Abstract
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.
Highlights
Physiologic adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades
Studies suggest that parameters of the metabolic syndrome such as insulin resistance, muscle mass, plasma triglycerides, and lowdensity lipoprotein cholesterol (LDL-c) are age dependent (Janssen et al 2000; Murakata et al 2015)
We study whether male E3L.cholesteryl ester transfer protein (CETP) mice are an adequate model to study the metabolic syndrome in man, by following their response to a high-fat high-cholesterol diet (HFCD) for 6 months. We found that both dyslipidemia and parameters of insulin resistance followed a biphasic trajectory
Summary
Physiologic adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. Hamer et al (2015) found that 45% of subjects classified as being “healthy obese” progressed to an unhealthy state (e.g., high triglycerides, impaired glycemic control) compared with 16% of normal-weight subjects over a period of 8 years While these longitudinal studies are very valuable, a major limitation is that (more laborious) metabolic flux measurements (i.e., VLDL – triglyceride [TG] production, sterol balance) have not been carried out, and for obvious reasons such studies can only sample a fraction of the human lifespan. We study whether male E3L.CETP mice are an adequate model to study the metabolic syndrome in man, by following their response to a high-fat high-cholesterol diet (HFCD) for 6 months We found that both dyslipidemia and parameters of insulin resistance followed a biphasic trajectory. These data indicate that male E3L.CETP mice on HFCD may be an adequate model to study the age-dependent changes of plasma lipids in man
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