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Endocrinology and metabolism 2016

Root, Allen W.

doi: 10.1097/MOP.0000000000000387
ENDOCRINOLOGY AND METABOLISM: Edited by Allen W. Root and Sally Radovick

Johns Hopkins medicine/All Children's Hospital, St Petersburg, Florida, USA

Correspondence to Dr Allen W. Root, MD, Division of Endocrinology and Diabetes, Johns Hopkins Medicine/All Children's Hospital, 501 Sixth Avenue South, St. Petersburg, FL 33701, USA. E-mail:

In the August 2016 endocrine and metabolism section of the Current Opinion in Pediatrics, Drs Isabel Iglesias-Platas and David Monk (pp. 521–528) review the epigenetic (or nongenomic) regulation of gene expression in eukaryotes. (Eukaryotes are all organisms composed of cells within which there is a defined nucleus with chromosomes containing the sequences of DNA that encode the genome of that organism.) Some definitions that may be helpful when reading this manuscript follow. ‘Epigenetics’ is the process by which nongenomic modifications of DNA affect the transcription and subsequent translation of genes that code for proteins but do so without altering the sequences of DNA bases that compose the specific gene. ‘Chromatin’ is the relatively amorphous appearing material within the cell nucleus that is composed of DNA and proteins that condenses to form chromosomes during cell division. ‘Euchromatin’ is loosely packed chromatin that is easily accessed by factors that favor gene transcription. ‘Heterochromatin’ is densely packed chromatin that is generally inaccessible to the factors that favor gene transcription. A ‘CpG dinucleotide’ is a site within a sequence of nucleotide bases in which the cytosine nucleotide is immediately followed by a guanine nucleotide (when grouped, multiple CpG dinucleotides are termed a ‘CpG island’); the significance of this pairing is that in this sequence the cytosine residue can be methylated – the most common epigenetic modification of DNA. Methylation usually then ‘silences’ that nucleotide site, rendering it incapable of being transcribed into RNA. Interestingly, methylation of a cytosine nucleotide is often stable and thus transmissible from generation-to-generation. A ‘retrotransposon’ is a sequence of DNA that can be replicated and then moved from its original site in the DNA sequence to a second location distant from the primary site.

Drs Eloise Giabicani, Irene Netchine, and Frédérick Brioude (pp. 529–535) discuss the clinical characteristics, pathophysiology, diagnosis, and management of patients with intrauterine growth retardation because of the Silver-Russell syndrome (SRS). Of great usefulness to the clinician is the scoring system devised by Dr Netchine (pp. 529–535) for the clinical diagnosis of SRS (Figure 2 in the manuscript by Giabicani et al.). In 50% of patients with SRS, a defect (demethylation of a critical imprinting center on chromosome 11p15.5) in the epigenetic regulation of paternal expression of the gene (IGF2) encoding insulin-like growth factor 2, an essential fetal growth promoting agent, is present resulting in decreased in-utero synthesis of IGF2. An opposite abnormality (hypermethylation) in epigenetic regulation of IGF2 expression leading to its biallelic expression and consequent excessive generation of IGF2 in utero is present in patients with the Beckwith-Wiedemann syndrome of fetal overgrowth, hemihypertrophy, and increased risk of embryonal neoplasms.

Drs Gary Francis and Andrew Bauer (pp. 536–544) consider the recently developed guidelines for the evaluation and management of thyroid nodules in children, a frequently encountered and always challenging problem. When a child has a thyroid nodule, the initial goal is to determine if this nodule is likely to harbor thyroid carcinoma. The authors present pathways to pursue and enumerate the characteristics that may be utilized to determine which thyroid nodules may be followed prospectively and which need to undergo ultrasonography and fine needle aspiration with pathologic evaluation of the aspirate to determine the presence and, if present, the histology of thyroid carcinoma. They also discuss the surgical management of the child whose thyroid nodule is malignant. Recently, in adults a variant of papillary thyroid carcinoma – ‘Noninvasive follicular thyroid neoplasm with papillary-like nuclear features’ – has been delineated [1]. This thyroid neoplasm, previously referred to as ‘Encapsulated follicular variant of papillary thyroid carcinoma’, is a relatively ‘benign’ form of thyroid carcinoma that is not associated with increased mortality and, therefore, does not require aggressive surgical or adjuvant therapy. Whether this form of thyroid carcinoma occurs in children and adolescents and behaves in a similar, clinically ‘benign’ manner is unknown at present.

Drs Antonis Voutetakis, Amalia Sertedaki, and Catherine Dacou-Voutetakis (pp. 545–550) consider the clinical, radiological, and genetic aspects of the pituitary stalk interruption syndrome (PSIS), one of the more common malformations of the central nervous system associated with hypopituitarism. Diagnostically, PSIS may be found by imaging of the hypothalamic-pituitary unit of a child with growth retardation due to isolated growth hormone deficiency (GHD). Often over time (not infrequently decades later), other anterior pituitary hormone secretory defects become apparent (particularly, deficiencies of thyrotropin and gonadotropin secretion) in PSIS patients. Voutetakis et al. present evidence that PSIS is related to the more visually striking central nervous malformation – holoprosencephaly. Variants of the same genes may be found in the two disorders (SHH, CDON, SIX3, TGIF, GLI2); however, variants in other genes (SOX3, GPR161, PROK2R) have also been identified in patients with PSIS. It seems likely that many of these genes are interlinked in a signaling network with sonic hedgehog (SHH) playing a particularly important role during embryonic differentiation of the ventral neural tube [2].

Drs Sarantis Livadas and George Chrousos (pp. 551–558) review the complex network of neuropeptides, peripheral hormones, and neurosteroids that interact to regulate the onset of puberty. Interestingly, the hypothalamic–pituitary–gonadal axis is quite active in early infancy, becomes quiescent during childhood, and is reactivated at adolescence. The authors discuss the effects of parental factors and epigenetic regulation of synthesis and release of pubertal factors, and the possible influential role of environmental chemicals upon this process.

Recently, there have been substantial advances in our understanding of the mechanisms that regulate weight gain and weight loss which processes reflect the difference between energy consumption (i.e., calories ingested) and energy expenditure (i.e., calories utilized). Calories are expended to maintain body homeostasis (e.g., organ function), purposeful movement (e.g., exercise), and thermogenesis. Adipose cells are derivatives of bone marrow-derived mesenchymal stem cells – differentiation of which gives rise to multiple cell lineages including: the prechondrocyte – a progenitor of cartilage and bone cells; myogenic and brown adipocyte progenitors that differentiate into muscle and brown fat cells, respectively; the beige adipocyte progenitor cell that matures into the beige adipocyte; the white adipocyte progenitor cell that becomes a white fat cell and under selected conditions may be further transformed into a beige adipocyte.

Energy is stored as triglycerides in white fat cells. Energy is utilized in brown and beige fat cells by thermogenesis that may be either ‘constitutive’ – heat dissipation by the large numbers of mitochondria within brown fat cells or ‘inducible or adaptive’ – heat dissipation by mitochondria of beige fat cells. Adaptive thermogenesis is the process whereby energy-storing white fat cells are transformed into energy-dissipating beige fat cells. Energy expenditure is accomplished by metabolism of carbohydrates, fatty acids, and glycerol through cellular activity and, in part, by leakage of protons across the mitochondrial inner membrane of brown and beige adipocytes which results in uncoupling of the processes of oxygen consumption and ATP synthesis – specifically during cold exposure. Hypertrophy of brown adipose tissue, increase in the number of mitochondria, and increased expression of UCP1 (encoding uncoupling protein 1) augment proton leakage and hence consumption of energy that is not utilized to generate ATP.

Two recent papers have explored the genetic and epigenetic control of the processes that lead to excessive storage of adipose tissue or obesity. FTO (chromosome 16q12.2; OMIM 610966) encodes the ‘Fat mass-related and obesity-related gene’ which several genome-wide association studies (GWAS) have identified as a key regulator of body weight. FTO is a nucleic acid demethylase that is abundantly expressed in hypothalamic areas that regulate energy intake and use; however, the hypothalamus may not be the primary site of action of this gene. Claussnitzer et al. [3] examined the mechanisms by which the product of FTO regulates the processes of energy utilization and weight maintenance, gain, or loss. These investigators were specifically interested in how the common nucleotide variants of FTO that were most specifically related to body fat mass influence the activity of the 500 aa protein product of FTO. The common nucleotide variants of FTO most closely associated with body mass (designated rs9930506, rs1421085, rs1558902 and considered ‘risk’ haplotypes) are present in introns 1 and 2 of FTO and thus, in noncoding portions of the gene.

These investigators first determined that the cell in which FTO exerts its effects is the preadipocyte, a precursor cell of the mature white adipocyte or white fat cell. They then identified the downstream target genes of FTO to be two genes designated IRX3 and IRX5. Both of these genes enhance preadipocyte maturation into the white fat cell and repress differentiation of brown and beige fat cells – adipocytes that consume rather than store energy. In mouse carriers of FTO risk alleles [e.g., variant rs1421085 (i.e., C = cytosine in place of T = thymine)] there was enhanced expression and hence activity of IRX3 and IRX5, and thus increased genesis of white adipocytes – leading to increased lipid storage and decreased thermogenesis. Additionally, risk allele carrier mice had lower expression of energy burning genes and higher expression of energy saving genes, larger adipocytes, decreased mitochondrial DNA, and loss of UCP1 response to cold and to β adrenergic stimuli – thereby enhancing storage of triglycerides, decreased mitochondrial oxidation, decreased formation of beige adipocytes, and reduced thermogenesis. Binding of FTO risk allele variant (T) rs1421085 to an ARID5B motif that surrounds the rs1421085 common nucleotide variant of FTO resulted in increased repressor activity of the ARID5B motif that in turn decreased expression and hence activity of IRX3 and IRX5 and consequently white fat cell differentiation. Thus, the FTO T-to-C variant (rs1421085) decreases ARID5B binding leading to increased expression of IRX3 and IRX5 resulting in increased differentiation of white adipose tissue and hence fat accumulation and decreased differentiation of brown and beige fat cell and thus lower mitochondrial adaptive thermogenesis.

As described by Drs Iglesias-Platas and Monk (pp. 521–528), epigenetics is the term applied to the regulation of gene expression that does not involve a change in the nucleotide sequence of the intronic or exonic DNA nucleotide sequence of the gene itself. Gene expression may be altered by methylation or hydroxymethylation of the cytosine nucleotide or by modification of histones (chromatin proteins around which DNA coils), for example, methylation, acetylation, ubiquitination, or sumoylation of lysine or phosphorylation of serine or threonine residues. Micro and silencing RNAs are also able to regulate expression of a gene without altering its nucleotide sequence. Epigenetic regulation of gene expression may be influenced by the environment including diet and chemical exposure as well as aging and other factors and may be transmissible through several generations. Dalgaard et al.[4] identified TRIM28 (encoding Tripartite motif-encoding 28; chromosome 19q13.4, OMIM 601742) as a gene that guides an imprinted (i.e., expression is related to the maternal or paternal origin of the specific gene) network of genes that influences body weight by interacting with chromatin. (Imprinting is the result of a parenterally discordant pattern of DNA nucleotide methylation at defined imprinting control regions.) Trim28 assembles the epigenetic factors needed to repress transcription of target genes [5]. Haploinsufficiency of Trim28 in mice resulted in a bimodal distribution of body weights; that is, one normal weight population and one overweight population of mice [4]. (In a set of numbers, the mode is the number that appears most often.) The increased weight was attributable to increased body fat mass due to increased number of adipocytes. In mice, heterozygosity of Trim28 led to down-regulation of a paternally expressed gene network composed of Nnat, Peg3, Cdkn1c, and Plagl1. Experimental deletion of either Nnat or Peg3 duplicated and exaggerated the effects of loss of Trim28 upon the bimodal distribution of body weight/fat mass in mice. [Nnat is expressed in neuronal tissue but its functional role is as yet unknown; Peg3 may be involved with the activation of nuclear factor (NF)-kappa-B.] The investigators presented similar findings in humans; that is, heterozygous TRIM28 individuals with less expression of this gene were more likely to be obese and expression of FTO was more likely to be low in TRIM28-low individuals, thus identifying a potential interrelationship of FTO and TRIM28 in the regulation of body fat mass.

Publication of the 2016 endocrine and metabolism section of the Current Opinion in Pediatrics marks the 25th and final year I have had the pleasure, honor, and distinction of being the editor of this section. I wish to thank the Editors of the Current Opinion in Pediatrics for according me this privilege and the subscribers to the journal for their loyal readership. Beginning in 2017, the Editor of the Endocrine and Metabolism section will be Sally Radovick, MD, Senior Associate Dean for clinical and translational research at Rutgers Robert Wood Johnson Medical School. Dr Radovick was previously Professor of Pediatrics and Head of the Sections of Pediatric Endocrinology at the University of Chicago Pritzker School of Medicine and the Johns Hopkins University School of Medicine.

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1. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma. A paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol [Epub ahead of print]. doi: 10.100/jamaoncol.2016.0386.
2. Choudhry Z, Rikani AA, Choudhry AM, et al. Sonic hedgehog signaling pathway: a complex network. Ann Neurosci 2014; 21:28–31.
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