Effects of Fructose/Glucose-rich Diet on Brown Fat in Healthy Subjects (GB7)
Condition: Type2 Diabetes
Study type: Interventional

Summary: 
      Activating brown and beige adipose tissue (herein described as BAT) has been recently
      recognized as a potential means to increase energy expenditure and lower blood glucose,
      however, BAT activity appears to be reduced with obesity, aging or Type 2 Diabetes (T2D). BAT
      has the unique capability to burn large amounts of sugar and fat and effectively dissipate
      this energy as heat due to the expression of uncoupling protein 1 (UCP1) which is controlled
      by a thermogenic gene program of transcription factors, co-activators and protein kinases.
      Thus, enhancing the thermogenic gene program may be beneficial for treating obesity and T2D.
      Despite the importance of BAT in regulating metabolism our understanding of the factors which
      suppress its metabolic activity with obesity, aging and T2D are largely unknown. Recently, it
      was shown that peripheral serotonin, which is regulated by the tryptophan hydroxylase 1
      (Tph1), is a negative regulator of BAT metabolic activity. In addition to serotonin, other
      studies have indicated that pro-inflammatory stimuli may also inhibit BAT metabolic activity.
      These data suggest that reduced activation of BAT may be due to increases in peripheral
      serotonin and inflammation. Importantly, the gut microbiome has recently been recognized as
      an important regulator of serotonin and inflammatory pathways suggesting the observed effects
      of the microbiome on obesity, T2D may be mediated in part through reductions in BAT activity.

      One mechanism by which the environment may impact BAT activity and the thermogenic gene
      program over the last 3 decades involves changes in our food supply as result of changes in
      agricultural production (chlorpyrifos, glyphosphate) and the addition of food additives
      (fructose). These agents have been reported to alter inflammation, serotonin metabolism and
      the gut microbiome indicating a potential bimodal (direct and indirect via the microbiome)
      mechanism by which they may alter the thermogenic gene program and contribute to chronic
      metabolic disease. Thus, our overarching hypothesis is that environmental agents and
      additives related to food production may contribute to the reduced metabolic activity of BAT.
      The objective is to identify and characterize how food production agents and additives reduce
      the metabolic activity of BAT.
    

Detailed description: 
      Each subject will follow 3 metabolic studies (A, B and C), each lasting 7.5h which includes a
      3h acute cold exposure.

      These studies will be almost identical: same perfusion of tracers, same number of Positron
      Emission Tomography (PET) acquisitions and same number of Magnetic Resonance Imaging (MRI)
      associated with Magnetic Resonance Spectroscopy (MRS) acquisitions .

      The difference will be in the diet ingested by the subjects two weeks before each metabolic
      study: during protocol A, the subjects will follow an isocaloric diet; during protocol B, the
      subjects will follow the same isocaloric diet supplemented with a daily beverage containing
      +25% of energy intake from fructose; and during protocol C, the subjects will follow the same
      isocaloric diet supplemented with a daily beverage containing +25% of energy intake from
      glucose.

      Stool samples will be collected for each metabolic study for microbiome flora and
      metabolites.
    

Intervention name(s): Diet; cold exposure; 18FDG; 11C-acetate; [3-3H]-glucose; [U-13C]-palmitate; 2H-Glycerol; MRI/MRS; Electromyogram (EMG); DXA; Indirect calorimetry
Intervention type(s): Dietary Supplement; Other; Radiation; Radiation; Radiation; Other; Other; Device; Device; Device; Device
Intervention description(s): A 2 weeks of hypercaloric diet supplemented with fructose or glucose; Acute cold exposure using a water-conditioned cooling suit will be applied from time 0 to 180 min. At the same time mean skin temperature will be measured by 11 thermocouples.; I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.; i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning; i.v. administration of 1.5 uCi/min of [3-3H]-glucose; i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate; i.v. administration of 0.05 µmol/kg/min of 2H-glycerol; Visceral and cervico-thoracic MRI and MRS acquisition.; Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes; Lean mass will be determined by dual-energy X-ray absorptiometry; VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.
Intervention MeSH terms: Glycerol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science