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

Gabriel Richard, Denis P Blondin, Saad A Syed, Laura Rossi, Michelle E Fontes, Mélanie Fortin, Serge Phoenix, Frédérique Frisch, Stéphanie Dubreuil, Brigitte Guérin, Éric E Turcotte, Martin Lepage, Michael G Surette, Jonathan D Schertzer, Gregory R Steinberg, Katherine M Morrison, André C Carpentier, Gabriel Richard, Denis P Blondin, Saad A Syed, Laura Rossi, Michelle E Fontes, Mélanie Fortin, Serge Phoenix, Frédérique Frisch, Stéphanie Dubreuil, Brigitte Guérin, Éric E Turcotte, Martin Lepage, Michael G Surette, Jonathan D Schertzer, Gregory R Steinberg, Katherine M Morrison, André C Carpentier

Abstract

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Keywords: brown adipose tissue; fructose; glucose; magnetic resonance; metabolic dysfunction; microbiome; overfeeding; positron emission tomography; short-chain fatty acids; stable isotopes.

Conflict of interest statement

Declaration of interests A.C.C. received research funding by Eli Lilly (2019–2021) and NovoNordisk (2021–ongoing) and consultation fees by HLS Therapeutics, Janssen Inc., Novartis Pharmaceuticals Canada Inc., and Novo Nordisk Canada Inc. K.M.M. is an advisory board member for NovoNordisk.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Body composition at baseline and following the high-carbohydrate diets No significant change in whole-body or tissue-specific composition was noted with the different diets. (A) Changes in body mass and composition assessed (after the diet - before the diet) by dual-energy X-ray absorptiometry (n = 10). (B) Energy expenditure from exercise assessed by uniaxial accelerometer at baseline (n = 8), during high fructose consumption (n = 10), and high glucose consumption (n = 9). (C) Whole-body energy expenditure at rest assessed by indirect calorimetry (n = 10). (D) Fat content of tissues assessed by Dixon MRI (n = 10). All p values are >0.05. BAT, brown adipose tissue; FM, fat mass; PDFF, proton-density fat fraction; LM, lean mass; scWAT, subcutaneous white adipose tissue; VAT, visceral adipose tissue. Participant 13 was excluded from the analyses due to antibiotic use (potential effects on the microbiome) before the fructose and glucose diets and is shown with a square symbol shape.
Figure 2
Figure 2
Fecal microbiome analyses and fecal short-chain fatty acids for the different diets (A) Relative abundance taxonomic summaries divided by diet and ordered by participant for all participants included in statistical analyses (n = 9). Top 12 genera in the data were colored and are identified in the legend. All other genera are in “other.” (B) Participants’ fecal microbial α-diversity assessed by Shannon and Simpson indices at baseline (n = 10), following high fructose consumption (n = 9) and high glucose consumption (n = 9). Each dot represents the value of the diversity metric from each sample. The boxes show the median and interquartile range. A generalized mixed-effects model found no significant differences by α-diversity. (C) Participants’ fecal microbial β-diversity assessed by Aitchison distance and visualized using a Principal-Coordinate Analysis plot. Each dot represents a sample and samples are colored by diet (baseline [n = 10], high fructose [n = 9], and high glucose [n = 9]). A permutational multivariate ANOVA found no significant differences by β-diversity. Percent variation explained by each axis is noted in square brackets. (D) Fecal short-chain fatty acid composition for baseline (n = 10), high fructose (n = 10), and high glucose (n = 9). No significant difference was observed between diets. (E) Fecal short-chain fatty acid ratios. No significant difference was observed between diets. All p values are >0.05. Participant 13 was excluded from the analyses due to antibiotic use (potential effects on the microbiome) before the fructose and glucose diets and is shown with a square symbol shape.
Figure 3
Figure 3
Brown adipose tissue oxidative metabolism and intracellular triglyceride depletion (A) Mean time-activity curves (with standard deviation) showing the uptake and elimination of 11C-acetate or its metabolites at room temperature (baseline) and during cold exposure (18°C) for baseline, fructose, and glucose diets. (B) Proton-density fat fraction shift in brown adipose tissue with cold exposure (18°C - room temperature) for the different diets (n = 10). There is no difference in shifts between diets. (C) Blood flow index at baseline (n = 10; room temperature and cold), high fructose (cold: n = 9), and high glucose (cold: n = 10). A repeated measures mixed-effects model found a significant difference between room temperature and cold exposure (all conditions). (D) Oxidative metabolism at baseline (n = 10; room temperature and cold), high fructose (cold: n = 9), and high glucose (cold: n = 10). A repeated measures mixed-effects model found a significant difference between room temperature and cold exposure (all conditions). p values are shown only for significant differences (i.e., p K1, 11C-acetate uptake rate; k2, 11C-acetate oxidation rate; RT, room temperature; SUV, standardized uptake value. Participant 13 was excluded from the analyses due to antibiotic use (potential effects on the microbiome) before the fructose and glucose diets and is shown with a square symbol shape. 11C-acetate was not performed for participant 13 fructose due to problems with tracer synthesis.
Figure 4
Figure 4
Glucose metabolism of tissues with cold exposure (A) Mean brown adipose tissue time-activity curves (with standard deviation) showing 18F-fluorodeoxyglucose uptake during cold exposure (18°C) for baseline, fructose, and glucose diets. (B) Brown adipose tissue fractional glucose uptake at baseline (cold: n = 10), high fructose (cold: n = 9), and high glucose (cold: n = 10). A repeated measures mixed-effects model found a significant difference between baseline and fructose. (C) Brown adipose tissue metabolic rate of glucose at baseline (cold: n = 10), high fructose (cold: n = 9), and high glucose (cold: n = 10). A repeated measures mixed-effects model found a significant difference between baseline and fructose. (D) Metabolic rate of glucose for brown adipose tissue compared with skeletal muscles and subcutaneous fat at baseline (cold: n = 10), high fructose (cold: n = 9), and high glucose (cold: n = 10). Data are shown as mean and 95% confidence interval. There was no significant difference for tissues other than BAT (repeated measures mixed-effects model baseline versus fructose). p values are shown only for significant differences (i.e., p 18F-FDG, 18F-fluorodeoxyglycose; BAT, brown adipose tissue; Ki, fractional glucose uptake; MRGlu, metabolic rate of glucose; SCM, sternocleidomastoid muscle; scWAT, lower back subcutaneous white adipose tissue; SUV, standardized uptake value. Participant 13 was excluded from the analyses due to antibiotic use (potential effects on the microbiome) before the fructose and glucose diets and is shown with a square symbol shape. Participant 2 fructose 18F-fluorodeoxyglucose was excluded due to excessive participant motion.
Figure 5
Figure 5
Effect of cold exposure on the liver and whole-body lipid metabolism (A) Proton-density fat fraction of the liver, visceral adipose tissue, and white adipose tissue at room temperature and in the cold (18°C) for each diet (n = 10). A two-way repeated measures ANOVA found a significant difference between room temperature and cold in the liver with fructose. (B) Changes in the rate of appearance of glycerol with cold exposure assessed by stable isotope dilution (n = 9). (C) Changes in the rate of appearance of non-esterified fatty acids with cold exposure assessed by stable isotope dilution at baseline (n = 9), high fructose (n = 10), and high glucose (n = 10). (D) Circulating very-low-density lipoprotein-triglycerides at room temperature and during cold (n = 10). A two-way repeated measures ANOVA found a significant difference between the baseline and high-carbohydrate diets in the cold. p values are shown only for significant differences (i.e., p a, rate of appearance; RT, room temperature; scWAT, subcutaneous white adipose tissue; VAT, visceral adipose tissue; VLDL-TG, very-low-density lipoprotein-triglycerides. Participant 13 was excluded from the analyses due to antibiotic use (potential effects on the microbiome) before the fructose and glucose diets and is shown with a square symbol shape.

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