Basal adrenergic tone is required for maximal stimulation of rat brown adipose tissue UCP1 expression by chronic PPAR-γ activation

Festuccia, William T.; Blanchard, Pierre‐Gilles; Richard, Denis; Deshaies, Yves

doi:10.1152/ajpregu.00821.2009

Cited by 54 publications

(41 citation statements)

References 44 publications

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“…Supporting these findings, 24 h of cold exposure did not additively increase BAT UCP1 expression further than that induced by rosiglitazone alone in rats (10). The absence of additive effects of simultaneous PPAR␥ and adrenergic activation on BAT gene expression was quite unexpected in the face of both the reduced sympathetic drive to BAT found upon PPAR␥ ligand treatment of rats living in a standard thermal environment (14), as well as our recent findings indicating that the optimal upregulation of UCP1 by PPAR␥ activation depends upon the presence of intact BAT sympathetic innervation and maintenance of minimal basal sympathetic tone (10).…”

supporting

confidence: 53%

“…The markedly increased BAT mass (10,11) and UCP1 content induced by rosiglitazone did not lead to higher energy expenditure upon cold exposure, as estimated by body weight gain, feed efficiency, and V O 2 . These findings are in contrast with the additive increase in energy expenditure found upon concomitant treatment of mice with a PPAR␥ ligand and the ␤3 adrenergic receptor agonist CL-316243 (26).…”

Section: Discussionmentioning

confidence: 75%

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PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2

Festuccia

Blanchard

Oliveira

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Here, we investigated whether pharmacological PPARγ activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPARγ signaling. Sprague-Dawley rats treated or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1), 7 days) were kept at 23°C or exposed to cold (5°C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, Vo(2), and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1α mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) β mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold-induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1α, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPARγ activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity.

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supporting

confidence: 53%

Section: Discussionmentioning

confidence: 75%

PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2

Festuccia

Blanchard

Oliveira

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…BAT was found to be recruited by rosiglitazone independently of sympathetic tone, but maximal UCP-1 expression required adrenergic 'priming' [33]. In their studies, the adrenergic 'prime' was reduced by lowered sympathetic drive linked to chronic reduction in thyroid signalling within BAT [31].…”

Section: Discussionmentioning

confidence: 96%

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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“…Interestingly, a third type of adipocyte, named brite (brownin-white) (42) or beige (27), has been identified in WAT and in cultures of human (6,7,16,26) and rodent (3,12,17,19,20,25,34,42,59,67) white adipocytes exposed to sustained treatment with high-affinity peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists (e.g., the thiazolidinedione rosiglitazone) and/or ␤-adrenergic agonists. These brite/beige cells (here referred to as brite cells) express many of the genes specifically expressed in brown adipocytes, but they also express genes that are characteristic for brite cells (e.g., the homeobox c9 [Hoxc9] and short stature homeobox 2 [Shox2] genes) (42,65).…”

mentioning

confidence: 99%

Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor γ in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression

Siersbæk

Loft

Aagaard

et al. 2012

Molecular and Cellular Biology

115

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPAR␥ binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPAR␥ differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPAR␥ binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPAR␥ binding profiles are overall similar, there are clear depot-selective binding sites. Most PPAR␥ binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPAR␥ binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPAR␥ is associated with highly depot-specific gene expression. This indicates that PPAR␥ plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPAR␥ lineage-specific recruitment even when differentiated in vitro.M ammals have fat depots at various locations in the body. Classically, these tissues have been characterized as either white adipose tissue (WAT) or brown adipose tissue (BAT). Both tissues store energy in the form of triglycerides; however, whereas WAT releases the energy as fatty acids that can be converted to metabolic energy in other tissues, BAT metabolizes the fatty acids in the adipocytes and releases the energy as heat. This unique energy-dispersing function of BAT relies on the high number of mitochondria in the adipocytes and the expression and activation of uncoupling protein 1 (UCP1), residing in the inner mitochondrial membrane (9). Previously, BAT was thought to be present only in newborn and hibernating mammals; however, recently it was demonstrated that also human adults have discrete BAT depots (13,38,46,58,61). It has been suggested that activation of these BAT depots could increase energy expenditure and lead to weight loss. Consistent with this, there seems to be a negative correlation between body mass index and the presence of BAT (13,68,69) Notably, it has also been indicated that different WAT depots are not identical but have different properties (57,62). It is currently unclear to what extent differences between the distinct WAT depots reflect differences at the cellular level between adipocytes in the depots or reflect context-dependent differences (e.g., microenvironment); however, recent evidence indicates that different subtypes of white adipocytes do exist. Thus, several studies have demonstrated different gene expression profiles between visceral and subcutaneous WAT and preadipocytes and adipocytes from these tiss...

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Basal adrenergic tone is required for maximal stimulation of rat brown adipose tissue UCP1 expression by chronic PPAR-γ activation

Cited by 54 publications

References 44 publications

PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2

PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2

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

Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor γ in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression

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