intramyocellular lipids; intrahepatocellular lipids; intramyocardial lipids; free fatty acids; total body fat mass (subcutaneous and visceral); insulin sensitivity; endurance trained athletes; hypopituitarism with growth hormone deficiency; type 1 diabetes mellitus; magnetic resonance spectroscopy; insulin resistance, insulin; fat diet; physical activity; insulin
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Background: Fat is not only stored in the intra-abdominal or subcutaneous department but also in non-adipose tissue (=”ectopic” tissues), such also skeletal muscle, liver and myocardium, also called intramyocellular lipids (IMCL), intrahepatocellular lipids (IHCL) and intramyocardial lipids (IMCaL). Lipid droplets accumulate in the cytoplasm of the corresponding cells and an excessive accumulation of these lipids may lead to cell dysfunction. Lipid accumulation in ectopic sites may depend on free fatty acids (FFA) availability and can occur either by increased uptake of FFA, increased synthesis within the tissue involved or reduced FFA oxidation/disposal. The relative contribution of these factors varies in different physiological conditions (i.e. physical exercise, dietary intervention) and depends on hormone secretion that influences systemic FFA availability. There is increasing evidence that ectopic fat and its intermediate metabolites interfere with insulin signalling, thereby contributing to the impaired insulin action on target tissues such as liver and skeletal muscle. Magnetic resonance spectroscopy (1H-MRS) is a non-invasive method that allows to repeatedly assessing ectopic lipid depots in skeletal muscle, liver and heart, thereby measuring the flexibility of ectopic fat depots. We have shown that IMCL levels are high after a dietary intervention (fat load) and readily utilized during exercise in individuals over a broad range of insulin sensitivity. Importantly, a pilot study suggests that the capacity to replete and deplete IMCLs correlates with insulin sensitivity in healthy subjects and not the absolute amount of IMCL. In contrast to IMCL, preliminary data in healthy subjects suggests that a 2 hours physical exercise result in an increase in IHCL. Whether IMCaL are flexible stores that can be repleted and depleted remains to be established. Thus, the role of ectopic fat depots flexibility and the partitioning of excess FFA on different non adipose tissue in the presence of positive (nutritional excess) or negative energy balance (physical activity) is ill defined. In particular the part of hormones in regulating FFA availability, thereby influencing ectopic fat tissue flexibility and partitioning remains to be established. Specific disease models like hypopituitarism or type 1 diabetes offer a unique opportunity to study the individual impact of two important hormones (growth hormone, insulin) centrally involved in lipid metabolism.Working Hypothesis: 1) Ectopic fat sores (IMCL, IHCL, and IMCaL) are flexible fuel stores that are influenced by diet and physical activity. 2) There is a tissue specific partitioning of FFA among non-adipose organs after a fat load and physical exercise. 3) The flexibility of ectopic fat stores (IMCL, IHCL and IMCaL) is related to insulin sensitivity. 4) FFA availability (uptake, storage and oxidation) plays an important role for the amount of ectopic lipid depots. 5) Lipolytic and anti-lipolytic hormones are critical in regulating FFA availability in resting condition and during physical exercise. They are, therefore, implicated in the regulation of ectopic fat stores. 6) Exposure to different doses of insulin will modify FFA availability and therefore ectopic lipid depots. Specific Aims: Based on 3 different sub-studies the present proposal aims at comprehensively assess the flexibility and partitioning of ectopic fat deposition and to define the role of relevant hormones (especially GH and insulin) with regard to FFA availability as well as their role in the process of ectopic fat deposition and consumption.Study A will investigate the effect of a standardized fat load followed by a short-term aerobic exercise on the flexibility and partitioning of ectopic fat stores (IMCL, IHCL, IMCaL) in relation to FFA availability in endurance trained athletes representing an insulin sensitive population with high lipid oxidative capacity. Study B will investigate the effect of a standardized fat load followed by a short-term aerobic exercise on the flexibility and partitioning of ectopic fat stores (IMCL, IHCL, IMCaL) in relation to FFA availability in hypopituitary patients with growth hormone deficiency (GHD patients). In addition, age gender, BMI and waist matched sedentary healthy control subjects will be studied.Study C will investigate the effect of a low and high insulinemia on the flexibility and partitioning of ectopic fat stores (IMCL, IHCL, IMCaL) in relation to FFA availability in patients with type 1 diabetes. Experimental Design: Using magnetic resonance spectroscopy IMCL, IHCL and IMCaL will be measured under standardized condition (diet and physical exercise) in all patients and controls subjects. Whole body fat (subcutaneous and visceral fat mass) will be assessed by magnetic resonance imaging. Insulin action will be determined by a two-step hyperinsulinaemic, euglycaemic clamp combined with stable isotope technique. Expected Value: 1) The results will give new insights into the effect of dietary intervention and physical activity on ectopic fat stores flexibility and partitioning 2) The data will improve the understanding of the role of FFA availability on ectopic lipid fuel and its relation with insulin resistance. 3) These data will allow to extend the investigations to other endocrine disorders that are associated with insulin resistance.