Hepatic Glycogen and Fat Oxidation
Condition: Fatty Liver, Nonalcoholic; Meal Time; Fasting; Glycogen Depletion
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      Excessive fat in the liver is associated with impairments in metabolic health. Low levels of
      DNL and high levels of hepatic fat oxidation are considered to be protective.

      A decrease in glycogen stores has been causally linked to improved whole body fat oxidation.
      Also on an organ level, it is suggested that hepatic fat oxidation is stimulated by low
      hepatic glycogen stores. Next to hepatic fat oxidation, DNL may be influenced by hepatic
      glycogen stores. Some studies have shown that prolongation of fasting time lowers hepatic
      glycogen content. It is therefore hypothesized that prolonging fasting time will lower
      glycogen content and thereby increases fat oxidation and decreases DNL in the liver. To this
      end, hepatic fat oxidation (plasma marker beta-hydroxybutyrate), de novo lipogenesis, hepatic
      glycogen content and intrahepatic fat content, will be measured upon a short overnight fast
      and an extended overnight fast in 13 overweight/obese subjects with hepatic steatosis.
    

Detailed description: 
      Rationale:

      Excessive fat in the liver is associated with impairments in metabolic health. Hepatic lipid
      storage can originate from several metabolic pathways, including de novo lipogenesis (DNL).
      On the other hand, there are several metabolic pathways that can decrease hepatic fat
      storage, such as hepatic fat oxidation. Therefore, low levels of DNL and high levels of
      hepatic fat oxidation are considered to be protective.

      A decrease in glycogen stores has been causally linked to improved whole body fat oxidation.
      Also on an organ level, it is suggested that hepatic fat oxidation is stimulated by low
      hepatic glycogen stores. Furthermore, whole body glycogen levels were also linked to DNL and
      in situations with increased whole body glycogen levels in animal models rates of DNL were
      also high. Therefore, next to hepatic fat oxidation, DNL may be influenced by hepatic
      glycogen stores.

      Some studies have shown that prolongation of fasting time lowers hepatic glycogen content. It
      is therefore hypothesized that prolonging fasting time will lower glycogen content and
      thereby increases fat oxidation and decreases DNL in the liver.

      Objective:

      The primary objective of this study is to investigate to what extent hepatic fat oxidation
      can be stimulated by lowering hepatic glycogen content during a prolonged overnight fast.

      The secondary objective is to investigate whether reductions in hepatic glycogen content are
      also accompanied by a decrease in DNL. In addition, the metabolic response to a meal
      (metabolites related to energy metabolism and substrate oxidation) will be studied upon
      prolonged overnight fasting. Finally, it will be studied whether reducing hepatic glycogen
      content by prolonged overnight fasting during a few consecutive days lowers intrahepatic fat
      storage and changes hepatic fat composition.

      Study design:

      This is a randomized cross-over study.

      Study population:

      Thirteen healthy overweight/obese males and postmenopausal females, aged between 45-75 years
      and BMI between 27-38 kg/m2, with liver fat content ≥ 5% will participate in the study. To be
      able to include enough people with a liver fat content ≥5%, around 27 participants are
      expected to be screened for liver fat. When liver fat content is <5%, participants will not
      be included in the study after determination of liver fat content.

      Main study parameters/endpoints:

      The primary study outcome is hepatic fat oxidation measured as plasma beta-hydroxybutyrate
      (BHB) levels, which will be measured before and after one night adherence to the fasting
      protocols. The secondary study outcome is DNL as determined by stable isotope techniques and
      will also be measured after one night adherence to the fasting protocols. Other study
      outcomes include hepatic glycogen content, substrate oxidation and plasma metabolites related
      to energy metabolism (measured before and after one night adherence to the fasting protocols)
      and intrahepatic fat content and composition (measured after 6 days of adherence to the
      fasting protocols).
    

Intervention name(s): Overnight fasting duration
Intervention type(s): Behavioral
Intervention description(s): Subjects will adhere to overnight fasting protocol for 6 days
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science