Adipose Subtype-Selective Recruitment of TLE3 or Prdm16 by PPARγ Specifies Lipid Storage versus Thermogenic Gene Programs

Villanueva, Claudio J.; Vergnes, Laurent; Wang, Jie‐Xin; Drew, Brian G.; Hong, Cynthia; Tu, Yiping; Hu, Yan; Xu, Peng; Xu, Feng; Sáez, Enrique; Wroblewski, Kevin; Hevener, Andrea L.; Reue, Karen; Fong, Loren G.; Young, Stephen G.; Tontonoz, Peter

doi:10.1016/j.cmet.2013.01.016

Cited by 136 publications

(148 citation statements)

References 46 publications

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“…Interestingly, we examined the expression of the two very recently described genes Ehmt1 and Tle3 {transducin-like enhancer of split 3 [E(sp1) homolog, Drosophila]}, which stabilize and counter Prdm16 activity, respectively. Rodents lacking Ehmt1 and Tle3 displayed a marked reduction in adaptive thermogenesis (and insulin resistance) and increased thermogenesis in inguinal adipose, respectively (29,36). However, we did not observe changes in Ehmt1 and Tle3 mRNA expression in inguinal fat tissue from chow-fed sg/sg mice (Fig.…”

Section: E163mentioning

confidence: 40%

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Lau

Tuong

Wang

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue. Am J Physiol Endocrinol Metab 308: E159-E171, 2015. First published November 25, 2014; doi:10.1152/ajpendo.00056.2014.-The Rarrelated orphan receptor-␣ (Ror␣) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Ror␣-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Ror␣-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Ppar␣, Err␣, Dio2, Acot11/Bfit, Cpt1␤, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesityresistant phenotype in Ror␣-deficient mice.retinoic acid receptor-related orphan receptor-␣; obesity; adiposity; adipose tissue; uncoupling protein-1 OBESITY IS A METABOLIC DISEASE that affects more than 10% of the global population. Energy imbalance as a result of excess dietary energy intake or genetic susceptibility results in increased energy storage and adiposity. Current strategies to ameliorate this disease include increasing energy expenditure through physical exercise and reducing energy consumption. However, the success rate is limited by compliance and the genetic disposition to maintain energy balance.Adaptive thermogenesis is an adrenergic/sympathetic-dependent mechanism utilized by mammals to increase energy expenditure in response to excessive dietary intake and/or cold stimulus. Thermogenesis occurs in both brown adipose tissue and beige fat [white adipose tissue cells that acquire a brown adipose phenotype (37, 41)]. This process involves increased (fatty acid-dependent) expression and activity of the thermogenic mitochondrial uncoupling protein (Ucp1). The function of Ucp1 is to me...

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Section: E163mentioning

confidence: 40%

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Lau

Tuong

Wang

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Groucho/TLE family proteins play critical roles in a wide array of developmental and cellular pathways [54]. TLE3 is expressed by placenta [55], brown and white adipose tissue [56,57], and bone marrow [25]. In addition, expression of TLE3 is known to increase with adipocyte differentiation [56].…”

Section: Discussionmentioning

confidence: 99%

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Kokabu¹,

Sato²,

Ohte³

et al. 2014

FEBS Letters

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Edited by Zhijie ChangKeywords: Osteoblastogenesis Osteoporosis Wnt Groucho Transducing-like enhancer of split Co-repressor a b s t r a c t Transducing-like enhancer of split 3 (TLE3), one of the Groucho/TLE family members, targets Runx2 transcription and suppresses osteoblast differentiation in bone marrow stromal cells (BMSCs). Here, we identify Wnt responsive elements of the TLE3 promoter region through comparative genomic and functional analyses and show that expression of TLE3 is increased by Wnt signaling, which is important for osteoblast differentiation. We also demonstrated that TLE3 is able to suppress canonical Wnt signaling in BMSCs. Taken together, our data suggest that induction of TLE3 by Wnt signaling is part of a negative feedback loop active during osteoblast differentiation.

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“…Notably, many of the well-characterized determinants of thermogenic function in adipocytes, including Prdm16 , Ppargc-1 , Tle3 , and Ebf2 , are differentially expressed between white and brown adipocytes. Tle3, a recently described antagonist of thermogenic gene expression, is more abundant in white adipocytes than in brown adipocytes ( 12 ). Prdm16, Pgc-1, and Ebf2, all activators of brown adipocyte development and/or thermogenic gene expression, are relatively enriched in brown adipocytes ( 9,(13)(14)(15)(16).…”

Section: Expression In White and Brown Adipose Tissue Depotsmentioning

confidence: 99%

“…Thus, the most effi cient and adipocyte-specifi c Cre line to date is the publically available Adpn -Cre BAC mouse line developed by Eguchi et al ( 23 ). This line, currently distributed through the Jackson Laboratory, has been used in a number of studies and has been demonstrated to be specifi c to adipocytes within WAT and BAT ( 12,31,112,113 ).…”

Section: Regulation Of Adipogenesismentioning

confidence: 99%

Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

Wang

Scherer

Gupta

2014

Journal of Lipid Research

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greater caution must be taken in interpreting studies of adipogenesis and adipocyte metabolism.In this review, we offer a consolidated view of the wideranging approaches that can be taken to study adipose biology and discuss important considerations and pitfalls associated with each method. We divide the discussion into three sections; the fi rst section describes model systems, ways to understand where and when molecules of interest may play a role in the adipose lineage, and recent insights gained from these approaches. The second and third sections provide guidelines for the study of adipocyte biology in vivo and in cellular systems, respectively. Along the way, we highlight improved genetic and cellular models that can aid researchers interested in studying the role of their favorite protein in the adipose tissue and discuss the insights gained from each approach. IS MY FAVORITE GENE EXPRESSED IN THE ADIPOSE LINEAGE? WHERE DO I LOOK?The establishment and maintenance of adipocytes in principle involves key regulatory steps ( 3 ). First, multipotent progenitor cells must commit to the adipocyte lineage, a process referred to as preadipose cell determination. Next, in response to appropriate spatial and temporal cues, committed preadipose cells undergo adipocyte differentiation, a morphological and biochemical transition into mature adipocytes. Finally, mechanisms must exist that function to maintain the differentiated state of the mature adipocyte (adipocyte maintenance). This includes factors critical for regulating the functional properties of Abstract Adipocyte differentiation and function have become areas of intense focus in the fi eld of energy metabolism; however, understanding the role of specifi c genes in the establishment and maintenance of fat cell function can be challenging and complex. In this review, we offer practical guidelines for the study of adipocyte development and function. We discuss improved cellular and genetic systems for the study of adipose biology and highlight recent insights gained from these new approaches. -Wang, Q. A., P. E. Scherer, and R. K. Gupta. Improved methodologies for the study of adipose biology: insights gained and opportunities ahead. J. Lipid Res. 2014. 55: 605-624. Supplementary key words energy metabolism • adipogenesis • obesitySince the 1970s, fat cell differentiation of immortalized fi broblast cell lines has been an extensively studied model of cellular differentiation ( 1 ). The ability to study this process in a tissue culture dish has allowed cellular biologists and biochemists to explore general mechanisms of cell fate determination and cellular differentiation, and to isolate novel regulatory proteins and signaling cascades that initiate these processes . However, it is now clear that adipocytes represent critical regulators of nearly all aspects of energy balance. Adipose tissues exhibit high plasticity with a tremendous capacity for expansion and contraction in response to the energy demands of an organism. The alarming rise in obesity and obesity-l...

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Adipose Subtype-Selective Recruitment of TLE3 or Prdm16 by PPARγ Specifies Lipid Storage versus Thermogenic Gene Programs

Cited by 136 publications

References 46 publications

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling

Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

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