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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

Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ

Olivia Sveidahl Johansen, Rebecca L. McIntyre, Janane F. Rahbani, Qiaoqiao Zhang, ... Zachary Gerhart-Hines

Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ

 

Objectives

Despite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. Gpr3 expression is physiologically induced in thermogenic adipocytes by cold exposure, and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological Gpr3 expression remain unknown.

Methods

Here, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.

Results

We show that ERRα directly binds the cold-induced promoter element of Gpr3 and that ERRα, ERRβ, and ERRγ each activate the Gpr3 promoter in vitro when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 cold-inducibility in adipose-specific ERRα and ERRγ KO mice is fully rescued by delivery of AAVs re-expressing either ERRα or ERRγ directly into brown adipose tissue.

Conclusions

ERRα and ERRγ are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.

 

 

Articles in Press

Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ

Olivia Sveidahl Johansen, Rebecca L. McIntyre, Janane F. Rahbani, Qiaoqiao Zhang, ... Zachary Gerhart-Hines

Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ

 

Objectives

Despite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. Gpr3 expression is physiologically induced in thermogenic adipocytes by cold exposure, and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological Gpr3 expression remain unknown.

Methods

Here, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.

Results

We show that ERRα directly binds the cold-induced promoter element of Gpr3 and that ERRα, ERRβ, and ERRγ each activate the Gpr3 promoter in vitro when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 cold-inducibility in adipose-specific ERRα and ERRγ KO mice is fully rescued by delivery of AAVs re-expressing either ERRα or ERRγ directly into brown adipose tissue.

Conclusions

ERRα and ERRγ are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.

 

 

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13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026

2024 impact factor: 6.6

You are what you eat

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