<scp>APOE</scp>*<scp>3Leiden</scp>.<scp>CETP</scp> transgenic mice as model for pharmaceutical treatment of the metabolic syndrome

Hoek, Anita M. van den; Hoorn, José W.A. van der; Maas, A; Hoogen, R.M. van den; Nieuwkoop, Anita van; Droog, S.; Offerman, Erik H.; Pieterman, Elsbet J.; Havekes, Louis M.; Princen, H.M.G.

doi:10.1111/dom.12252

Cited by 43 publications

(36 citation statements)

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“…In line with expectations 39 , ApoE*3Leiden.CETP mice, a model with humanized lipoprotein metabolism, rapidly developed obesity and metabolic dysfunction on a VHFD. In general, ApoE*3Leiden.CETP mice were highly prone to cartilage degradation, independent of the level of diet-induced metabolic dysfunction.…”

Section: Discussionsupporting

confidence: 89%

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

Kozijn

Gierman

Ham

et al. 2018

Osteoarthritis and Cartilage

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Mouse model s u m m a r yObjective: Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. Design: Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr À/À . Leiden and ApoE*3-Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls. Results: Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr À/À . Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender. Conclusions: Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors. © 2017 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. IntroductionOsteoarthritis (OA) is a progressive joint disease that is characterised by focal loss of articular cartilage, which impedes smooth joint movement and causes stiffness and pain. The most important risk factors for OA are age, gender and obesity. The latter being of specific interest in developed countries, where prolonged life expectancy and a progressive sedentary lifestyle in combination with a high caloric diet is predicted to exponentially increase the number of obese individuals and hence the prevalence of OA The association between knee OA and obesity has been comprehensively studied in humans. Weight loss was found to significantly reduce pain and increase mobility in knee OA patients 3 and reduced the risk of onset of the disease 4 . In obese adults, weight loss combined with exercise appears to be the most promising treatment and is therefore recommended by several international guidelines on the management of metabolic OA 5,6 .Moreover, overweight was found to ...

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Section: Discussionsupporting

confidence: 89%

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

Kozijn

Gierman

Ham

et al. 2018

Osteoarthritis and Cartilage

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“…Moreover, E3L.CETP mice respond similar to humans to antidiabetic drugs as well (van den Hoek et al. ). However, whether E3L.CETP mice are a good model to study the development of metabolic syndrome through time is unclear to date.…”

Section: Introductionmentioning

confidence: 99%

Male apoE*3-Leiden.CETP mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men

et al. 2017

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Physiological adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. This combined with the prohibitive financial cost and ethical concerns to measure key metabolic parameters repeatedly in subjects for the major part of their life span makes that comprehensive longitudinal human data sets are virtually nonexistent. While experimental mice are often used, little is known whether this species is in fact an adequate model to better understand the mechanisms that drive the metabolic syndrome in man. We took up the challenge to study the response of male apoE*3‐Leiden.CETP mice (with a humanized lipid profile) to a high‐fat high‐cholesterol diet for 6 months. Study parameters include body weight, food intake, plasma and liver lipids, hepatic transcriptome, VLDL – triglyceride production and importantly the use of stable isotopes to measure hepatic de novo lipogenesis, gluconeogenesis, and biliary/fecal sterol secretion to assess metabolic fluxes. The key observations include (1) high inter‐individual variation; (2) a largely unaffected hepatic transcriptome at 2, 3, and 6 months; (3) a biphasic response curve of the main metabolic features over time; and (4) maximum insulin resistance preceding dyslipidemia. The biphasic response in plasma triglyceride and total cholesterol appears to mimic that of men in cross‐sectional studies. Combined, these observations suggest that studies such as these can help to delineate the causes of metabolic derangements in patients suffering from metabolic syndrome.

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“…To analyze the effect of VEGFB on glucose metabolism and insulin action in more detail, we performed experiments using a glucose tracer in an established preclinical model of the metabolic syndrome, the apoE*3Leiden;hCETP-Tg mouse (van den Hoek et al, 2014). Similar to the results obtained using wildtype mice, the apoE*3Leiden;hCETP-Tg mice transduced with VEGFB had significantly lower fasting insulin levels and improved glucose tolerance (Figures S14A–S14C).…”

Section: Resultsmentioning

confidence: 99%

VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications

et al. 2016

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SUMMARY Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway.

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APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome

Abstract: We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

Cited by 43 publications

References 45 publications

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

Male apoE*3-Leiden.CETP mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men

VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications

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