Lithium inhibits brown adipocyte differentiation

Lithium impairs the appearance of the characteristic morphology of brown adipocytes and downregulates the expression of marker genes of brown adipocyte differentiation. These effects are dose-dependent and are more pronounced when exposure of preadipocytes to lithium is initiated at early stages of differentiation. Although lithium reduces the expression of genes common to both white and brown adipocytes [fatty acid binding protein aP2 (aP2/FABP) or peroxisome proliferating activated receptor gamma], genes expressed differentially in brown adipocytes, i.e., uncoupling protein 1, PPAR gamma coactivator-1alpha, and peroxisome proliferating activated receptor alpha, are particularly sensitive to lithium treatment-dependent downregulation. Brown adipocytes appear as preferential targets of the inhibitory action of lithium on adipocyte differentiation.     

调控褐色脂肪细胞分化的microRNAs

MicroRNA(miRNA)是近年来在真核生物中发现的一类长约22nt的内源性非编码RNA,在动物中主要通过抑制靶mRNA翻译,在转录后水平调控基因表达。动物体内有两种类型的脂肪组织：褐色和白色脂肪,白色脂肪以甘油三脂形式贮存能量,而褐色脂肪利用甘油三酯产生能量。褐色脂肪因其对肥胖的拮抗作用而对研究肥胖等代谢疾病具有重要意义,大量研究表明miRNA在褐色脂肪细胞分化中扮演着重要角色,其自身也受到多种转录因子和环境因子调控,这个复杂的调控网络维持了体内脂肪组织稳态。文章主要综述了miRNA在褐色脂肪细胞分化中的最新研究进展,以期为利用miRNA进行肥胖、糖尿病等相关疾病及其并发症的治疗提供新思路。     

Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development

Overgrowth of white adipose tissue (WAT) in obesity occurs as a result of adipocyte hypertrophy and hyperplasia. Expansion and renewal of adipocytes relies on proliferation and differentiation of white adipocyte progenitors (WAP); however, the requirement of WAP for obesity development has not been proven. Here, we investigate whether depletion of WAP can be used to prevent WAT expansion. We test this approach by using a hunter-killer peptide designed to induce apoptosis selectively in WAP. We show that targeted WAP cytoablation results in a long-term WAT growth suppression despite increased caloric intake in a mouse diet-induced obesity model. Our data indicate that WAP depletion results in a compensatory population of adipose tissue with beige adipocytes. Consistent with reported thermogenic capacity of beige adipose tissue, WAP-depleted mice display increased energy expenditure. We conclude that targeting of white adipocyte progenitors could be developed as a strategy to sustained modulation of WAT metabolic activity.Obesity, a medical condition predisposing to diabetes, cardiovascular diseases, cancer, and complicating other life-threatening diseases, is becoming an increasingly important social problem.^{1, 2, 3} Development of pharmacological approaches to reduction of body fat has remained a daunting task.⁴ Approved obesity treatments typically produce only moderate and temporary effects.^2,5 White adipocytes are the differentiated cells of white adipose tissue (WAT) that store triglycerides in lipid droplets.^6,7 In contrast, adipocytes of brown adipose tissue (BAT) dissipate excess energy through adaptive thermogenesis. Under certain conditions, white adipocytes can become partially replaced with brown-like ‘beige'' (‘brite'') adipocytes that simulate the thermogenic function of BAT adipocytes.^7,8 Obesity develops in the context of positive energy balance as a result of hypertrophy and hyperplasia of white adipocytes.⁹Expansion and renewal of the white adipocyte pool in WAT continues in adulthood.^10,11 This process is believed to rely on proliferation and self-renewal of mesenchymal precursor cells¹² that we term white adipocyte progenitors (WAPs). WAPs reside within the population of adipose stromal cells (ASCs)¹³ and are functionally similar to bone marrow mesenchymal stem cells (MSCs).^{14, 15, 16} ASCs can be isolated from the stromal/vascular fraction (SVF) of WAT based on negativity for hematopoietic (CD45) and endothelial (CD31) markers.^17,18 ASCs support vascularization as mural/adventitial cells secreting angiogenic factors^5,19 and, unlike bone marrow MSCs, express CD34.^19,20 WAPs have been identified within the ASC population based on expression of mesenchymal markers, such as platelet-derived growth factor receptor-β (PDGFRβ, aka CD140b) and pericyte markers.^17,18 Recently, a distinct ASC progenitor population capable of differentiating into both white and brown adipocytes has been identified in WAT based on PDGFRα (CD140a) expression and lack of PDGFRβ expression.^21,22 The physiological relevance of the two precursor populations residing in WAT has not been explored.We have previously established an approach to isolate peptide ligands binding to receptors selectively expressed on the surface of cell populations of interest.^{23, 24, 25, 26, 27} Such cell-targeted peptides can be used for targeted delivery of experimental therapeutic agents in vivo. A number of ‘hunter-killer'' peptides²⁸ composed of a cell-homing domain binding to a surface marker and of KLAKLAK₂ (sequence KLAKLAKKLAKLAK), a moiety inducing apoptosis upon receptor-mediated internalization, has been described by our group.^26,29 Such bimodal peptides have been used for depletion of malignant cells and organ-specific endothelial cells in preclinical animal models.^26,30,31 Recently, we isolated a cyclic peptide WAT7 (amino acid sequence CSWKYWFGEC) based on its specific binding to ASCs.²⁰ We identified Δ-decorin (ΔDCN), a proteolytic cleavage fragment of decorin, as the WAT7 receptor specifically expressed on the surface of CD34+PDGFRβ+CD31-CD45- WAPs and absent on MSCs in other organs.²⁰Here, we investigated whether WAPs are required for obesity development in adulthood. By designing a new hunter-killer peptide that directs KLAKLAK₂ to WAPs through WAT7/ΔDCN interaction, we depleted WAP in the mouse diet-induced obesity model. We demonstrate that WAP depletion suppresses WAT growth. We show that, in response to WAP deficiency, WAT becomes populated with beige adipocytes. Consistent with the reported thermogenic function of beige adipocytes,^32,33 the observed WAT remodeling is associated with increased energy expenditure. We identify a population of PDGFRα-positive, PDGFRβ-negative ASCs reported recently²² as a population surviving WAP depletion and responsible for WAT browning.     

A novel brown adipocyte-enriched long non-coding RNA that is required for brown adipocyte differentiation and sufficient to drive thermogenic gene program in white adipocytes

The thermogenic activities of brown and beige adipocytes can be exploited to reduce energy surplus and counteract obesity. Recent RNA sequencing studies have uncovered a number of long noncoding RNAs (lncRNAs) uniquely expressed in white and brown adipose tissues (WAT and BAT), but whether and how these lncRNAs function in adipogenesis remain largely unknown. Here, we report the identification of a novel brown adipocyte-enriched LncRNA (AK079912), and its nuclear localization, function and regulation. The expression of AK079912 increases during brown preadipocyte differentiation and in response to cold-stimulated browning of white adipocytes. Knockdown of AK079912 inhibits brown preadipocyte differentiation, manifested by reductions in lipid accumulation and down-regulation of adipogenic and BAT-specific genes. Conversely, ectopic expression of AK079912 in white preadipocytes up-regulates the expression of genes involved in thermogenesis. Mechanistically, inhibition of AK079912 reduces mitochondrial copy number and protein levels of mitochondria electron transport chain (ETC) complexes, whereas AK079912 overexpression increases the levels of ETC proteins. Lastly, reporter and pharmacological assays identify Pparγ as an upstream regulator of AK079912. These results provide new insights into the function of non-coding RNAs in brown adipogenesis and regulating browning of white adipocytes.     

The forkhead transcription factor FoxC2 inhibits white adipocyte differentiation

In this study, we show that expression of FoxC2 blocks the capacity of 3T3-L1 preadipocytes to undergo adipogenesis in the presence of dexamethasone, isobutylmethylxanthine, and insulin. This block is characterized by an extensive decrease in the expression of proteins associated with the function of the mature fat cell, most notably C/EBPalpha, adiponectin, perilipin, and the adipose-specific fatty acid-binding protein, FABP4/aP2. Since the expression of these proteins lies downstream of PPARgamma, we overexpressed PPARgamma in Swiss mouse fibroblasts to promote adipocyte differentiation. We show that FoxC2 blocks the ability of PPARgamma to induce adipogenic gene expression in response to exposure of the cells to dexamethasone, isobutylmethylxanthine, insulin, and a PPARgamma ligand. Interestingly, the expression of aP2 escapes the inhibitory action of FoxC2 under conditions that promote maximum PPARgamma activity. In contrast, FoxC2 inhibits the expression of C/EBPalpha, perilipin, and adiponectin even in the presence of potent PPARgamma ligands. Finally, we show that FoxC2 does not affect the ability of PPARgamma to bind to or transactivate from a PPARgamma response element. These data suggest that FoxC2 blocks adipogenesis by inhibiting the capacity of PPARgamma to promote the expression of a subset of adipogenic genes.     

A new era for brown adipose tissue: New insights into brown adipocyte function and differentiation

Until quite recently, brown adipose tissue was considered of metabolic significance only in small mammals and human newborns, since it was thought to disappear rapidly after birth in humans. However, nowadays this tissue is known to play a role in the regulation of energy balance not only in rodents, but also in humans. In this review we highlight new features regarding brown adipose tissue origin and function and revise old paradigms about brown adipocyte differentiation.     

The brown adipocyte differentiation pathway in birds: An evolutionary road not taken

Background  

Thermogenic brown adipose tissue has never been described in birds or other non-mammalian vertebrates. Brown adipocytes in mammals are distinguished from the more common white fat adipocytes by having numerous small lipid droplets rather than a single large one, elevated numbers of mitochondria, and mitochondrial expression of the nuclear gene UCP1, the uncoupler of oxidative phosphorylation responsible for non-shivering thermogenesis.     

Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes

The concept of clonal deletion of immune cells that carry an autoreactive antigen receptor was a central prediction of Burnet's clonal selection theory. A series of classical experiments in the late 1980s revealed that certain immature thymocytes upon encounter of 'self' are indeed removed from the T-cell repertoire before their release into the blood circulation. A second essential cornerstone of immunological tolerance, not anticipated by Burnett, has more recently surfaced through the discovery of Foxp3(+) regulatory T cells (Treg). Intriguingly, it appears that the expression of an autoreactive T-cell receptor is a shared characteristic of T cells that are subject to clonal deletion as well as of those deviated into the Treg lineage. This is all the more striking as Treg differentiation for the most part branches off from mainstream CD4T cell development during thymocyte maturation in the thymus, that is, it may neither temporally nor spatially be separated from clonal deletion. This raises the question of how an apparently identical stimulus, namely the encounter of 'self' during thymocyte development, can elicit fundamentally different outcomes such as apoptotic cell death on the one hand or differentiation into a highly specialized T-cell lineage on the other hand. Here, we will review the T-cell intrinsic and extrinsic factors that have been implicated in intrathymic Treg differentiation and discuss how these parameters may determine whether an autoreactive major histocompatibility complex class II-restricted thymocyte is deviated into the Treg lineage or subject to clonal deletion.