The Effect of Dietary Fat Load and Physical Exercise on the Flexibility and Partitioning of Ectopic Lipids.
Condition: Ectopic Lipids; Insulin Sensitivity; Aerobic Exercise; Fat Load; Growth Hormone Deficiency
MeSH terms: Cardiac Complexes, Premature; Insulin Resistance
Study type: Observational

Summary: 
      This study aims at assessing the effect of standardized dietary fat load and short-term
      aerobic exercise on systemic lipolysis, flexibility and partitioning of ectopic fat stores
      (intramyocellular = IMCL, intrahepatocellular = IHCL, intramyocardial lipids = IMCaL) in
      relation to FFA in endurance trained athletes and hypopituitary patients compared to
      sedentary healthy control subjects.

      Exercise is a powerful stimulation for growth hormone (GH) secretion in health. A
      standardised exercise test can, therefore, be discriminative for the diagnosis of
      GH-deficiency in adults. This will be assessed.

      Hypothesis (ectopic fat stores)

        1. Ectopic fats stores are flexible fuel stores and are influenced by diet and physical
           activity.FFA availability may play an important regulatory role.

        2. There is a tissue specific partitioning of triglycerides and/or FFA among non-adipose
           organs after fat load and physical exercise

        3. The flexibility of ectopic fat stores is related to insulin sensitivity

        4. Lipolytic and anti-lipolytic hormones are critical for regulating FFA availability (at
           rest or during exercise) and therefore also for the regulation of ectopic fat stores.

        5. GH is a lipolytica hormone. Lack of GH in adulthood is related to decreased FFA
           availability thereby influencing ectopic lipid stores Hypothesis diagnosis of GHD

        6. A short intensive physical exercise shows a good discriminative power to diagnose GHD.
    

Detailed description: 
      Background

      Obesity, in particular visceral obesity, is associated with impaired insulin action on target
      tissues (insulin resistance or metabolic syndrome) that, in turn, is related to an increased
      risk for cardiovascular mortality and morbidity. Pathophysiological mechanism remains
      unclear. Interventions in patients with impaired glucose tolerance/impaired fasting glucose
      have consistently demonstrated that by increasing physical activity and reducing calorie
      intake the risk to convert to frank type 2 diabetes is decreased, even more efficiently than
      by early medical therapy with metformin.

      Physically inactive and overweight subjects do not only store the excess of fat 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).This
      ectopic lipid accumulation occurs either by increased free fatty acids (FFA) uptake, increase
      synthesis in the involved tissues or reduced FFA oxidation.

      The relative contribution of these factors to ectopic lipid accumulation varies in different
      physiological conditions (i.e. physical exercise, fasting, postprandial condition) and in
      different tissues. In addition, it may be influenced by hormones that regulate lipid
      metabolism. 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. It has been well showed that high fat
      oxydation capacity allows to keep a lower lipolytic activity and therefore low levels of
      lipolyse degradation products. Strong evidence is accumulating that these intermediates
      interact with insulin signalling finally resulting in insulin resistance.

      There is still scarce data about the behaviour of ectopic fat stores in the presence of
      positive(nutritional fat excess) or negative energy balance (physical activity) and the role
      of hormones in regulating these fat depots.

      Additionally,we have previously shown that GH values obtained during a 2h standardized
      aerobic exercise of moderate intensity revealed a high diagnostic accuracy in predicting
      severe GHD in adult individuals. Whether a shorter exercise on higher intensity may lead to
      comparable results has to be assessed.

      Objective

      The study aims to comprehensively assess the flexibility and partitioning of ectopic fat
      deposition and to define the role of relevant hormones (especially GH and insulin) in
      relation to the availability of FFAs as well as their role in the process of ectopic fat
      deposition and consumption. Another objective is to investigate the role of a standardized
      fat load and aerobic exercise on IMCaL.

      Methods

      Using the two-step hyperinsulinaemic-euglycaemic clamp technique hepatic and peripheral
      insulin sensitivity is assessed.

      Lipid depots (skeletal muscle and liver) are repeatedly measured by MR-spectroscopy,
      subcutaneous and visceral fat mass by whole body MR-imaging.

      Exercise capacity ist measured on a bicycle (incl. spiroergometry). Counterregulatory
      hormones, glucose and free fatty acids are measured during a 2h physical exercise at 50-60
      VO2max.

      Blood samples to evaluate GH will be taken immediately before and after the Vo2 max-test, as
      well as 15, 30 and 45minutes after the end of the exercise test.
    

Intervention name(s): Fat diet; 2h standardized aerobic exercise
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Instructions for a high fat diet will be given at the end of visit 2. This consists of the usual food intake with a supplementary fat intake of 0.75g fat/kg BW, administered as 3 additional snacks. These snacks will be distributed in pre-packed bags. A food diary will be kept. All arms will receive this diet during the 3 days preceding the clamp.; Aerobic (50-60% of Vo2 max) standardized exercise on a bicycle during 2 hours
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Athletes:Endurance trained athletes: minimal >50 mlO2/KG body weight

        GH-deficient adult patients: NO GH-replacement therapy during the last 6 months

        Sedentary controls: age, BMI, Gender and waist matched (to the growth hormone deficient
        patients) healthy control subjects