RESUMO
BACKGROUND: Recruiting thermogenic adipocytes in white adipose tissue represents a potential therapeutic strategy for obesity. Interestingly, PPARγ, a major regulator of lipogenesis, is also a key factor in inducing thermogenic genes in adipose tissue. SCOPE OF THE REVIEW: We summarize some of the recent findings regarding the biology of beige adipocytes and their potential significance for metabolic health. We also discuss the role of PPARγ in development of beige adipocyte phenotype and in inducing two apparently divergent processes, namely, lipogenesis and thermogenesis. MAJOR CONCLUSIONS: PPARγ post-translation modifications and differential coregulator recruitment may be key factors in defining adipocyte commitment with lipogenesis or thermogenesis. GENERAL SIGNIFICANCE: Dissecting the mechanisms underlying its thermogenic effects may prompt the development of a new generation of PPARγ-based therapies.
Assuntos
Tecido Adiposo Branco/metabolismo , PPAR gama/fisiologia , Termogênese/fisiologia , Animais , Humanos , Lipogênese/fisiologiaRESUMO
Chromatin is the major regulator of gene expression and genome maintenance. Proteins that bind the nucleosome, the repetitive unit of chromatin, and the histone H4 tail are critical to establishing chromatin architecture and phenotypic outcomes. Intriguingly, nucleosome-binding proteins (NBPs) and the H4 tail peptide compete for the same binding site at an acidic region on the nucleosome surface. Although the essential facts about the nucleosome were revealed 17 years ago, new insights into its atomic structure and molecular mechanisms are still emerging. Several complex nucleosome:NBP structures were recently revealed, characterizing the NBP-binding sites on the nucleosome surface. Here we discuss the potential of the nucleosome surface as a therapeutic target and the impact and development of exogenous nucleosome-binding molecules (eNBMs).
Assuntos
Nucleossomos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sequência de Bases , Humanos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Nucleossomos/química , Nucleossomos/metabolismo , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Ligação ProteicaRESUMO
BACKGROUND: Much is known about how genes regulated by nuclear receptors (NRs) are switched on in the presence of a ligand. However, the molecular mechanism for gene down-regulation by liganded NRs remains a conundrum. The interaction between two zinc-finger transcription factors, Nuclear Receptor and GATA, was described almost a decade ago as a strategy adopted by the cell to up- or down-regulate gene expression. More recently, cell-based assays have shown that the Zn-finger region of GATA2 (GATA2-Zf) has an important role in down-regulation of the thyrotropin gene (TSHß) by liganded thyroid hormone receptor (TR). METHODOLOGY/PRINCIPAL FINDINGS: In an effort to better understand the mechanism that drives TSHß down-regulation by a liganded TR and GATA2, we have carried out equilibrium binding assays using fluorescence anisotropy to study the interaction of recombinant TR and GATA2-Zf with regulatory elements present in the TSHß promoter. Surprisingly, we observed that ligand (T3) weakens TR binding to a negative regulatory element (NRE) present in the TSHß promoter. We also show that TR may interact with GATA2-Zf in the absence of ligand, but T3 is crucial for increasing the affinity of this complex for different GATA response elements (GATA-REs). Importantly, these results indicate that TR complex formation enhances DNA binding of the TR-GATA2 in a ligand-dependent manner. CONCLUSIONS: Our findings extend previous results obtained in vivo, further improving our understanding of how liganded nuclear receptors down-regulate gene transcription, with the cooperative binding of transcription factors to DNA forming the core of this process.
Assuntos
Regulação para Baixo , Fator de Transcrição GATA2/metabolismo , Regiões Promotoras Genéticas , Receptores beta dos Hormônios Tireóideos/metabolismo , Tireotropina Subunidade beta/genética , Sequência de Bases , Fator de Transcrição GATA2/química , Fator de Transcrição GATA2/genética , Regulação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Elementos de Resposta , Receptores beta dos Hormônios Tireóideos/química , Receptores beta dos Hormônios Tireóideos/genética , Tireotropina Subunidade beta/metabolismo , Tri-Iodotironina/metabolismoRESUMO
PURPOSE OF REVIEW: Chronic kidney disease is characterized by multiple abnormalities in the thyroid hormone physiology. In the present review, we will briefly discuss the effects of uremia on thyroid hormone synthesis, metabolism, transport, and action. RECENT FINDINGS: Uremic toxins have been shown to interfere at various levels of the thyroid hormone action, including thyroid hormone transport across plasma membrane and thyroid hormone receptor activity. These abnormalities could explain the resistance to thyroid hormone action in uremia, at least in some tissues. SUMMARY: The pathogenesis of thyroid axis abnormalities in uremia is incompletely understood, and its clinical significance remains unclear. The increasing prevalence of chronic kidney disease underscores the need for further efforts to understand the metabolic consequences of uremia and address questions such as the impact of thyroid hormone therapy.