Scientists discover a fat-burning switch that helps mice resist obesity

Inside the fat tissue of mammals lies a quiet furnace that burns surplus calories as heat instead of storing them as fat. A new study published in Experimental & Molecular Medicine has identified a previously overlooked enzyme that helps keep this furnace lit, and the discovery is drawing attention because switching it on in mice made them noticeably more resistant to obesity. The enzyme, called dual-specificity phosphatase 4, or DUSP4, appears to act as a molecular gatekeeper for adaptive thermogenesis, the process by which brown and beige fat dissipate excess energy through the mitochondrial protein uncoupling protein 1, better known as UCP1.

The research, led by Min Jeong Son, Kwang-Hee Bae and Won Kon Kim of the Korea Research Institute of Bioscience and Biotechnology together with colleagues in Korea, began with a simple observation. When mice were exposed to cold or given a beta-adrenergic drug that mimics cold stimulation, DUSP4 levels rose sharply in their inguinal white adipose tissue and brown fat. Conversely, when the animals were kept at thermoneutrality, a warm 30 degrees Celsius at which thermogenic genes are largely switched off, DUSP4 expression fell. The enzyme was also strongly induced in cultured adipocytes treated with norepinephrine, the chemical messenger that sympathetic nerves release to activate heat production. Notably, the induction was confined to the adipocytes themselves rather than to immune or stromal cells in the tissue, and it was most pronounced in the inducible beige fat depot, while the epididymal fat pad, which is metabolically inert with respect to thermogenesis, showed little response.

To find out whether DUSP4 actually matters for metabolism, the team studied mice in which the Dusp4 gene had been deleted. On a standard chow diet the knockout animals looked essentially normal, with only a modestly higher body weight and slightly reduced thermogenic gene expression. But when the researchers challenged them with a high-fat diet, the picture changed dramatically. The DUSP4-deficient mice gained significantly more weight than controls, accumulated enlarged fat cells across multiple depots, and showed the molecular hallmarks of a fat tissue that had shifted from burning to storing: thermogenic genes such as Ucp1 and Pgc1alpha were substantially suppressed, while lipogenic genes including Srebp1c, Fas and Acc were elevated. The animals also developed markedly worse glucose tolerance and insulin resistance than their wild-type littermates on the same diet.

The most striking evidence came from cold-exposure experiments. When placed at 6 degrees Celsius for a week, mice lacking DUSP4 could not defend their body temperature as effectively as normal mice. Their rectal temperatures dropped further and stayed lower throughout the challenge, and infrared thermal imaging confirmed that their body surfaces were cooler. Indirect calorimetry revealed the underlying cause: the knockout mice consumed less oxygen, produced less carbon dioxide and expended significantly less energy than controls during cold exposure, even though they ate the same amount of food. Their inguinal fat also failed to undergo the normal mitochondrial remodeling that cold triggers, showing blunted increases in mitochondrial DNA copy number, reduced levels of respiratory chain proteins and an attenuated induction of mitochondrial biogenesis markers such as Tfam, Erralpha and Nrf1.

These defects pointed to a problem in the signaling machinery that switches on thermogenic genes. The researchers focused on CRTC3, a transcriptional coactivator that is abundant in adipocytes and known to control energy metabolism through its location within the cell. CRTC3 is regulated by phosphorylation: when serine residues on the protein are decorated with phosphate groups, it is retained in the cytoplasm and unable to assist gene transcription; when those phosphates are removed, CRTC3 moves into the nucleus, where it can boost the activity of genes such as Ucp1. What had remained unclear was which phosphatase, if any, performs this dephosphorylation in fat cells.

The answer, according to the new study, is DUSP4. Co-immunoprecipitation experiments showed that DUSP4 physically associates with CRTC3, an interaction that was strengthened by forskolin, a compound that mimics the cAMP signaling triggered by cold. When the team overexpressed DUSP4 in mature inguinal adipocytes, the serine phosphorylation of CRTC3 dropped; when they expressed a catalytically dead version of the enzyme, in which a single cysteine at position 284 was replaced by serine, CRTC3 phosphorylation actually increased. Crucially, DUSP4’s effect was selective: phosphorylation of AMPK and CREB, upstream signaling proteins, was left intact, indicating that DUSP4 acts at a specific phosphatase layer rather than globally dampening kinase pathways. In the fat tissue of DUSP4-knockout mice, CRTC3 phosphorylation was elevated, consistent with the enzyme’s role in living animals.

The functional consequences followed directly. With DUSP4 present, CRTC3 accumulated in the nucleus, as shown by both immunofluorescence imaging and biochemical fractionation of cells into nuclear and cytosolic compartments. Nuclear-localized CRTC3 enhanced the activity of reporter constructs driven by the Ucp1 and Pgc1alpha promoters, and this boost was abolished by the catalytically inactive mutant. In epistasis experiments using stable DUSP4-overexpressing adipocytes, silencing CRTC3 with shRNA blunted the UCP1 induction that DUSP4 would otherwise drive, while adding extra CRTC3 amplified it. Oxygen consumption measurements tracked the same pattern: CRTC3 knockdown reduced mitochondrial respiration in DUSP4-overexpressing cells, whereas CRTC3 overexpression raised it. Together these results establish CRTC3 as the functional mediator through which DUSP4 activates the thermogenic program.

The catalytic activity of DUSP4 proved essential at every level. Cells expressing wild-type DUSP4 responded to norepinephrine with robust UCP1 production, increased mitochondrial mass visible with MitoTracker staining, higher mitochondrial DNA copy number, and a coordinated induction of respiratory chain genes such as Ndufa9, Sdha, Uqcrc2, Cox4 and Atp5a1. Cells carrying the inactive mutant showed none of these responses, and the mutant also failed to dephosphorylate p38 MAPK, a known DUSP4 substrate, confirming that its enzymatic deadness was genuine. In other words, it is not merely the presence of DUSP4 but its phosphatase activity that turns on the fat-burning machinery.

Perhaps the most clinically suggestive result came from a rescue experiment. The researchers injected a lentivirus carrying the Dusp4 gene directly into the inguinal fat pads of knockout mice, then exposed the animals to cold. Restoring DUSP4 in this single depot reduced lipid droplet accumulation, raised UCP1 and PGC1alpha expression, decreased CRTC3 phosphorylation, enhanced CRTC3 nuclear localization, and brought UCP1 levels back to near-normal. This depot-targeted reconstitution demonstrates that DUSP4 acts in an adipocyte-autonomous fashion, although the authors caution that whether such localized rescue can improve whole-body metabolic parameters would require adipose-wide delivery strategies and dedicated systemic phenotyping.

The findings arrive amid intense interest in thermogenic fat as a therapeutic target. Adult humans do possess metabolically active brown fat that can be activated by cold, its presence correlates with better cardiometabolic health in large cohort studies, and the beta3-adrenergic drug mirabegron has been shown to increase brown fat activity and improve insulin sensitivity in people. Because DUSP4 is an enzyme, it is considered pharmacologically tractable: small molecules that enhance its catalytic activity or stabilize its interaction with CRTC3 could in principle augment energy expenditure. The authors acknowledge important limitations, including the use of a global knockout model, relatively modest replicate numbers for some assays, and the fact that the specific DUSP4-sensitive phosphorylation sites on CRTC3 have not yet been mapped. Validation in human adipose tissue will also be essential. Still, the identification of a DUSP4-CRTC3-UCP1 axis adds a genuinely new node to the thermogenic signaling network, and it suggests that the road to obesity treatment may one day run through a phosphatase that teaches fat cells to burn rather than store.

Subject of Research: Regulation of adipocyte thermogenesis by the phosphatase DUSP4 via CRTC3 dephosphorylation and UCP1 expression

Article Title: DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression

Article References: Son, M. J., Kook, H. U., Jung, J., Park, S.-J., Jeon, Y. J., Oh, K.-J., Lee, E.-W., Han, B. S., Choi, J. H., Bae, K.-H., & Kim, W. K. (2026). DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01850-9

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01850-9

Keywords: DUSP4, CRTC3, UCP1, thermogenesis, obesity, adipocytes, brown fat, beige fat, phosphatase, mitochondria, insulin resistance, energy expenditure