Regulation of Human Adipocyte Gene Expression by Thyroid Hormone

Viguerie, Nathalie; Millet, L; Avizou, Sebastien; Vidal, Hubert; Larrouy, Dominique; Langin, Dominique

doi:10.1210/jcem.87.2.8200

Cited by 92 publications

(75 citation statements)

References 32 publications

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“…7, C and D). These data are consistent with recent studies using human primary adipocyte culture (42). These results indicated that impaired lipolysis in P398H mice was not due to reduced expression of ␤-adrenergic receptors.…”

Section: Generation Of P398h Mutantsupporting

confidence: 93%

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

Liu

Schultz

Brent

2003

Journal of Biological Chemistry

149

102

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Thyroid hormone has profound effects on metabolic homeostasis, regulating both lipogenesis and lipolysis, primarily by modulating adrenergic activity. We generated mice with a point mutation in the thyroid hormone receptor ␣ (TR␣) gene producing a dominant-negative TR␣ mutant receptor with a proline to histidine substitution (P398H). The heterozygous P398H mutant mice had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat (as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose levels (p < 0.01) were observed in P398H compared with wild-type mice. There was a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced glycerol release from white adipose tissue isolated from P398H mice. Heart rate and cold-induced adaptive thermogenesis, mediated by thyroid hormone-catecholamine interaction, were also reduced in P398H mice. In conclusion, the TR␣ P398H mutation is associated with visceral adiposity and insulin resistance primarily due to a marked reduction in catecholamine-stimulated lipolysis. The observed phenotype in the TR␣ P398H mouse is likely due to interference with TR␣ action as well as influence on other metabolic signaling pathways. The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation.Thyroid hormone plays a central role in metabolic homeostasis. Thyroid hormone stimulates basal metabolic rate and adaptive thermogenesis. Hyperthyroidism amplifies catecholamine-stimulated lipolysis and increases thermogenesis and oxygen consumption in adipose tissue (1-3). Hypothyroidism reduces the response to catecholamines and increases energy-saving anabolic activity in adipose tissue (4).Thyroid hormone has long been recognized to augment adrenergic activity, and influences adrenergic signaling at multiple levels. Catecholamines bind at least five subtypes of adrenergic receptors (␣1, ␣2, ␤1, ␤2, and ␤3) that are expressed in fat cells and are coupled with the adenylylcyclase system to activate (via ␤ receptors) or inhibit (via ␣2 receptor) the cAMPactivated hormone-sensitive lipase (HSL) 1 (5-9). Reduced catecholamine-stimulated lipolysis in hypothyroidism is thought to be due to a reduced number of ␤-adrenergic receptors (␤1 and ␤2) in fat cells (4, 10 -13), reduced interaction with G s , and enhanced G i protein interaction via ␣2-adrenergic receptorcoupled stimulation (14). Additionally, hypothyroidism is associated with low intracellular levels of protein kinase, known to phosphorylate and activate HSL (2,12,13). No significant alteration of ␣2-adrenergic receptor number has been found in fat cells isolated from either hypo-or hyperthyroid animals (6).The two majo...

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Section: Generation Of P398h Mutantsupporting

confidence: 93%

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

Liu

Schultz

Brent

2003

Journal of Biological Chemistry

149

102

View full text Add to dashboard Cite

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“…Previous work has clearly established the importance of transcriptional activation by nuclear receptors in both the control of adipogenesis and the regulation of energy balance by thermogenesis, with PPARs playing a central role (4)(5)(6)(7)(8)(9)(10)(11)(12). Spiegelman and coworkers (22,23,24) have provided substantial evidence to indicate that PGC-1␣ is a key transcriptional coactivator and metabolic regulator in BAT, muscle, and liver.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, energy is dissipated by generating heat in brown adipose tissue (BAT) and skeletal muscles by regulating the uncoupling of ATP production from respiration. Many of these metabolic processes are controlled in part by nuclear receptors (4,5), including peroxisome proliferatoractivated receptors (PPARs) (6,7), thyroid hormone receptor (8,9), estrogen receptor ␣ (ER␣) (10,11), and ER-related receptor ␣ (ERR␣) (12). The best characterized of these are the PPARs, with PPAR␥ and PPAR␣ playing an essential role in adipogenesis (13)(14)(15)(16) and in thermogenesis and fatty acid oxidation (17)(18)(19), respectively, whereas recent studies have implicated a role for PPAR␦ in lipid homeostasis (20).…”

mentioning

confidence: 99%

Nuclear receptor corepressor RIP140 regulates fat accumulation

Leonardsson

Steel

Christian

et al. 2004

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

340

355

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Nuclear receptors and their coactivators have been shown to function as key regulators of adipose tissue biology. Here we show that a ligand-dependent transcriptional repressor for nuclear receptors plays a crucial role in regulating the balance between energy storage and energy expenditure. Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption. Although the process of adipogenesis is unaffected, expression of certain lipogenic enzymes is reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1, are markedly increased. Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders. E nergy homeostasis is a highly regulated process that requires precise control of food intake and energy expenditure (1). The major and most efficient storage of energy occurs in the form of triglycerides in white adipose tissue (WAT), and it is now clear that the adipocyte itself may act as an endocrine cell such that altered adipocyte function would cause changes in systemic energy balance (2, 3). From adipogenic stores, fatty acids are easily mobilized during periods of energy restriction or increased physical activity to provide enough fuel for energy synthesis in the form of ATP. In addition, energy is dissipated by generating heat in brown adipose tissue (BAT) and skeletal muscles by regulating the uncoupling of ATP production from respiration. Many of these metabolic processes are controlled in part by nuclear receptors (4, 5), including peroxisome proliferatoractivated receptors (PPARs) (6, 7), thyroid hormone receptor (8, 9), estrogen receptor ␣ (ER␣) (10, 11), and ER-related receptor ␣ (ERR␣) (12). The best characterized of these are the PPARs, with PPAR␥ and PPAR␣ playing an essential role in adipogenesis (13-16) and in thermogenesis and fatty acid oxidation (17-19), respectively, whereas recent studies have implicated a role for PPAR␦ in lipid homeostasis (20).Nuclear receptors stimulate target gene transcription by recruiting coactivators that are required to remodel chromatin and facilitate the assembly of the basal transcription machinery (21). The key coactivator in metabolic processes is the PPAR␥ coactivator 1␣ (PGC-1␣) (22-25), which was initially shown to promote adaptive thermogenesis in BAT and which has emerged as a target for integrating signals in the regulation of specific metabolic programs in other tissues, including muscle and liver. More recently, the related coactivator PGC-1␤ (26, 27) has been implicated in the regulation of energy expenditure as a potential coactivator for ERR␣ (28). In addition, the p160 family of coactivators has also been found to control energy balance in adipose tissue. For instance, SRC1, in associatio...

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“…The specimens of subcutaneous fat were digested using collagenase (type 1; Biochrom, Berlin, Germany) as described previously [23]. Mature adipocytes and the stroma vascular fraction (SVF) were separated by centrifugation, lysed with denaturing buffer from the RNeasy total RNA Mini Kit (Qiagen), and then stored at −80°C prior to mRNA preparation.…”

Section: Clinical Investigation Protocolsmentioning

confidence: 99%

Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition

et al. 2005

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Aims/hypothesis: The acute-phase proteins, serum amyloid As (SAA), are precursors of amyloid A, involved in the pathogenesis of AA amyloidosis. This work started with the characterisation of systemic AA amyloidosis concurrent with SAA overexpression in the subcutaneous white adipose tissue (sWAT) of an obese patient with a leptin receptor deficiency. In the present study a series of histopathological, cellular and gene expression studies was performed to assess the importance of SAA in common obesity and its possible production by mature adipocytes. Materials and methods: Gene expression profiling was performed in the sWAT of two extremely obese patients with a leptin receptor deficiency. Levels of the mRNAs of the different SAA isoforms were quantified in sWAT cellular fractions from lean subjects and from obese subjects before and after a very-low-calorie diet. These values were subsequently compared with serum levels of SAA in these individuals. In addition, histopathological analyses of sWAT were performed in lean and obese subjects. Results: In sWAT, the expression of SAA is more than 20-fold higher in mature adipocytes than in the cells of the stroma vascular fraction (p<0.01). Levels of SAA mRNA expression and circulating levels of the protein are sixfold (p<0.001) and 3.5-fold (p<0.01) higher in obese subjects than in lean subjects, respectively. In lean subjects, 5% of adipocytes are immunoreactive for SAA, whereas the corresponding value is greater than 20% in obese subjects. Caloric restriction results in decreases of 45-75% in levels of the transcripts for the SAA isoforms and in circulating levels of the protein. Conclusions/interpretation: The results of the present study indicate that SAA is expressed by sWAT, and its production at this site is regulated by nutritional status. If amyloidosis is seen in the context of obesity, it is possible that production of SAA by adipocytes could be a contributory factor.

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Regulation of Human Adipocyte Gene Expression by Thyroid Hormone

Cited by 92 publications

References 32 publications

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

Nuclear receptor corepressor RIP140 regulates fat accumulation

Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition

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