MEDAG functions as an A-kinase-anchoring protein in adipocytes
Induction of catabolic adipocyte activity independent of mitochondrial uncoupling to induce energy expenditure has received increasing attention. In this study, we identified mesenteric estrogen-dependent adipogenesis gene (MEDAG), a poorly studied gene, as a promising therapeutic target for enhancing energy expenditure in adipocytes. We demonstrated that adipose MEDAG expression positively correlates with obesity and metabolic dysfunction in humans. Consistently, adipocyte-specific ablation of Medag in mice leads to increased energy expenditure, offering protection from diet-induced obesity. Mechanistically, we show that MEDAG functions as an A-kinase-anchoring protein (AKAP), which can directly regulate protein kinase A (PKA) activity through a negative feedback loop, involving direct interaction with PKA leading to MEDAG phosphorylation and consequent feedback fine-tuning of PKA activity. Specifically, the direct interaction of MEDAG with the PKA-RIIβ subunit regulates the stability of PKA-RIIβ to prevent PKA hyperactivation. These findings position MEDAG as a target for adipose energy expenditure and uncover its AKAP activity.
Authors
- Lukáš Varga (ORCID: https://orcid.org/0000-0001-9141-3596)
- Adhideb Ghosh (ORCID: https://orcid.org/0000-0002-5160-4571)
- Christian Wolfrum (ORCID: https://orcid.org/0000-0002-3862-6805)
- Patrik Štefanička (ORCID: https://orcid.org/0000-0001-9732-4041)
- A. Hoffmann (ORCID: https://orcid.org/0009-0008-3394-4063)
- Falko Noé (ORCID: https://orcid.org/0009-0002-3360-5455)
- Radhika Khandelwal (ORCID: https://orcid.org/0000-0002-5323-9846)
- Hua Dong (ORCID: https://orcid.org/0000-0002-8235-726X)
- Anand K. Sharma (ORCID: https://orcid.org/0000-0001-7532-5983)
- Bart Deplancke (ORCID: https://orcid.org/0000-0001-9935-843X)
- Miroslav Baláž (ORCID: https://orcid.org/0000-0002-5740-4896)
- Vincent Gardeux (ORCID: https://orcid.org/0000-0001-8954-2161)
- Wenfei Sun
- Tianyu Xu (ORCID: https://orcid.org/0000-0002-2929-6760)
- Tongtong Wang (ORCID: https://orcid.org/0009-0002-0408-7556)
- Laith Abu-Nawwas
- Chunyan Wu
- Lianggong Ding
- Fen Long
- Jonatan R. Ruiz
- Matthias Blüher
Institutions
- Nanyang Technological University (SG)
- California Institute for Regenerative Medicine (US)
- Helmholtz Zentrum München (DE)
- ETH Zurich (CH)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- University Hospital Bratislava (SK)
- Instituto de Investigación Biosanitaria de Granada (ES)
- Biomedical Research Center of the Slovak Academy of Sciences (SK)
- University Hospital Leipzig (DE)
- Regenerative Medicine Institute (MX)
- Nutrition Sciences (Belgium) (BE)
- Imperial College London (GB)
- École Polytechnique Fédérale de Lausanne (CH)
- Comenius University Bratislava (SK)
- Stanford University (US)
Publication Details
- Journal
- Molecular Cell
- Published
- 2026-02-25
- DOI
- https://doi.org/10.1016/j.molcel.2026.02.001
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00