Abstract
Poly-unsaturated fatty acids (PUFAs) are considered to be healthier than saturated fatty acids (SFAs), but others postulate that especially the ratio of omega-6 to omega-3 PUFAs (n6/n3 ratio) determines health. Health can be determined with biomarkers, but functional health status is likely better reflected by challenge tests that assess metabolic flexibility. The aim of this study was to determine the effect of high-fat diets with different fatty acid compositions, but similar n6/n3 ratio, on metabolic flexibility. Therefore, adult male mice received isocaloric high-fat diets with either predominantly PUFAs (HFpu diet) or predominantly SFAs (HFs diet) but similar n6/n3 ratio for six months, during and after which several biomarkers for health were measured. Metabolic flexibility was assessed by the response to an oral glucose tolerance test, a fasting and re-feeding test and an oxygen restriction test (OxR; normobaric hypoxia). The latter two are non-invasive, indirect calorimetry-based tests that measure the adaptive capacity of the body as a whole. We found that the HFs diet, compared to the HFpu diet, increased mean adipocyte size, liver damage, and ectopic lipid storage in liver and muscle; although, we did not find differences in body weight, total adiposity, adipose tissue health, serum adipokines, whole body energy balance, or circadian rhythm between HFs and HFpu mice. HFs mice were, furthermore, less flexible in their response to both fasting- re-feeding and OxR, while glucose tolerance was indistinguishable. To conclude, the HFs versus the HFpu diet increased ectopic fat storage, liver damage, and mean adipocyte size and reduced metabolic flexibility in male mice. This study underscores the physiological relevance of indirect calorimetry-based challenge tests.
Highlights
Excessive dietary fat intake is positively associated with weight gain and the development of metabolic diseases [1], such as insulin resistance, cardiovascular diseases, and type 2 diabetes
Metabolic inflexibility arises from deficiencies in the handling of incoming and circulating nutrients by one or several of the organs that play a major role in metabolism, such as the liver, skeletal muscle, adipose tissue, brain or pancreas [2]
Adipocytes in epididymal WAT (eWAT) were significantly larger in HFs mice compared to HFpu mice (Fig 2A and 2B), whereas no difference in the number of crown-like structures in eWAT was observed (Fig 2C)
Summary
Excessive dietary fat intake is positively associated with weight gain and the development of metabolic diseases [1], such as insulin resistance, cardiovascular diseases, and type 2 diabetes. Be seen in a broader sense, in which it is defined as the capability to maintain homeostasis during a nutritional or environmental challenge [3]. Such a challenge can consist of administration of a single nutrient, such as glucose [4, 5] or lipid [6], or a combination of nutrients like in a meal test [7, 8]. Detection of metabolic inflexibility would, benefit from a multiple level approach, in which different organs or metabolic systems are challenged
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