Inhibition of adipocyte differentiation by RORα

Duez, Hélène; Duhem, Christian; Laitinen, Saara; Patole, Prashant S.; Abdelkarim, Mouaadh; Bois-Joyeux, Brigitte; Danan, Jean‐Louis; Staels, Bart

doi:10.1016/j.febslet.2009.05.019

Cited by 34 publications

(39 citation statements)

References 30 publications

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“…Furthermore, sg/sg mice display reduced adiposity, increased metabolic rate, improved insulin sensitivity, resistance to diet-induced obesity, and hepatic steatosis (17,18). However, studies utilizing either 3T3-L1 cells or sg/sg MEF cells have indicated a contrary role whereby attenuation of Ror␣ enhanced adipogenesis (11,30). Therefore, we investigated overall body composition and adi-posity [by dual-energy X-ray absorptiometry (DEXA) and MRI] and then analyzed adipose tissue samples [by quantative PCR (qPCR) and Western blotting], comparing sg/sg mice with their wild-type (WT) counterparts.…”

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confidence: 98%

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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confidence: 98%

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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“…ROR␣ overexpression in 3T3L1 cells also blocks the adipogenic process. 52 Interestingly, REV-ERB␣ regulates this process in a subtle manner because the REV-ERB␣ protein must increase and then decrease to allow proper differentiation of fibroblasts into mature adipocytes. 53,54 Human data are still scarce.…”

Section: Duez and Staels Circadian Metabolic Control By Nuclear Recepmentioning

confidence: 99%

Nuclear Receptors Linking Circadian Rhythms and Cardiometabolic Control

Duez

Staels

2010

ATVB

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Abstract-Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. Circadian Rhythms in PhysiologyCircadian rhythms are variations that occur with a period of approximately 1 day ("circa diem") and allow the organism to anticipate and optimize its metabolic, hormonal, and locomotor activity to predictable environmental daily changes. 1 In mammals, a central clock resides in the suprachiasmatic nuclei of the hypothalamus and synchronizes physiology to day/night cycles. In metabolic organs, output signals from the suprachiasmatic nuclei clock, conveyed by peripheral oscillators, are combined to additional circadian cues, such as food availability, information concerning local fuel availability, and the hormonal milieu to drive circadian rhythms in intermediary metabolites (eg, AMP/ATP or oxidized nicotinamide-adenosine dinucleotide (NAD ϩ )/reduced nicotinamide adenine dinucleotide ratios) and enzymes involved in local physiology. Consequently, many metabolic functions, including lipid and carbohydrate metabolism, and hormone secretion follow circadian variations. 2 The circadian clock also synchronizes the cardiovascular system. The heart and vasculature have an autonomous circadian pacemaker to anticipate physiological demand in heart fuel use and contractile function. 3 For instance, blood pressure displays marked circadian variations, increasing in the morning and decreasing at night. Heart beat and blood flow, vascular tone, fibrinolytic activity, and endothelial function are all naturally subjected to diurnal variations. 4 Interestingly, the incidence of acute myocardial infarction, sudden cardiac death, and ischemic stroke is highest early in the morning. Adverse Cardiometabolic Consequences of Altered Circadian Rhythms: Clinical EvidenceThe metabolic syndrome comprises a constellation of abnormalities, including dyslipidemia, high fasting blood glucose level, and hypertension. 5 It is precipitated by central obesity and increases the risk for type 2 diabetes mellitus and cardiovascular complications. In addition to genetic risk factors, numerous environmental factors (eg, increased food intake and physical inactivity) contribute to the etiology of the metabolic syndrome. Chronic circadian derangement, experienced by shift workers, also increases the risk of developing features of the metabolic syndrome (Figure 1). 6,7 Interestingly, in humans subjected to a progressive forced desynchrony, circadian misalignment increased blood glucose despite increased insulin, suggestive of decreased insulin sensitivity and increased blood pressure, with a maximal disturbance during maximal misalignment (ie, 180°phase shift). 8 A decrease in sleep duration and poor-quality sleep, although not circadian disorders per se, are often seen in nightshift workers, travelers, and patients with obstructive sleep apnea. Sleep curtailment results in reduced glucose tolerance and

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“…26), could be due to a diminished deposition of TG in adipose tissue under fasting conditions. Indeed, reduced adiposity was not described to be linked to a defect of adipogenesis, which, on the contrary, was found to be improved (12,35), nor to an altered lipolysis [observation based on the gene expression of two major lipolytic enzymes, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) (26)]. We confirmed that ROR sg/sg mice exhibited no clear defect in lipogenesis under feeding conditions on the basis of similar sterol regulatory element-binding protein-1c (SREBP)-1c, PPAR␥, or fatty acid-binding protein 4 mRNA amount in inguinal fat (not shown).…”

Section: Discussionmentioning

confidence: 99%

“…1) This pathway shares with liver gluconeogenesis the same key gene, PCK1; 2) previously, we revealed that GOT1, encoding aspartate aminotransferase, another enzyme involved in glyceroneogenesis, was an in vitro ROR␣ target gene (45); and 3) ROR sg/sg mouse, a natural mutant ROR␣-deficient strain (13), exhibits a lean phenotype with decreased fat mass and small adipocytes for an unsolved reason (26). Indeed, adipocyte precursors from these mice are fully competent to differentiate in vitro (12,35). This raised the possibility that ROR sg/sg mice could harbor specific adipose defects that limit their capacity for energy storage.…”

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confidence: 99%

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

Kadiri

Monnier

Ganbold

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Circadian rhythms have an essential role in feeding behavior and metabolism. ROR␣ is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phosphoenolpyruvate carboxykinase c (PEPCKc), whose gene is a ROR␣ target in the liver. ROR␣-deficient mice (staggerer, ROR sg/sg ) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of ROR␣, and we further evaluated the role of ROR␣ in hepatocyte gluconeogenesis. In vivo investigations comparing ROR sg/sg mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of ROR␣, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the ROR sg/sg mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with ROR␣ agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not ROR sg/sg mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by ROR␣. This study demonstrates the physiological function of ROR␣ in regulating both glucose and FFA homeostasis. glyceroneogenesis; phosphoenolpyruvate carboxykinase c; nuclear retinoid-related orphan receptor-␣; adipose tissue RETINOID-RELATED ORPHAN RECEPTORS (RORs) are members of the nuclear receptor family. The ROR family comprises three members: ROR␣ (NR1F1), ROR␤ (NR1F2), and ROR␥ (NR1F3), with ROR␣ being the most abundant isoform present in the adipose tissue (18). RORs regulate gene transcription by binding to specific DNA response elements (RORE) consisting of the consensus RGGTCA core motif. Reciprocally, the nuclear receptor Rev-erb␣ (NR1D1) acts as a transcriptional repressor by competing with RORs for RORE binding and thereby antagonizes ROR action. Indeed, both receptors are often coexpressed in the same tissues (14).ROR␣ and Rev-erb␣ are involved in many pathways implicated in various physiological functions, including immune function, circadian rhythms, and metabolism. They appear to be pivotal players at the interface between the circadian system and metabolism (49). Among the direct target genes of ROR␣ and Rev-erb␣ are several clock genes such as Bmal1, thus ensuring a fine tuning of circadian rhythms, as well as some metabolic genes involved in the control of cholesterol and bile acid metabolism (11, 29) apolipoprotein synthesis (39), lipogene...

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Inhibition of adipocyte differentiation by RORα

Cited by 34 publications

References 30 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

Nuclear Receptors Linking Circadian Rhythms and Cardiometabolic Control

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

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