. 2021 Sep 14;2(9):100397.

doi: 10.1016/j.xcrm.2021.100397. eCollection 2021 Sep 21.

Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota

Basma A Ahmed^{1

2}, Frank J Ong^{1

3}, Nicole G Barra^{1

2

4}, Denis P Blondin⁵, Elizabeth Gunn^{1

3}, Stephan M Oreskovich^{1

3}, Jake C Szamosi^{4

6}, Saad A Syed², Emily K Hutchings^{1

3}, Norman B Konyer⁷, Nina P Singh⁸, Julian M Yabut^{1

9}, Eric M Desjardins^{1

9}, Fernando F Anhê^{1

2

4}, Kevin P Foley^{1

2

4}, Alison C Holloway^{1

10}, Michael D Noseworthy^{1

7

8

11

12}, Francois Haman¹³, Andre C Carpentier¹⁴, Michael G Surette^{1

2

4

15}, Jonathan D Schertzer^{1

2

4}, Zubin Punthakee^{1

3

9}, Gregory R Steinberg^{1

2

9}, Katherine M Morrison^{1

3}

Affiliations

¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
³ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴ Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Faculty of Medicine and Health Sciences, Department of Medicine, Division of Neurology, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
⁶ Farncombe Metagenomics Facility, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁷ Imaging Research Centre, St. Joseph's Healthcare, Hamilton, ON L8N 4A6, Canada.
⁸ Department of Radiology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁹ Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹⁰ Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹¹ Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹² School of Biomedical Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹³ Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
¹⁴ Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
¹⁵ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.

PMID: 34622234
PMCID: PMC8484690
DOI: 10.1016/j.xcrm.2021.100397

Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota

Basma A Ahmed et al. Cell Rep Med. 2021.

. 2021 Sep 14;2(9):100397.

doi: 10.1016/j.xcrm.2021.100397. eCollection 2021 Sep 21.

Authors

Affiliations

¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
³ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴ Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Faculty of Medicine and Health Sciences, Department of Medicine, Division of Neurology, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
⁶ Farncombe Metagenomics Facility, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁷ Imaging Research Centre, St. Joseph's Healthcare, Hamilton, ON L8N 4A6, Canada.
⁸ Department of Radiology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁹ Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹⁰ Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹¹ Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹² School of Biomedical Engineering, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹³ Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
¹⁴ Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
¹⁵ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.

PMID: 34622234
PMCID: PMC8484690
DOI: 10.1016/j.xcrm.2021.100397

Abstract

In rodents, lower brown adipose tissue (BAT) activity is associated with greater liver steatosis and changes in the gut microbiome. However, little is known about these relationships in humans. In adults (n = 60), we assessed hepatic fat and cold-stimulated BAT activity using magnetic resonance imaging and the gut microbiota with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity through the microbiota. Individuals with NAFLD (n = 29) have lower BAT activity than those without, and BAT activity is inversely related to hepatic fat content. BAT activity is not related to the characteristics of the fecal microbiota and is not transmissible through fecal transplantation to mice. Thus, low BAT activity is associated with higher hepatic fat accumulation in human adults, but this does not appear to have been mediated through the gut microbiota.

Keywords: adult humans; brown adipose tissue; cold exposure; fecal transplant; germ-free mice; hepatic fat; magnetic resonance imaging; microbiota; non-alcoholic fatty liver disease; proton density fat fraction.

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Conflict of interest statement

B.A.A. holds the Lau Family scholarship for science and engineering and was funded by the Ontario graduate scholarship. D.P.B. holds the GlaxoSmithKline (GSK) Chair in Diabetes of Université de Sherbrooke, which was created in part through a donation of $1 million by GSK to Université de Sherbrooke. D.P.B. has received honoraria and consulting fees from Boehringer Ingelheim. S.A.S. holds a CIHR Vanier Canada Graduate Scholarship. E.M.D. holds a CIHR Vanier Canada Graduate Scholarship. F.F.A. holds a CIHR postdoctoral fellowship and Diabetes Canada incentive funding. A.C.H. holds research funding from the CIHR and the Natural Sciences and Engineering Research Council of Canada. A.C.C. holds the Canada Research Chair in Molecular Imaging of Diabetes and research funding from the CIHR, Fonds de recherche Québec – Santé, and has participated in advisory boards for Amgen, UniQure, Merck, Janssen, Novo Nordisk, Novartis, HLS Therapeutics Inc., TVM Life Science Management, AstraZeneca, and Eli Lilly and participated in one conference sponsored by AstraZeneca. M.G.S. is funded by the CIHR, Genome Canada, and the W. Garfield Weston Foundation and holds a Tier 1 Canada Research Chair in Interdisciplinary Microbiome Research. J.D.S. receives funding from the CIHR (FDN-154295) and holds a Canada Research Chair in Metabolic Inflammation. Z.P. has received honoraria for advice and speaking from Abbott, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi, and has received research funds from Amgen, Astra Zeneca/Bristol Myers Squibb, Lexicon, Merck, Novo Nordisk, Sanofi, and the CIHR. G.R.S. receives funding from the CIHR (201709FDN-CEBA-116200), Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Tier 1 Canada Research Chair, and the J. Bruce Duncan Endowed Chair in Metabolic Diseases. He also receives research funding from Espervita Therapeutics, Esperion Therapeutics, Novo Nordisk, and Poxel Pharma and honoraria and consulting fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Poxel, and Merck. K.M.M. holds research funding from the CIHR, Heart and Stroke Foundation of Canada, McMaster Children’s Hospital Foundation, and McMaster University. She has received research funds from Astra Zeneca and is an advisory board member for Novo Nordisk and Akcea Therapeutics, Canada.

Figures

**Figure 1**
Individuals with hepatic steatosis have lower cold-induced percentage decline in supraclavicular proton density fat fraction (A) Comparison of the cold-induced percentage decline in supraclavicular (SCV) proton density fat fraction (PDFF) (%) between those without (non-alcoholic fatty liver disease [NAFLD] negative, n = 30) and with (NAFLD positive, n = 29) hepatic steatosis; data are presented as mean ± standard error of the mean (SEM) for each group. (B) Relationship of the cold-induced percentage decline in SCV PDFF (%) with hepatic PDFF (%) in men (blue circles) and women (red triangles). †p < 0.05, Mann-Whitney U test; §p < 0.05, Spearman’s correlation.

**Figure 2**
Cold-induced percentage decline in supraclavicular proton density fat fraction, age, adiposity, and glucose homeostasis (A–F) Relationship of the cold-induced percentage decline in supraclavicular (SCV) proton density fat fraction (PDFF) (%) with age (A), body fat percentage (B), waist circumference (C), hemoglobin A_1c (HbA_1c) (D), fasting glucose (E), and 2 h 75 g oral glucose tolerance test (OGTT) glucose (F) in men (blue circles) and women (red triangles). ∗p < 0.05, Pearson’s correlation; §p < 0.05, Spearman’s correlation. See Table S3.

**Figure 3**
Relationship of gut microbiota to cold-induced percent decline in supraclavicular fat fraction (A) Alpha diversity between brown adipose tissue (BAT) groups (low and high BAT activity). (B) Principal coordinate analysis (PCoA) plot on Bray-Curtis dissimilarity distances between BAT groups. (C) Relative abundance of top 25 genera between BAT groups. For (A), data are represented as the median, interquartile range, and 95% range of the data. The colored points and lines are the point estimates of the means from the regression models and the 95% confidence intervals of the model estimates of the means, respectively. For (B), axes 1 and 2 captured 16.4% and 7.3% in the variation between samples, respectively. See Tables S3 and S4 and Figure S3.

**Figure 4**
Human brown adipose tissue activity and NAFLD status are not transmissible via gut microbes in germ-free mice (A and B) Weekly body mass (A) and percentage fat mass (B). (C) Average oxygen consumption (Vo₂) during light and dark cycles and over a 24 h period (average of light and dark) after 5 weeks of colonization. (D and E) Oxygen consumption (D) and dorsal interscapular surface temperature of anesthetized mice following saline or CL-316,243 administration after 6–7 weeks of colonization (E). (F) Representative infrared images from each group after saline or CL-316,243. (G) Liver triglycerides after 7–8 weeks of colonization (n = 9 H-BAT/NAFLD− and n = 12 L-BAT/NAFLD+). Data are expressed as mean ± SEM. Significance was determined using Student’s t test or two-way repeated-measure analysis of variance (ANOVA) and Sidak’s post hoc test; †p < 0.05 versus saline. See Figures S4 and S5 and Table S5.

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Comment in

Low brown adipose tissue activity linked to NAFLD.
Greenhill C. Greenhill C. Nat Rev Endocrinol. 2021 Dec;17(12):707. doi: 10.1038/s41574-021-00579-x. Nat Rev Endocrinol. 2021. PMID: 34594015 No abstract available.

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Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota

Affiliations

Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

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