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Die Wirkung von fettreicher Diät und körperlicher Aktivität auf die Flexibilität und die Einlagerung von Lipiden in ektope Fett Depots (intramyocellulär, intrahepatocellulär, intramyokardiale Lipide)

English title The effect of dietary fat load and physical exerciseon the flexibility and partitioning of ectopic lipids (intramyocellular, intrahepatoclellular, intramyocardial lipids)
Applicant Christ Emanuel
Number 130331
Funding scheme Project funding (Div. I-III)
Research institution Poliklinik für Endokrinologie, Diabetologie und Klinische Ernährung Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Endocrinology
Start/End 01.03.2011 - 29.02.2016
Approved amount 216'000.00
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Keywords (14)

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

Lay Summary (English)

Lead
Lay summary
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. 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 (physical exercise, diet) and depends on hormones that influences FFA availability. There is increasing evidence that ectopic fat 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 assessing ectopic lipid depots, thereby measuring the flexibility of ectopic fat depots. Working Hypotheses: 1) Ectopic fat sores 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 is critical in regulating FFA availabilityAims: Based on 3 different sub-studies (A-C) the present proposal aims at assessing the flexibility of ectopic fat deposition and at defining the role of hormones with regard to FFA availability. Study A and 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 in relation to FFA availability in endurance trained athletes (study A), in hypopituitary patients with growth hormone deficiency and sedentary healthy controls (study B). Study C will investigate the effect of a low and high insulinemia on the flexibility and partitioning of ectopic fat stores in relation to FFA availability in patients with type 1 diabetes. Experimental Design: Ectopic fat depots will be measured after dietary intervention and physical activity using magnetic resonance spectroscopy. 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.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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Impaired repletion of intramyocellular lipids in patients with growth hormone deficiency after a bout of aerobic exercise
Loher Hannah, Jenni Stefan, Bucher Julie, Krüsi Marion, Kreis Roland, Boesch Chris, Christ Emanuel (2018), Impaired repletion of intramyocellular lipids in patients with growth hormone deficiency after a bout of aerobic exercise, in Growth Hormone & IGF Research, 42-43, 32-39.
The Flexibility of Ectopic Lipids
Loher Hannah, Kreis Roland, Boesch Chris, Christ Emanuel (2016), The Flexibility of Ectopic Lipids, in International Journal of Molecular Sciences, 17(9), 1554-1554.
Effects of exercise aerobic on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy.
E Christ A Egger S Allemann T Buehler R Kreis C Boesch (2016), Effects of exercise aerobic on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy., in Scientific Reports, 21, 6.
Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency.
R Locher A Egger C Zwimpfer L Sze C Schmid E Christ. (2015), Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency., in Clin Endocrinol, 83(4), 593.
Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance.
A Galimov A Hartung R Trepp A Mader M Flück A Linke M Blüher E Christ J Krützfeldt. (2015), Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance., in J Mol Med, 93(12), 1369.
Peak oxygen uptake test in the assessment of growth hormone deficiency
T Zueger J Bucher ER Christ C Stettler (2014), Peak oxygen uptake test in the assessment of growth hormone deficiency, in Applied Physiology, Nutrition, and Metabolism , 39, 1.
The effect of a single 2 h bout of aerobic exercise on ectopic lipids in skeletal muscle, liver and the myocardium
J Bucher M Krüsi T Zueger M Ith C Stettler P Diem C Boesch R Kreis ER Christ. (2014), The effect of a single 2 h bout of aerobic exercise on ectopic lipids in skeletal muscle, liver and the myocardium, in Diabetologia, 57(5), 1001.
The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects
A Egger R Kreis S Allemann C Stettler P Diem T Buehler C Boesch ER Christ (2013), The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects, in PloS one, 14(8), 70865.
Glucocorticoid replacement and mortality in patients with nonfunctioning pituitary adenoma
Zueger T, Kirchner P, Herren C, Fischli S, Zwahlen M, Christ E, Stettler C (2012), Glucocorticoid replacement and mortality in patients with nonfunctioning pituitary adenoma, in Journal of Clinical Endocrinology and Metabolism, 97(10), E1938-E1942.
Exercise-induced GH secretion in the assessment of GH deficiency in adult individuals
Zueger T, Alleman S, Christ ER, Stettler C (2011), Exercise-induced GH secretion in the assessment of GH deficiency in adult individuals, in EUROPEAN JOURNAL OF ENDOCRINOLOGY, 165(5), 723-728.
Noninvasive Assessment of Exercise-Related Intramyocellular Acetylcarnitine in Euglycemia and Hyperglycemia in Patients With Type 1 Diabetes Using 1H Magnetic Resonance Spectroscopy A randomized singl
A Boss R Kreis S Jenni M Ith JM Nuoffer E Christ C Boesch C Stettler (2011), Noninvasive Assessment of Exercise-Related Intramyocellular Acetylcarnitine in Euglycemia and Hyperglycemia in Patients With Type 1 Diabetes Using 1H Magnetic Resonance Spectroscopy A randomized singl, in Diabetes Care, 34(1), 220.
Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise
R Oosterhof M Ith R Trepp E Christ M Flück (2011), Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise, in Physiological genomics , 43(12), 739.
Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise
Oosterhof R, Ith M, Trepp R, Christ E, Fluck M (2011), Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise, in PHYSIOLOGICAL GENOMICS, 43(12), 739-748.
The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study
A Egger T Buehler C Boesch P Diem C Stettler ER Christ (2011), The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study, in Europ J Endocrinol, 164(1), 23.
Regulation of fuel metabolism during exercise in hypopituitarism with growth hormone-deficiency (GHD
T Zueger*, H Loher*, A Egger, C. Boesch E Christ., Regulation of fuel metabolism during exercise in hypopituitarism with growth hormone-deficiency (GHD, in GH and IGF-1 research, in press.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ENDO 2016 Poster Repletion of Intramyocellular (IMCL) is different in patients with Growth Hormone Deficiency (GHD) Compared to Control Subjects (CS) 24h after a 2h Aerobic Exercise 01.04.2016 Boston, United States of America Boesch Chris; Bucher Julie; Christ Emanuel; Krüsi Marion; Loher Hannah;
Schweizerische Gesellschaft für Endokrinologie und Diabetologie (SGED/SSED), wisseschaftliches Meeting Poster Repletion of Intramyocellular (IMCL) and intramyocellular lipids in patients with Growth Hormone Deficiency (GHD) Compared to Control Subjects (CS) 24h after a 2h Aerobic Exercise 12.11.2015 Bern, Switzerland Christ Emanuel; Bucher Julie; Krüsi Marion; Boesch Chris; Loher Hannah;
ECE 2014 Poster Flexibility of ectopic lipids in physically active, healthy individuals 03.05.2014 Wrozlow, Poland Boesch Chris; Krüsi Marion; Christ Emanuel; Bucher Julie;
Schweizerische Gesellschaft für Endokrinologie und Diabetologie (SGED/SSED), wissenschaftliche Tagung Talk given at a conference Effect of GH replacement therapy (GHRT) on soluble Klotho in patients with GH deficiency (GHD) 14.11.2013 Bern, Switzerland Christ Emanuel; Boesch Chris;
ENDO 2013 Poster The effect of aerobic exercise on ectopic lipids [intramyocellular (IMCL), intrahepatocellular (IHCL) and intracardiomyocellular (ICCL) lipids] in physically active, healthy individuals 18.06.2013 San Francisco, United States of America Bucher Julie; Boesch Chris; Christ Emanuel; Krüsi Marion;
ECE 2013 Poster The effect of aerobic exercise on ectopic lipids [intramyocellular (IMCL), intrahepatocellular (IHCL) and intracardiomyocellular (ICCL) lipids] in physically active, healthy individuals 27.04.2013 Copenhagen, Denmark Krüsi Marion; Boesch Chris; Christ Emanuel; Bucher Julie;
Schweizerische Gesellschaft für Endokrinologie und Diabetologie (SGED/SSED), wissenschaftliches Meeting Talk given at a conference The effect of aerobic exercise on ectopic lipids [intramyocellular (IMCL), intrahepatocellular lipids (IHCL) and intramyocardial lipids (IMCaL)] in endurance trained athletes. 23.11.2012 Bern, Switzerland Boesch Chris; Christ Emanuel; Stettler Christoph; Bucher Julie; Krüsi Marion;
GRS and IGF-1 Society Talk given at a conference Regulation of fuel metabolism during exercise in hypopituitarism with growth hormone-deficiency (GHD) 17.10.2012 Munich, Germany Christ Emanuel; Boesch Chris; Bucher Julie; Krüsi Marion;
GH and IGF-research Poster The effect of growth hormone replacement therapy (GHRT) on exercise capacity, fat mass, ectopic lipids [intramyocellular (IMCL) and intrahepatocellular lipids (IHCL)] and insulin resistance in hypopituitary patients with growth hormone deficiency (GHD) 17.10.2012 Munich, Germany Stettler Christoph; Boesch Chris; Christ Emanuel;
ECE 2012 Poster The effect of growth hormone replacement therapy (GHRT) on exercise capacity, fat mass, ectopic lipids [intramyocellular (IMCL) and intrahepatocellular lipids (IHCL)] and insulin resistance in hypopituitary patients with growth hormone deficiency (GHD) 05.05.2012 Florence, Italy Christ Emanuel; Boesch Chris;
Schweizerische Gesellschaft für Endokrinologie und Diabetologie (SGED/SSED), wissenschaftliches Meeting Talk given at a conference The effect of growth hormone replacement therapy (GHRT) on exercise capacity, fat mass, ectopic lipids [intramyocellular (IMCL) and intrahepatocellular lipids (IHCL)] and insulin resistance in hypopituitary patients with growth hormone deficiency (GHD) 01.12.2011 Bern, Switzerland Boesch Chris; Stettler Christoph; Christ Emanuel;
ENDO 2011 Poster The effect of aerobic exercise on intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) in hypopituitary patients with growth hormone deficiency (GHD), sedentary control subjects (CS) and endurance trained athletes (EA). 04.06.2011 Boston, United States of America Stettler Christoph; Boesch Chris; Christ Emanuel;


Awards

Title Year
President's poster competition, ENDO 2016 2016
Poster Price GRS and IGF-1 research society 2012

Associated projects

Number Title Start Funding scheme
118219 Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: integration and application of the MR-toolbox for studies on insulin resistance 01.12.2007 Project funding (Div. I-III)
149321 Exercise-related Fuel Metabolism and Glucose Stability in Individuals with Type 1 Diabetes Mellitus 01.03.2014 Project funding (Div. I-III)
109522 The effect of growth hormone (GH) on intramyocellular (IMCL), intrahepatic lipids (IHCL) and visceral fat mass in relation to insulin resistance 01.04.2006 Project funding (Div. I-III)
100146 Effects of growth hormone on skeletal muscle fuel metabolism 01.10.2003 Project funding (Div. I-III)

Abstract

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.
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