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

NCT ID: NCT03188835

Last Updated: 2025-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-23
• Study Completion Date: 2021-04-30

Brief 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.

Conditions

Type2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Isocaloric Diet

Two weeks of isocaloric diet

Group Type: OTHER

2H-Glycerol

Intervention Type: OTHER

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

MRI/MRS

Intervention Type: DEVICE

Visceral and cervico-thoracic MRI and MRS acquisition.

Electromyogram (EMG)

Intervention Type: DEVICE

Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes

DXA

Intervention Type: DEVICE

Lean mass will be determined by dual-energy X-ray absorptiometry

Indirect calorimetry

Intervention Type: DEVICE

VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.

cold exposure

Intervention Type: OTHER

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.

18FDG

Intervention Type: RADIATION

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.

11C-acetate

Intervention Type: RADIATION

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

[3-3H]-glucose

Intervention Type: RADIATION

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

[U-13C]-palmitate

Intervention Type: OTHER

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

Fructose diet

Two weeks of hypercaloric diet supplemented with fructose

Group Type: OTHER

2H-Glycerol

Intervention Type: OTHER

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

MRI/MRS

Intervention Type: DEVICE

Visceral and cervico-thoracic MRI and MRS acquisition.

Electromyogram (EMG)

Intervention Type: DEVICE

Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes

DXA

Intervention Type: DEVICE

Lean mass will be determined by dual-energy X-ray absorptiometry

Indirect calorimetry

Intervention Type: DEVICE

VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.

Diet

Intervention Type: DIETARY_SUPPLEMENT

A 2 weeks of hypercaloric diet supplemented with fructose or glucose

cold exposure

Intervention Type: OTHER

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.

18FDG

Intervention Type: RADIATION

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.

11C-acetate

Intervention Type: RADIATION

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

[3-3H]-glucose

Intervention Type: RADIATION

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

[U-13C]-palmitate

Intervention Type: OTHER

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

Glucose diet

Two weeks of hypercaloric diet supplemented with glucose

Group Type: OTHER

2H-Glycerol

Intervention Type: OTHER

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

MRI/MRS

Intervention Type: DEVICE

Visceral and cervico-thoracic MRI and MRS acquisition.

Electromyogram (EMG)

Intervention Type: DEVICE

Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes

DXA

Intervention Type: DEVICE

Lean mass will be determined by dual-energy X-ray absorptiometry

Indirect calorimetry

Intervention Type: DEVICE

VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.

Diet

Intervention Type: DIETARY_SUPPLEMENT

A 2 weeks of hypercaloric diet supplemented with fructose or glucose

cold exposure

Intervention Type: OTHER

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.

18FDG

Intervention Type: RADIATION

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.

11C-acetate

Intervention Type: RADIATION

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

[3-3H]-glucose

Intervention Type: RADIATION

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

[U-13C]-palmitate

Intervention Type: OTHER

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

Interventions

2H-Glycerol

i.v. administration of 0.05 µmol/kg/min of 2H-glycerol

Intervention Type: OTHER

MRI/MRS

Visceral and cervico-thoracic MRI and MRS acquisition.

Intervention Type: DEVICE

Electromyogram (EMG)

Skeletal muscle activity and shivering intensity will be measured by electromyography using surface electrodes

Intervention Type: DEVICE

DXA

Lean mass will be determined by dual-energy X-ray absorptiometry

Intervention Type: DEVICE

Indirect calorimetry

VCO2 will be measured by indirect calorimetry between 15 and 20 min every hour until time 180.

Intervention Type: DEVICE

Diet

A 2 weeks of hypercaloric diet supplemented with fructose or glucose

Intervention Type: DIETARY_SUPPLEMENT

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.

Intervention Type: OTHER

18FDG

I.v. injection of 18-fluorodeoxyglucose (18FDG) will be performed, followed by 30 min dynamic and 50 min wholebody PET/CT scanning.

Intervention Type: RADIATION

11C-acetate

i.v. injection of 11C-acetate will be performed, followed by 20 min dynamic PET/CT scanning

Intervention Type: RADIATION

[3-3H]-glucose

i.v. administration of 1.5 uCi/min of \[3-3H\]-glucose

Intervention Type: RADIATION

[U-13C]-palmitate

i.v. administration of 0.08 umol/kg/min of \[U-13C\]-palmitate

Intervention Type: OTHER

Eligibility Criteria

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;

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

McMaster University

OTHER

Sponsor Role: collaborator

University of Ottawa

OTHER

Sponsor Role: collaborator

Université de Sherbrooke

OTHER

Sponsor Role: lead

Responsible Party

André Carpentier

tenured professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

André C. Carpentier

Role: PRINCIPAL_INVESTIGATOR

Université de Sherbrooke

Locations

Centre de recherche du CHUS

Sherbrooke, Quebec, Canada

Countries

Canada

References

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.

Reference Type: DERIVED

PMID: 36130480 (View on PubMed)

Related Links

https://pubmed.ncbi.nlm.nih.gov/36130480/

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome

https://www.jci.org/articles/view/175288

Human brown adipose tissue is not enough to combat cardiometabolic diseases

Other Identifiers

2017-1459

Identifier Type: -

Identifier Source: org_study_id