How many patients were enrolled in the “in depth” study?

32 patients (33 for cell-samples) (26 women and 7 men) scheduled for operation due to benign thyroid disease were enrolled in the “in depth” study, which included perioperative collection of supraclavicular deep neck fat and abdominal subcutaneous fat and a pre-surgical metabolic characterization.

Why did the authors perform a multivariate regression analysis?

Due to the well-established relationship between age, sex, BMI and WHR, the authors next performed a multivariate regression analysis, including the above-mentioned variables as well as mean outdoor temperature one week prior to surgery, and applied manual backwards elimination of independent variables.

What is the role of brown fat in energy homeostasis and metabolism in humans?

Since the establishment of functionally competent BAT in adult humans, several studies have examined the role of active BAT in energy homeostasis and metabolism in human adult populations7–13.

Why were two of the participants excluded after the supplemental testing?

Two of the participants of the main study were excluded after the supplemental testing, in one case because surgery was cancelled, and in the other because of acute rescheduling, which made collection of biopsies unachievable.

What is the phenotypical feature of deep neck cells associated with UCP1?

the only phenotypical feature which was significantly associated with any aspect of cellular UCP1 levels was AGFR, which was negatively correlated to both basal and stimulated deep neck UCP1 (P = 0.012, R2 = 0.20, and P = 0.006, R2 = 0.23 respectively) (Figure S4B, and data not shown).

What is the relationship between UCP1 mRNA and obesity?

5Decreased UCP1 mRNA in human BAT is associated with increased abdominal obesity UCP1 mRNA expression was substantially higher in deep neck fat compared to subcutaneous adipose tissue (AT) (P < 0.0001) but displayed substantial variation between subjects.

What is the reason for the discrepancy in the biopsies?

A possible explanation for this discrepancy, is that the biopsies in their cohort were obtained at room temperature where variations in UCP1 might not reflect thermogenic capacity to the same extent as when subjects are subjected to cold, as UCP1 is highly induced in brown adipocytes upon norepinephrine stimulation31,32.

What is the effect of NE on UCP1 levels in deep neck cells?

Taken together these results indicate that despite an observed inverse effect of age, abdominal obesity, and impaired glucose tolerance on UCP1 expression in deep neck fat of adult humans, only the ratio between upper and lower fat deposition seem to negatively affect the abundance or determination of the brown fat precursor cells residing within the tissue, abide not to the extent where such precursors were absent.

What is the cellular UCP1 mRNA level in the deep neck depot?

In line with what the authors observed in the tissue, cellular UCP1 mRNA levels were highly variable between cultures from the deep neck depot, whereas all subcutaneous adipocytes expressed low basal UCP1 levels and only very few displayed a modest NE-induction (Figure 4A).

What was the study protocol and amendments?

The Scientific-Ethics Committees of the Capital Region of Denmark approved the study protocol and amendments, journal number; H-1-2014-015 and the study was performed in accordance with the Helsinki declaration.

What was the inverse of UCP1 expression in non-obese subjects?

Somewhat surprisingly, but possibly relating to the large variability in UCP1 expression in non-obese subjects, UCP1 expression was not consistently different between BMI groups and did not negatively correlate with BMI (Figure 1C-D).

Open AccessPosted Content10.1101/2020.05.07.082057

Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity

Q: What contributions have the authors mentioned in the paper "Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity" ?

In this paper, Naja Z. Jespersen, Maja W. Andersen, Verena H. Jensen, Thit W Stærkær, Mai C. Hahn, Preben Homøe, Susanne Mandrup, Bente K. Pedersen, Søren Nielsen, Camilla Scheele,

Q: How many adipocytes are present in the deep neck of adult humans with obesity?

Brown fat precursor cells are present in deep neck fat of adult humans with obesityTo further address the effects of obesity on deep neck brown adipose identity, the authors examined adipose derived progenitor cells from the described cohort.

Q: What was used to predict the contribution of thermogenic phenotype in each sample?

To predict the contribution of thermogenic phenotype in each sample, the computational tool ProFAT (REF) was employed on raw reads.

Q: What is the role of MZB1 in the immune response?

It has been demonstrated to be essential for the terminal differentiation of B-cells into antibody-secreting plasma cells, and specifically play an important role in the adaptive, T-cell-independent immune response51.

Naja Z. Jespersen, +15 more

- 08 May 2020

- bioRxiv

TL;DR: The data suggest a retained BAT identity, with a selective reduction of thermogenic genes, in human obesity.

Abstract: Obesity associates with a reduction in cold-induced glucose tracer uptake in brown adipose tissue in humans, suggesting loss of thermogenic capacity. We therefore hypothesized that a whitening of BAT occurs in obesity and assessed the molecular characteristics of deep neck BAT in a cohort of 24 normal weight, 24 overweight and 22 obese individuals in comparison with subcutaneous abdominal white adipose tissue (WAT). We found that the major marker of BAT thermogenesis, UCP1, was associated with central but not general obesity. We performed transcriptomic analysis of BAT in a cohort of 27 individuals classified as normal weight, over-weight or obese, and additionally four subjects with type 2 diabetes (T2DM), dispersed among the 3 BMI groups. We identified 3204 differentially expressed genes between BAT and WAT in samples from normal weight individuals, including genes involved in thermogenesis, but also revealing differences in developmental and immune system related genes. In BAT from individuals with overweight or obesity, 202 genes were downregulated and 66 of these were involved in cellular respiratory pathways, likely reflecting previously observed reduction in thermogenic function with obesity. Importantly, most BAT selective genes were not affected, and isolated adipose progenitors differentiated into thermogenic adipocytes with equal frequency regardless of BMI group. In conclusion, our data suggest a retained BAT identity, with a selective reduction of thermogenic genes, in human obesity.

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Most frequently asked questions

1. What contributions have the authors mentioned in the paper "Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity" ?

In this paper, Naja Z. Jespersen, Maja W. Andersen, Verena H. Jensen, Thit W Stærkær, Mai C. Hahn, Preben Homøe, Susanne Mandrup, Bente K. Pedersen, Søren Nielsen, Camilla Scheele,

2. How many adipocytes are present in the deep neck of adult humans with obesity?

Brown fat precursor cells are present in deep neck fat of adult humans with obesityTo further address the effects of obesity on deep neck brown adipose identity, the authors examined adipose derived progenitor cells from the described cohort.

3. What was used to predict the contribution of thermogenic phenotype in each sample?

To predict the contribution of thermogenic phenotype in each sample, the computational tool ProFAT (REF) was employed on raw reads.

4. What is the role of MZB1 in the immune response?

It has been demonstrated to be essential for the terminal differentiation of B-cells into antibody-secreting plasma cells, and specifically play an important role in the adaptive, T-cell-independent immune response51.

Citations

•Journal Article•10.1016/J.CMET.2020.07.005

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Denis P. Blondin, +22 more

- 04 Aug 2020

- Cell Metabolism

TL;DR: It is reported that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β3-AR, and pharmacological stimulation and inhibition of the β2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β2

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•Journal Article•10.1038/S42255-020-0205-X

Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

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- 21 May 2020

TL;DR: It is suggested that LINC00473 is a key regulator of human thermogenic adipocyte function and reveal a role for a lncRNA in interorganelle communication and human energy metabolism.

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•Journal Article•10.1016/J.CELL.2021.04.037

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Olivia Sveidahl Johansen, +57 more

- 24 Jun 2021

- Cell

TL;DR: In this paper, the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand.

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Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution

Christian Schlein, +20 more

- 12 Jan 2021

- Cell Reports

TL;DR: Using metabolic and lipidomic approaches, this article showed that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition.

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Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans

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- 10 Aug 2022

- Cardiovascular Research

TL;DR: The latest knowledge on the role of BAT in lipoprotein metabolism is described and the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes is addressed.

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References

•Journal Article•10.1186/S13059-014-0550-8

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Michael I. Love, +3 more

- 05 Dec 2014

- Genome Biology

TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.

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•Journal Article•10.1093/BIOINFORMATICS/BTS635

STAR: ultrafast universal RNA-seq aligner

Alexander Dobin, +8 more

- 01 Jan 2013

- Bioinformatics

TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.

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•Posted Content•10.1101/002832

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Michael I. Love, +2 more

- 17 Nov 2014

- bioRxiv

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Homeostasis model assessment : insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

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- 01 Jul 1985

- Diabetologia

TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

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•Journal Article•10.1016/J.MOLCEL.2010.05.004

Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

Sven Heinz, +10 more

- 28 May 2010

- Molecular Cell

TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.

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Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity

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Most frequently asked questions

1. What contributions have the authors mentioned in the paper "Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity" ?

2. How many adipocytes are present in the deep neck of adult humans with obesity?

3. What was used to predict the contribution of thermogenic phenotype in each sample?

4. What is the role of MZB1 in the immune response?

5. How many patients were enrolled in the “in depth” study?

6. Why did the authors perform a multivariate regression analysis?

7. What is the role of brown fat in energy homeostasis and metabolism in humans?

8. Why were two of the participants excluded after the supplemental testing?

9. What is the phenotypical feature of deep neck cells associated with UCP1?

10. What is the relationship between UCP1 mRNA and obesity?

11. What is the reason for the discrepancy in the biopsies?

12. What is the effect of NE on UCP1 levels in deep neck cells?

13. What is the cellular UCP1 mRNA level in the deep neck depot?

14. What was the study protocol and amendments?

15. What was the inverse of UCP1 expression in non-obese subjects?

Figures

Citations

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution

Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans

References

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

STAR: ultrafast universal RNA-seq aligner

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Homeostasis model assessment : insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

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