Twist-1 Is a PPARδ-Inducible, Negative-Feedback Regulator of PGC-1α in Brown Fat Metabolism

Pan, Dongning; Fujimoto, M.; Lopes, Andréa Cintra; Wang, Yong-Xu

doi:10.1016/j.cell.2009.01.051

Cited by 206 publications

(237 citation statements)

References 50 publications

Supporting

Mentioning

226

Contrasting

Unclassified

Order By: Relevance

“…Consistent with deficient adaptive thermogenesis, these animals also have compromised ability to maintain their body temperature during cold exposure [81]. In contrast, targeted activation of PPAR in adipose tissue specifically induces expression of genes required for FFA oxidation and energy dissipation in BAT and UCP1 expression in WAT thereby leading to reduced adiposity and improved lipid profiles.…”

Section: Ppar and Insulin Resistancementioning

confidence: 93%

“…Interestingly, TWIST1, a helix-loop-helix containing transcriptional regulator selectively expressed in adipose tissue was recently demonstrated to act as a negative-feedback regulator of PGC1 /PPAR -mediated brown fat metabolism [81]. TWIST1 was shown to interact with PGC1 , and to be recruited to PGC1 "s target gene promoters to suppress mitochondrial oxidative metabolism and uncoupling (by promoting histone deacetylation).…”

mentioning

confidence: 99%

“…These phenotypes were consequent to altered mitochondrial metabolism and uncoupling in brown fat. Interestingly, PPAR was shown to induce TWIST1 expression (both in vitro and in vivo) in response to pharmacological activation, suggesting a negative-feedback regulatory mechanism [81].…”

mentioning

confidence: 99%

See 2 more Smart Citations

PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

115

View full text Add to dashboard Cite

Abstract:For long viewed as passive lipid storage depots, adipocytes are now recognised as key players in the pathogenesis of insulin resistance and metabolic disease. In parallel, the last two decades of research have seen the emergence of transcription factors of the peroxisome proliferator-activated receptor (PPAR) family as central regulators of lipid and glucose homeostasis and molecular targets for drugs to treat hyper-lipidaemia and type 2 diabetes mellitus. In this review we discuss the characteristics of PPARs and the role of the different isotypes in adipocyte biology.

show abstract

Section: Ppar and Insulin Resistancementioning

confidence: 93%

mentioning

confidence: 99%

See 1 more Smart Citation

PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

115

View full text Add to dashboard Cite

show abstract

“…Therefore, it is likely that a reciprocal regulation of the Twist transcription factors occurs with different BMP/TGFb and Wnt signaling components that collectively act to regulate the lineage commitment of MSC toward adipogenic or ostechondrogenic development [49,50,62,65,68]. A recent publication reported a potential role for Twist-1 in the maintenance of energy, where transgenic mice expressing Twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas Twist-1 heterozygous knockout mice are obesity resistant [69]. Therefore, physiological consequences caused by altered Twist-1 and Dermo-1 expression may be caused by the aberrant growth and differentiation of mesenchymal precursor cells in different tissues.…”

Section: Discussionmentioning

confidence: 99%

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

et al. 2009

View full text Add to dashboard Cite

The TWIST family of basic helix-loop-helix transcription factors, Twist-1 and Dermo-1 are known mediators of mesodermal tissue development and contribute to correct patterning of the skeleton. In this study, we demonstrate that freshly purified human bone marrow-derived mesenchymal stromal/stem cells (MSC) express high levels of Twist-1 and Dermo-1 which are downregulated following ex vivo expansion. Enforced expression of Twist-1 or Dermo-1 in human MSC cultures increased expression of the MSC marker, STRO-1, and the early osteogenic transcription factors, Runx2 and Msx2. Conversely, overexpression of Twist-1 and Dermo-1 was associated with a decrease in the gene expression of osteoblast-associated markers, bone morphogenic protein-2, bone sialoprotein, osteopontin, alkaline phosphatase and osteocalcin. High expressing Twist-1 or Dermo-1 MSC lines exhibited an enhanced proliferative potential of approximately 2.5-fold compared with control MSC populations that were associated with elevated levels of Id-1 and Id-2 gene expression. Functional studies demonstrated that high expressing Twist-1 and Dermo-1 MSC displayed a decreased capacity for osteo/chondrogenic differentiation and an enhanced capacity to undergo adipogenesis. These findings implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues by exerting their effects on genes involved in the early stages of bone development.

show abstract

“…The goal is to open the box for all possible disease-modifying therapies to realistically resolve the pandemic of over-nutritioned phenotypes. Blue line, energy (ATP level) in which Á V O 2 was shown to be increased this effect was repeatedly found to be 'disease modifying' [43,[66][67][68][69]. Insulin resistance, increased body weight, adiposity, steatosis, and elevated plasma lipids and cholesterol can be resolved by chronic increases in Á V O 2 , suggesting a positive effect upon increasing energy expenditure.…”

Section: Animal Models With Dermis Issuesmentioning

confidence: 99%

Targeting energy expenditure via fuel switching and beyond

Geisler

2010

Diabetologia

View full text Add to dashboard Cite

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an overnutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

show abstract

Twist-1 Is a PPARδ-Inducible, Negative-Feedback Regulator of PGC-1α in Brown Fat Metabolism

Cited by 206 publications

References 50 publications

PPARs and adipocyte function

PPARs and adipocyte function

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

Targeting energy expenditure via fuel switching and beyond

Contact Info

Product

Resources

About