High-fat Overfeeding, Hepatokines and Appetite Regulation
Condition: Insulin Resistance; Type2 Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Obesity
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Insulin Resistance
Study type: Interventional

Summary: 
      The present study will investigate the effect of high-fat overfeeding on a group of
      liver-secreted proteins linked to worsened blood sugar control, as well as proteins involved
      in appetite control. Participants will consume both a high-fat diet, consisting of 50% extra
      calories above their daily required intake, and a control diet, consisting of their normal
      'habitual' diet, with each diet lasting seven days. The diets will be undertaken in a
      randomised order, with a period of three weeks separating the two diets. Blood samples will
      be taken before and after each diet to measure blood sugar control. Further blood samples
      will also be taken 24 hours and 72 hours into each diet to see how levels of the liver and
      appetite-regulating proteins change over the course of the seven days.

      It is expected that blood sugar control will be worsened by the high-fat diet and this will
      be accompanied by increases in levels of the liver-secreted proteins and an impaired release
      of the appetite-regulating proteins into the blood.
    

Detailed description: 
      In recent years, researchers have identified a number of liver-secreted proteins, termed
      "hepatokines", which are thought to play an important role in inter-organ crosstalk between
      the liver and other metabolically active tissues such as skeletal muscle and adipose tissue.
      Specifically, previous studies have demonstrated that hepatokines contribute to whole body
      glucose and lipid homeostasis through acting in an endocrine-like fashion. Understanding how
      circulating concentrations of these hepatokines can be manipulated in humans is essential, as
      impaired blood glucose and lipid control is a key feature of metabolic diseases, such as type
      2 diabetes and non-alcoholic fatty liver disease.

      Previous research at Loughborough University has found that acute high-fat overfeeding for up
      to seven days can impair glycaemic control; however, the exact mechanisms responsible for
      these detrimental changes are not fully understood. Based upon previous evidence that
      hepatokine production is nutritionally modulated, the investigators believe that changes in
      hepatokine production may play a role in the detrimental metabolic effects seen following
      short-term, high-fat overfeeding which has implications for long-term metabolic health.

      Appetite regulation is also thought to play a role in the pathophysiology of obesity and
      insulin resistance, as the impaired secretion of several appetite regulatory hormones in both
      fasting and postprandial conditions has been observed in obesity, which is characterised by
      an chronic excessive energy intake. Therefore, the investigators are also interested to
      examine the appetite regulatory hormone response to short-term, high-fat overfeeding.

      The present study is a randomised, controlled, crossover study in which twelve recreationally
      active, healthy males will consume both a hypercaloric, high-fat diet (consisting of 50%
      extra energy above the daily requirement, 65% of which is fat) and a control diet (the
      participants' habitual diet) in a randomised fashion. A three-week washout period will
      separate the two diets in order to remove any lasting effects confounding the subsequent
      diet.

      Following a prescreening session in which anthropometric data will be collected, participants
      will commence their first dietary condition. An oral glucose tolerance test will be performed
      before and after the two diets to measure changes in glycaemic control/whole body insulin
      sensitivity. Further blood samples will be taken 24 hours and 72 hours after commencing the
      diets in order to observe the time course of any changes in circulating hepatokine and
      appetite hormone concentrations. Physical activity will also be monitored for the duration of
      the two dietary conditions to ensure that habitual physical activity levels are maintained.
    

Intervention name(s): High-fat diet
Intervention type(s): Dietary Supplement
Intervention description(s): The high-fat diet will provide 7 days of overfeeding comprising of: +50% extra calories above the daily required intake, 65% of which is fat.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The study design is a randomised, controlled, crossover design in which participants undertake two 7-day dietary conditions in a randomised order with a three week washout period in between.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Hepatokines; High Fat Diet; Glycaemic Control; Fibroblast Growth Factor 21; Leukocyte Cell-derived Chemotaxin 2; Fetuin-A; Appetite; Ghrelin; Peptide YY