Kazak, L. | bioRxiv Science

bioRxiv2025

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

ObjectivesDespite 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. MethodsHere, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERR and ERR{gamma}, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno associated virus (AAV)-mediated rescue. ResultsWe show that ERR directly binds the cold-induced promoter element of Gpr3 and that adipocyte ERR and ERR{gamma} are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 cold-inducibility in adipose-specific ERR and ERR{gamma} KO mice is fully rescued by delivery of AAVs re-expressing either ERR or ERR{gamma} directly into brown adipose tissue. ConclusionsERR and ERR{gamma} are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.

molecular biology↗

bioRxiv2018

Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner

Skeletal muscle and brown adipose tissue (BAT) share a common lineage and have been functionally linked, as exercise increases browning through the actions of various myokines. It is unknown, however, whether BAT can affect skeletal muscle function. Our prior work has shown that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces adaptive thermogenesis. Here, we note that these mice also have reduced exercise capacity relative to wild-type littermates, associated with diminished mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle, in addition to the signature ultrastructural abnormalities of tubular aggregate myopathy. Within brown adipose tissue, loss of IRF4 caused the induction of a myogenic gene expression signature, which includes an increase in the secreted factor myostatin, a known inhibitor of muscle function. Reduction of myostatin activity by the injection of neutralizing antibodies or soluble ActRIIB receptor rescued the exercise capacity of BATI4KO mice. Additionally, overexpression of IRF4 in brown adipocytes reduced serum myostatin and increased mitochondrial function and exercise capacity in muscle. A physiological role for this system is suggested by the observation that mice housed at thermoneutrality show lower exercise capacity with increased serum myostatin; both of these abnormalities are corrected by surgical removal of BAT. Collectively, our data point to an unsuspected level of BAT-muscle cross-talk driven by IRF4 and myostatin.\n\nHighlightsO_LIMice lacking IRF4 in BAT have a decrease in exercise capacity, accompanied by histological, ultrastructural, signaling, gene expression, and bioenergetic evidence of myopathy in white vastus.\nC_LIO_LILoss of IRF4 promotes the expression of a myogenic signature in BAT, including the myokine myostatin.\nC_LIO_LINeutralization of serum myostatin rescues the ability of BATI4KO mice to exercise normally, while overexpression of IRF4 in BAT allows mice to run better than wild-type counterparts.\nC_LIO_LIThermoneutrality reduces the level of IRF4 in BAT of WT mice, resulting in a myopathic phenotype that can be reversed by surgical excision of BAT.\nC_LI

physiology↗