Effects of Fructose/Glucose-rich Diet on Brown Fat in Healthy Subjects (GB7) (GB7)

Brown Fat Energy Metabolism During Cold Exposure: Effects of Fructose- or Glucose-rich Diet in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes
• Intervention / Treatment: Other: cold exposure; Radiation: 18FDG; Radiation: 11C-acetate; Radiation: [3-3H]-glucose; Other: [U-13C]-palmitate; Other: 2H-Glycerol; Device: MRI/MRS; Device: Electromyogram (EMG); Device: DXA; Device: Indirect calorimetry; Dietary supplement: Diet

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre de Recherche du CHUS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy subjects: subjects with normal glucose tolerance determined according to an oral glucose tolerance test and with a BMI < 27 kg/m2 without first degree of familial history of type 2 diabetes (parents, siblings).

Exclusion Criteria:

1. Plasma triglycerides > 5.0 mmol/L at fasting;
2. More than 2 alcohol consumption per day;
3. More than 1 cigarette per day;
4. History of total cholesterol level > 7 mmol/L, of cardiovascular disease, hypertensive crisis;
5. Treatment with fibrates, thiazolidinedione, insulin, beta-blockers or other drugs with effects on insulin resistance or lipid metabolism (exception for anti-hypertensive drugs, statins or metformin);
6. Presence of a non-controlled thyroid disease, renal or hepatic disease, history of pancreatitis, bleeding diatheses, cardiovascular disease or any other serious medical conditions;
7. History of serious gastrointestinal disorders (malabsorption, peptic ulcer, gastroesophageal reflux having required a surgery, etc.);
8. Presence of a pacemaker;
9. Have undergone of PET study or CT scan in the past year;
10. Chronic administration of any medication;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Isocaloric Diet; Two weeks of isocaloric diet	Other: cold exposure; 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.; Radiation: 18FDG; I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.; Radiation: 11C-acetate; i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning; Radiation: [3-3H]-glucose; i.v. administration of 1.5 uCi/min of [3-3H]-glucose; Other: [U-13C]-palmitate; i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate; Other: 2H-Glycerol; i.v. administration of 0.05 µmol/kg/min of 2H-glycerol; Device: MRI/MRS; Visceral and cervico-thoracic MRI and MRS acquisition.; Device: Electromyogram (EMG); Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes; Device: DXA; Lean mass will be determined by dual-energy X-ray absorptiometry; Device: Indirect calorimetry; VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.
Other: Fructose diet; Two weeks of hypercaloric diet supplemented with fructose	Other: cold exposure; 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.; Radiation: 18FDG; I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.; Radiation: 11C-acetate; i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning; Radiation: [3-3H]-glucose; i.v. administration of 1.5 uCi/min of [3-3H]-glucose; Other: [U-13C]-palmitate; i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate; Other: 2H-Glycerol; i.v. administration of 0.05 µmol/kg/min of 2H-glycerol; Device: MRI/MRS; Visceral and cervico-thoracic MRI and MRS acquisition.; Device: Electromyogram (EMG); Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes; Device: DXA; Lean mass will be determined by dual-energy X-ray absorptiometry; Device: Indirect calorimetry; VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.; Dietary supplement: Diet; A 2 weeks of hypercaloric diet supplemented with fructose or glucose
Other: Glucose diet; Two weeks of hypercaloric diet supplemented with glucose	Other: cold exposure; 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.; Radiation: 18FDG; I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.; Radiation: 11C-acetate; i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning; Radiation: [3-3H]-glucose; i.v. administration of 1.5 uCi/min of [3-3H]-glucose; Other: [U-13C]-palmitate; i.v. administration of 0.08 umol/kg/min of [U-13C]-palmitate; Other: 2H-Glycerol; i.v. administration of 0.05 µmol/kg/min of 2H-glycerol; Device: MRI/MRS; Visceral and cervico-thoracic MRI and MRS acquisition.; Device: Electromyogram (EMG); Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes; Device: DXA; Lean mass will be determined by dual-energy X-ray absorptiometry; Device: Indirect calorimetry; VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.; Dietary supplement: Diet; A 2 weeks of hypercaloric diet supplemented with fructose or glucose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome flora	assessed from stool samples	4 months
Microbiome metabolites	assessed from stool samples	4 months
BAT oxidative metabolism	will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning	4 months
BAT triglyceride content	will be determined by radiodensity or MRS	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
energy metabolism (whole body production)	by indirect calorimetry	4 months
BAT blood flow	will be determined using i.v. injection of 11C-acetate during dynamic PET/CT scanning	4 months
BAT net glucose uptake	will be assessed using i.v. injection of 18FDG with sequential dynamic PET/CT scanning.	4 months
Whole-body glucose partitioning	will be assessed using i.v. injection of 18FDG with static PET/CT scanning	4 months
BAT volume of metabolic activity	will be determined using a total body CT (16 mA) followed by a PET acquisition	4 months
metabolites appearance rate	will be determined by perfusion of stable isotope tracers	12 months
hormonal responses	analysed by colorimetric and Elisa tests	12 months

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: McMaster University; University of Ottawa
• Investigators: Principal Investigator: André C. Carpentier, Université de Sherbrooke

Publications and helpful links

General Publications

• Richard G, Blondin DP, Syed SA, Rossi L, Fontes ME, Fortin M, Phoenix S, Frisch F, Dubreuil S, Guerin B, Turcotte EE, Lepage M, Surette MG, Schertzer JD, Steinberg GR, Morrison KM, Carpentier AC. High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome. Cell Rep Med. 2022 Sep 20;3(9):100742. doi: 10.1016/j.xcrm.2022.100742.

Helpful Links

• High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome
• Human brown adipose tissue is not enough to combat cardiometabolic diseases

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2017
• Primary Completion (Actual): December 17, 2020
• Study Completion (Actual): April 30, 2021

Study Registration Dates

• First Submitted: June 13, 2017
• First Submitted That Met QC Criteria: June 14, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 22, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Protective Agents; Cryoprotective Agents; Glycerol
• Other Study ID Numbers: 2017-1459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No