah1 and liver lipid accumulation. Liver triglyceride accumulation in Iah1-KO mice of B6 or A12 background did not differ from their respective Iah1-wild type mice under a high-fat diet. These results indicated that loss of Iah1 did not contribute to fatty liver. On the other hands, adipose tissue dysfunction causes lipid accumulation in ectopic tissues (liver, skeletal muscle, and pancreas). To investigate the effect of Iah1 deficiency on white adipose tissue, we performed DNA microarray analysis of epididymal fat in Iah1-KO mice of A12 background. This result showed that Iah1 deficiency might decrease adipokines Sfrp4 and Metrnl gene expression in epididymal fat. This study demonstrated that Iah1 deficiency did not cause liver lipid accumulation and that Iah1 was not a suitable candidate gene for Fl1sa.

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“…These mice are characterized by hyperglycemia, hepatic steatosis, and hyperinsulinemia potentiated by secreted frizzled-related protein. 49,51 To better recapitulate the various aspects of the metabolic syndrome combinations such as obesity and hyperlipidemia, obesity and hypertension have also been employed and reviewed in detail by Kennedy et al 34 ►Table 1 summarizes the mouse models described above.…”

Section: Nonobese-lipodystrophic Modelsmentioning

confidence: 99%

Cardiometabolic Syndrome: An Update on Available Mouse Models

et al. 2020

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Cardiometabolic syndrome (CMS), a disease entity characterized by abdominal obesity, insulin resistance (IR), hypertension, and hyperlipidemia, is a global epidemic with approximately 25% prevalence in adults globally. CMS is associated with increased risk for cardiovascular disease (CVD) and development of diabetes. Due to its multifactorial etiology, the development of several animal models to simulate CMS has contributed significantly to the elucidation of the disease pathophysiology and the design of therapies. In this review we aimed to present the most common mouse models used in the research of CMS. We found that CMS can be induced either by genetic manipulation, leading to dyslipidemia, lipodystrophy, obesity and IR, or obesity and hypertension, or by administration of specific diets and drugs. In the last decade, the ob/ob and db/db mice were the most common obesity and IR models, whereas Ldlr−/− and Apoe−/− were widely used to induce hyperlipidemia. These mice have been used either as a single transgenic or combined with a different background with or without diet treatment. High-fat diet with modifications is the preferred protocol, generally leading to increased body weight, hyperlipidemia, and IR. A plethora of genetically engineered mouse models, diets, drugs, or synthetic compounds that are available have advanced the understanding of CMS. However, each researcher should carefully select the most appropriate model and validate its consistency. It is important to consider the differences between strains of the same animal species, different animals, and most importantly differences to human when translating results.

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The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

Cited by 33 publications

References 38 publications

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Ablation of Iah1, a candidate gene for diet-induced fatty liver, does not affect liver lipid accumulation in mice

Cardiometabolic Syndrome: An Update on Available Mouse Models

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