Cyclooxygenase-2 Controls Energy Homeostasis in Mice by de Novo Recruitment of Brown Adipocytes

Vegiopoulos, Alexandros; Müller‐Decker, Karin; Strzoda, Daniela; Schmitt, Iris; Chichelnitskiy, Evgeny; Ostertag, Agnès; Díaz, Mauricio Berriel; Rozman, Jan; Angelis, Martin Hrabě de; Nüsing, Rolf M.; Meyer, Carola W.; Wahli, Walter; Klingenspor, Martin; Herzig, Stephan

doi:10.1126/science.1186034

Cited by 400 publications

(407 citation statements)

References 23 publications

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“…In current and previous studies, we have demonstrated that BMP7 functions as a brown-fat inducer in both committed and noncommitted adipose progenitors. Recently, Vegiopoulos et al showed that Sca-1 + cells resident in white fat can respond to prostaglandin stimulation by differentiating into mature brown adipocytes (49). In addition, a subset of adipose progenitors resident in white fat acquires a brown-fat phenotype in response to rosiglitazone treatment (15).…”

Section: Discussionmentioning

confidence: 99%

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Schulz

Huang

Tran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

426

420

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Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1 + /CD45 − /Mac1 − ; referred to as Sca-1 + progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1 + cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.

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Section: Discussionmentioning

confidence: 99%

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Schulz

Huang

Tran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

426

420

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“…Recent studies [44,45] demonstrated the involvement of COX-2 in the induction of these fatburning cells and the importance of the COX-2-mediated mechanisms for the resistance to dietary obesity in mice. Our results convincingly demonstrate a marked induction of mitochondrial oxidative capacity in permeabilised adipocytes isolated from epididymal fat in response to mild calorie restriction combined with LC n-3 PUFA intake, using succinate as the optimum fuel [46].…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

et al. 2011

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Aims/hypothesis Calorie restriction is an essential component in the treatment of obesity and associated diseases. Longchain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. Methods Male mice (C57BL/6J) were habituated to a cornoil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF+F), ad libitum; (3) cHF with calorie restriction (CR; cHF+CR); and (4) cHF+F+CR. Mice fed a chow diet were also studied. Results We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ 12,15 -prostaglandin J 2 and protectin D1. Conclusions/interpretation White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.

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“…11 The first use of the term 'beige', to our knowledge, was by the Seale laboratory 12 in a commentary about a paper by Vegiopoulos et al 13 The first reports of the presence of 'brown adipocytes' among white adipocytes in traditionally white adipocyte depots to our knowledge, however, occurred 26 years earlier in the pioneering studies of Young et al 14 They reported brown adipocytes in the parametrial WAT pad of BALB/c mice acclimated to the cold, as identified morphologically by light and electron microscopy, and as possessing increases in a marker of brown adipocytes, mitochondrial UCP-1 content, 14 the finding of which the field and we turned a blind eye toward because such a presence was almost heretical, given the Zeitgeist of the time that WAT and BAT were separate tissues with separate functions. Loncar et al 15 soon after reported that young (10-13 weeks old) domestic cats exposed to − 30°C for 1 h twice a day during a week displayed brown-like adipocyte changes, most notably increases in mitochondria volume and surface density of mitochondrial cristae in several WAT depots not seen in the room temperature controls and more typical of brown adipocytes, not white ones.…”

Section: Methodsmentioning

confidence: 99%

Neural control of white, beige and brown adipocytes

Bartness

Ryu

2015

Int J Obes Supp

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Reports of brown-like adipocytes in traditionally white adipose tissue (WAT) depots occurred~30 years ago, but interest in white adipocyte 'browning' only has gained attention more recently. We integrate some of what is known about the sympathetic nervous system (SNS) innervation of WAT and brown adipose tissue (BAT) with the few studies focusing on the sympathetic innervation of the so-called 'brite' or 'beige' adipocytes that appear when WAT sympathetic drive increases (for example, cold exposure and food deprivation). Only one brain site, the dorsomedial hypothalamic nucleus (DMH), selectively browns some (inguinal WAT (IWAT) and dorsomedial subcutaneous WAT), but not all WAT depots and only when DMH neuropeptide Y gene expression is knocked down, a browning effect is mediated by WAT SNS innervation. Other studies show that WAT sympathetic fiber density is correlated with the number of brown-like adipocytes (multilocular lipid droplets, uncoupling protein-1 immunoreactivity) at both warm and cold ambient temperatures. WAT and BAT have sensory innervation, the latter important for acute BAT cold-induced temperature increases, therefore suggesting the possible importance of sensory neural feedback from brite/beige cells for heat production. Only one report shows browned WAT capable of producing heat in vivo. Collectively, increases in WAT sympathetic drive and the phenotype of these stimulated adipocytes seems critical for the production of new and/or transdifferentiation of white to brite/ beige adipocytes. Selective harnessing of WAT SNS drive to produce browning or selective browning independent of the SNS to counter increases in adiposity by increasing expenditure appears to be extremely challenging.

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Cyclooxygenase-2 Controls Energy Homeostasis in Mice by de Novo Recruitment of Brown Adipocytes

Cited by 400 publications

References 23 publications

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

Neural control of white, beige and brown adipocytes

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