Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages

Timmons, James A.; Wennmalm, Kristian; Larsson, Ola; Waldén, Tomas B.; Lassmann, Timo; Petrovič, Nataša; Hamilton, D. Lee; Gimeno, Ruth E.; Wahlestedt, Claes; Baar, Keith; Nedergaard, Jan; Cannon, Barbara

doi:10.1073/pnas.0610615104

Cited by 636 publications

(577 citation statements)

References 54 publications

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“…In addition, it has been suggested that a molecular signature of some precursors of brown adipocytes is the expression of muscle developmental gene, myogenic factor 5 (Myf5). 15,16 In this study, we did not detect mRNA of this gene in retroperitoneal fat in either ND or HFD rats (Supplementary Figure S4).…”

Section: Diet-induced Emergence Of Brown Fat In White Fatmentioning

confidence: 53%

“…43 In case of the latter, precursors of brown adipocytes are of the skeletal muscle lineage and are characterized by the expression of muscle developmental gene Myf5. 15,16 Their fate as to whether they develop into muscle or brown fat cells is determined to a great degree by the transcription factor PRDM16, which activates a complete brown fat-differentiation program in these precursor cells. 16 In the case of brown fat islands present in WAT, it is still debated whether they develop from specific precursors present in WAT or by a true transformation of white to brown adipocytes.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Importantly, the presence of these brownlike adipocytes in WAT, even in very small quantities, is associated with a significant reduction in whole-body adiposity. 14 Despite the recent advances in understanding brown fat adipogenesis, [15][16][17][18] the molecular mechanisms of brown fat emergence in traditional WAT have yet to be elucidated. A complex network of transcription factors that includes peroxisome proliferator-activated receptor-g coactivator1a (PGC-1a) controls brown fat adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

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High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

et al. 2011

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Obesity has a profound adverse impact on health. In this study, we present evidence for high-fat diet (HFD)-induced emergence of brown-like adipocytes in white adipose tissue (WAT) of the spontaneously hypertensive rat (SHR). We studied adult males fed a HFD or normal diet (ND) for 12 weeks. At the end of the 12-week dietary intervention, HFD compared with ND rats showed significantly higher whole-body energy expenditure. HFD vs. ND rats also showed higher expression of genes involved in fatty acid oxidation, mitochondrial biogenesis and brown fat adipogenesis, as well as augmented mitochondrial mass in WAT but not in the liver or skeletal muscle. Consistent with the molecular changes, in HFD but not in ND rats, histological and immunohistochemistry-based analyses of WAT demonstrated the presence of small multilocular cells staining positively for uncoupling protein 1, indicating the emergence of brown-like adipocytes in WAT. Our results suggest that SHR may have the capacity to increase energy expenditure in response to a chronic HFD that may be linked to the emergence of brown-like adipocytes in WAT. Thus, the SHR may be an important genetic model to uncover novel mechanisms of resistance to dietary obesity.

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Section: Diet-induced Emergence Of Brown Fat In White Fatmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

et al. 2011

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“…Again it should not be surprising that acquirement of thermogenic competence is not paralleled by promotion of adipose conversion, as the brown adipocytes studied here are of a different lineage from those giving rise to white adipocytes and are more related to muscle cells. 19,20,44,45 …”

Section: Discussionmentioning

confidence: 99%

“…Classically, brown adipocytes and white adipocytes were considered closely related cell types, and adipose conversion was therefore considered a positive sign of differentiation even of brown adipocytes. However, in the early phases of differentiation, brown adipocytes express a series of myogenic genes, both transcription factors and structural proteins, 19 and the lineage of classical brown adipocytes is closely related to that of skeletal muscle. 20 Thus, acquisition of an adipocyte phenotype may not indicate progression to fully differentiated brown adipocyte characteristics.…”

Section: Introductionmentioning

confidence: 99%

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

2018

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Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (“fetal bovine” versus “newborn calf”) on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion (Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.

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Time‐series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis

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Stone

et al. 2012

Arthritis & Rheumatism

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Objective. Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non-OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression.Methods. Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice.Results. We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-B signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice.Conclusion. This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-B signaling pathways, skeletal musclerelated genes, and induction and/or progression of OA.Osteoarthritis (OA) is a complex age-related, multifactorial, polygenic disease characterized by degradation and consequent loss of the extracellular matrix (ECM) of the articular cartilage (AC) (1). Chondrocytes, the only resident cells of AC, are vital for maintaining the integrity of normal joints, but they also contribute to the initiation and progression of the loss of AC in OA (2,3). These dual roles in healthy ECM remodeling and in pathologic changes in the AC have made it difficult to identify targets by which to limit OA development or protect against increased susceptibility during aging.The study of OA currently relies upon in vivo animal models, partly because it is difficult to obtain AC samples during specific stages of OA in humans, as well as healthy site-and age-matched samples for comparison. Preclinical models of OA are also needed for drug development (4). Alternative comparative approaches in humans have relied mostly upon using normal AC samples and samples obtained during late-stage OA or

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Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages

Cited by 636 publications

References 54 publications

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

Time‐series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis

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