Cover Story Current Issue

Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.

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Current Issue

The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation

Yang Chen, Lin Liu, Ryan P. Calhoun, Lan Cheng, ... Patrick Seale

The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation

 

Objective

Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.

Methods

We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. In vivo relevance was tested using adipocyte precursor–selective Cux1 knockout and lineage reporter mice.

Results

Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including PPARG in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. Cux1 deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. In vivo, Cux1 deletion in APCs of mice increased de novo adipocyte formation during early stages of obesity development.

Conclusions

The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,

 

Articles in Press

The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation

Yang Chen, Lin Liu, Ryan P. Calhoun, Lan Cheng, ... Patrick Seale

The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation

 

Objective

Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.

Methods

We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. In vivo relevance was tested using adipocyte precursor–selective Cux1 knockout and lineage reporter mice.

Results

Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including PPARG in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. Cux1 deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. In vivo, Cux1 deletion in APCs of mice increased de novo adipocyte formation during early stages of obesity development.

Conclusions

The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,

 

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