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Decreased adipocyte-specific Olfactomedin 2 in obesity is a critical driver of defective fat cell cycle and adipose tissue accretion

ABSTRACT: Olfactomedin 2 (OLFM2) is a central player in development that also appears to be a critical mediator for energy handling. Here we report that in adipose tissue, expression of OLFM2 is opposite to obesity, being increased upon weight loss. Concurrently, we show steadily increased OLFM2 during adipogenesis, with expression levels reaching its zenith in terminally differentiated adipocytes. Notably, we demonstrate that the loss of this specific olfactomedin domain-containing protein in fat cell progenitors dampens adipogenesis, while the adipogenic conversion is bolstered in engineered 3T3-L1 cells with increased OLFM2. Our seminal findings also bound dwindled expressions of adipocyte-specific OLFM2 to the inflammatory state in the context of obesity, mainly characterized by the influence of macrophage-derived cytokines. Then, we show that the loss of OLFM2 in human adipocytes displays the transient downregulation of genes related to cell cycle, also coupled to deranged energy storage. Next, we transitioned our results to mice models in which whole-body knockout and transcriptionally regulated adipose-specific Olfm2 compel a cluster of molecular changes tightly related to impaired cell cycle (in both) and fat mass accretion (in the later). Current findings unveil the previously unknown expression of OLFM2 in adipocytes and the control of cellular mechanisms related to the obese phenotype exercised by this scaffold protein in adipose tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE214900 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

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Decreased adipocyte-specific Olfactomedin 2 in obesity is a critical driver of defective fat cell cycle and adipose tissue accretion

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