Ana G. Cristancho

Forming functional fat: a growing understanding of adipocyte differentiation

Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally.

Retinol saturase promotes adipogenesis and is downregulated in obesity

Adipocyte differentiation is controlled by many transcription factors, but few known downstream targets of these factors are necessary for adipogenesis. Here we report that retinol saturase (RetSat), which is an enzyme implicated in the generation of dihydroretinoid metabolites, is induced during adipogenesis and is directly regulated by the transcription factor peroxisome proliferator activated receptor γ (PPARγ). Ablation of RetSat dramatically inhibited adipogenesis but, surprisingly, this block was not overcome by the putative product of RetSat enzymatic activity. On the other hand, ectopic RetSat with an intact, but not a mutated, FAD/NAD dinucleotide-binding motif increased endogenous PPARγ transcriptional activity and promoted adipogenesis. Indeed, RetSat was not required for adipogenesis when cells were provided with exogenous PPARγ ligands. In adipose tissue, RetSat is expressed in adipocytes but is unexpectedly downregulated in obesity, most likely owing to infiltration of macrophages that we demonstrate to repress RetSat expression. Thiazolidinedione treatment reversed low RetSat expression in adipose tissue of obese mice. Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease.

Re-expression of GATA2 Cooperates with Peroxisome Proliferator-activated Receptor-γ Depletion to Revert the Adipocyte Phenotype

Nuclear peroxisome proliferator-activated receptor-γ (PPARγ) is required for adipocyte differentiation, but its role in mature adipocytes is less clear. Here, we report that knockdown of PPARγ expression in 3T3-L1 adipocytes returned the expression of most adipocyte genes to preadipocyte levels. Consistently, down-regulated but not up-regulated genes showed strong enrichment of PPARγ binding. Surprisingly, not all adipocyte genes were reversed, and the adipocyte morphology was maintained for an extended period after PPARγ depletion. To explain this, we focused on transcriptional regulators whose adipogenic regulation was not reversed upon PPARγ depletion. We identified GATA2, a transcription factor whose down-regulation early in adipogenesis is required for preadipocyte differentiation and whose levels remain low after PPARγ knockdown. Forced expression of GATA2 in mature adipocytes complemented PPARγ depletion and impaired adipocyte functionality with a more preadipocyte-like gene expression profile. Ectopic expression of GATA2 in adipose tissue in vivo had a similar effect on adipogenic gene expression. These results suggest that PPARγ-independent down-regulation of GATA2 prevents reversion of mature adipocytes after PPARγ depletion.

Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells

The identification of factors that define adipocyte precursor potential has important implications for obesity. Preadipocytes are fibroblastoid cells committed to becoming round lipid-laden adipocytes. In vitro, this differentiation process is facilitated by confluency, followed by adipogenic stimuli. During adipogenesis, a large number of cytostructural genes are repressed before adipocyte gene induction. Here we report that the transcriptional repressor transcription factor 7-like 1 (TCF7L1) binds and directly regulates the expression of cell structure genes. Depletion of TCF7L1 inhibits differentiation, because TCF7L1 indirectly induces the adipogenic transcription factor peroxisome proliferator-activated receptor γ in a manner that can be replaced by inhibition of myosin II activity. TCF7L1 is induced by cell contact in adipogenic cell lines, and ectopic expression of TCF7L1 alleviates the confluency requirement for adipocytic differentiation of precursor cells. In contrast, TCF7L1 is not induced during confluency of non-adipogenic fibroblasts, and, remarkably, forced expression of TCF7L1 is sufficient to commit non-adipogenic fibroblasts to an adipogenic fate. These results establish TCF7L1 as a transcriptional hub coordinating cell–cell contact with the transcriptional repression required for adipogenic competency.

Stereospecificity of Retinol Saturase: Absolute Configuration, Synthesis, and Biological Evaluation of Dihydroretinoids

Retinol saturase carries out a stereospecific saturation of the C13−C14 double bond of all-trans-retinol to generate (13R)-all-trans-13,14-dihydroretinol. This compound is found in cells expressing mouse or zebrafish retinol saturase and in the livers of mice fed retinyl palmitate. All-trans-13,14-dihydroretinol is oxidized in vivo to all-trans-13,14-dihydroretinoic acid, a highly selective agonist of the retinoic acid receptor. The naturally occurring (13R)-all-trans-13,14-dihydroretinoic acid is a weaker agonist than the (13S) enantiomer, indicating enantioselective recognition by the ligand-binding pocket of this receptor. Consequently the (13S) enantiomer, acting through the retinoic acid receptor, also inhibits adipose differentiation more potently than the (13R) enantiomer.

A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A

Microtubules are dynamic polymers of α/β tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either α‐ or β‐tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly.

Ocular Dipping in a Patient With Hemiplegic Migraine

A 5-year-old girl presented with acute, rapidly progressive encephalopathy following minor head trauma and was found to have ocular dipping. Her encephalopathy was secondary to a channelopathy caused by a CACNA1A mutation. This is the first reported case of ocular dipping in an encephalopathic child with CACNA1A-confirmed hemiplegic migraine. [J Pediatr Ophthalmol Strabismus. 2018;55:e4-e6.].

Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

This Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

IQSEC2 -related encephalopathy in males and females: a comparative study including 37 novel patients

PurposeVariants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.MethodsWe collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.ResultsIQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.ConclusionThis study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Double SET point: G9a makes its mark in adipogenesis.

EMBO J (2013) 32 1, 45–59 doi:10.1038/emboj.2012.306; published online November232012 Sequence-specific DNA-binding transcription factors (TFs) bind throughout the genome to orchestrate the process of adipocyte differentiation in an exquisitely timed and precise manner. TF binding recruits histone-modifying enzymes, resulting in dynamic epigenomic modifications that correlate with extensive gene expression changes. In this issue of The EMBO Journal, Wang et al (2012) demonstrate a critical role for the SET-containing histone methyltransferase G9a in generating repressive chromatin marks that are lost in the process of adipogenesis.