A Classical Brown Adipose Tissue mRNA Signature Partly Overlaps with Brite in the Supraclavicular Region of Adult Humans

Jespersen, Naja Zenius; Larsen, Therese Juhlin; Peijs, Lone; Daugaard, Søren; Homøe, Preben; Loft, Annika; Jong, Jasper de; Mathur, Neha; Cannon, Barbara; Nedergaard, Jan; Pedersen, Bente Klarlund; Møller, Kirsten; Schéele, Camilla

doi:10.1016/j.cmet.2013.04.011

Cited by 491 publications

(477 citation statements)

References 32 publications

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“…TZDs also induce browning in human adipocyte culture models [13] and rosiglitazone is used almost universally to promote differentiation and browning of human cultured brown adipocytes [13][14][15][16][17]. Rosiglitazone and, to a lesser extent, pioglitazone were widely prescribed for type 2 diabetes until safety concerns were raised (primarily with rosiglitazone [18]), leaving pioglitazone as the predominantly prescribed TZD worldwide [19].…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

et al. 2017

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Aims/hypothesis Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans. Methods We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [ 18 F]fluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention. Results Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, coldElectronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4479-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. -017-4479-9 induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (−57 ± 6% vs −12 ± 18%, respectively; p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (−50 ± 10% vs −6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected. Conclusions/interpretation The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs.Trial registration ClinicalTrials.gov NCT02236962

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Section: Introductionmentioning

confidence: 99%

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

et al. 2017

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“…Wu et al 10 and Sharp et al 11 reported that supraclavicular tissue, the largest FDG-PET-positive depot in humans, expresses selective markers of beige fat cells. By contrast, Jesperson et al 37 found that tissue and in vitro-differentiated adipocytes from this depot express both brownand beige-specific markers. A different depot in the neck region was shown to have the molecular characteristics of mouse brown fat 38 .…”

Section: Yesmentioning

confidence: 99%

Brown and beige fat: development, function and therapeutic potential

Harms

Seale

2013

Nat Med

1,889

2,000

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Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.npg

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“…2e, f). Moreover, two white adipose tissue markers (HOXC8, HOXC9) that are downregulated in human brown adipose tissue [29] were upregulated by HFO (ESM Table 3). Comparison with mRNA data from other overfeeding studies…”

Section: Changes In Sat Expression In Response To Hfomentioning

confidence: 99%

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

et al. 2016

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Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes-and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

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A Classical Brown Adipose Tissue mRNA Signature Partly Overlaps with Brite in the Supraclavicular Region of Adult Humans

Cited by 491 publications

References 32 publications

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

Brown and beige fat: development, function and therapeutic potential

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

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