Obesity is a global health concern impacting 650 million individuals and is a major risk factor for cardiometabolic diseases. Despite its global prevalence, the molecular mechanisms and several factors linking obesity to cardiometabolic diseases remain poorly understood. Adipose tissue (AT) is a primary fat storage organ and an essential regulator of whole-body metabolism by providing thermal insulation, energy storage, and mechanical protection. AT also supports endocrine functions, non-shivering thermogenesis, and immune responses. Due to the critical role of whole-body metabolic control, altering AT function may offer protective action against obesity.
Brown adipose tissue (BAT) is essential for maintaining body temperature by burning fat in response to cold or other stimuli. The mitochondrial transmembrane protein methylation-controlled J protein (MCJ/DnaJC15) plays a crucial role in adipocyte metabolism by inhibiting the respiratory chain complex. A study by Cintia Folgueira et al. published in Nature Communications on January 13, 2025, highlights the regulatory role of MCJ/DnaJC15 in BAT thermogenesis through analysis of human and mouse adipose tissue samples.
The study included male MCJKO and uncoupling protein 1 (UCP1)KO mice (B6.129-Ucp1tm1Kz/J) aged 8 to 20 weeks fed either a chow diet (CD) or a high-fat diet (HFD) for 8–10 weeks. This study also recruited 135 adult patients from the University Hospital of Salamanca. These were divided into 2 groups: 114 patients with obesity (mean age = 47.69 years and body mass index [BMI] ≥ 35 kg/m2) underwent elective bariatric surgery, and 21 control participants (mean age = 49.33 years and BMI ≤ 30) underwent laparoscopic cholecystectomy for gallstone disease.
The reduced levels of MCJ protein were noted in obese patients and mRNA levels of DNAJC15 are inversely proportional to BMI and body fat percentage. Similarly, HFD mice showed decreased MCJ levels compared to CD mice in subcutaneous white adipose tissue (WATsc) and BAT. Moreover, lower levels of MCJ were also observed in response to cold exposure. There is no significant difference in metabolic parameters, BAT histology, and body weight were observed between MCJKO and WT mice fed with CD. However, under HFD conditions, MCJKO mice showed reduced weight gain less fat mass accumulation, and increased lipid droplet accumulations in BAT compared to WT mice.
Administration of adeno-associated virus (AAV) carrying MCJ-targeting shRNA into BAT did not trigger any inflammatory responses in mice. This targeted downregulation of MCJ in AT led to a significant increase in BAT temperature. The lack of MCJ expression in BAT enhances thermogenesis improved lipid profiles, increased insulin, and glucose tolerance in HFD-fed shMCJ BAT mice. BAT transplantation with MCJKO BAT reduced weight gain and increased BAT temperature. This highlights the MCJ is a potential target in reducing obesity. The increase in fatty acid oxidation (FAO) and glycolytic flux was observed in HFD MCJKO BAT compared to WATsc. There is an enhancement in the thermogenesis process observed in MCJKO BAT mice after administering Adrβ3 antagonist SR59230A. Moreover, no difference in interscapular temperature was observed in both the groups of MCJKO-treated mice and WT mice after Adrβ3 antagonist treatment.
UCP1MCJKO mice reported reduced BMI and fat mass, along with elevated BAT temperature compared to UCP1KO mice following an HFD. The improvement in proteins of FAO, BCAA, and TCA were found in human mitochondria from activated BAT. Furthermore, eIF2α is responsible for increased thermogenesis in MCJKO mice and WT mice after HFD.
In conclusion, MCJ/DnaJC15 protein is a promising novel therapeutic target for combating obesity and play a key regulator in BAT thermogenesis.
Reference: Cicuéndez B, Mora A, López JA, et al. Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis. Nat Commun. 2025;16:229. doi:10.1038/s41467-024-54353-4
