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

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.

Conditions

• Type2 Diabetes

Interventions

DIETARY_SUPPLEMENT

Diet

A 2 weeks of hypercaloric diet supplemented with fructose or 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.

Sponsors & Collaborators

• McMaster University

  collaborator OTHER

• University of Ottawa

  collaborator OTHER

• Université de Sherbrooke

  lead OTHER

Principal Investigators

• André C. Carpentier · Université de Sherbrooke

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

20 Years

Max Age

35 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-05-23

Primary Completion

2020-12-17

Completion

2021-04-30

Countries

• Canada

Study Locations