The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice
Xinxin Yu. et al.
Cell Metab. 2024
This study investigates the role of the GIP receptor (GIPR) in adipocytes and its impact on energy metabolism and weight regulation. The authors generate a mouse model with inducible GIPR expression specifically in adipocytes, using the Doxycycline (Dox)-inducible system to activate the receptor. The findings highlight that activation of GIPR in adipose tissue leads to significant weight loss and protection against diet-induced obesity. This effect is achieved through enhanced lipid oxidation, thermogenesis, and increased energy expenditure, which are regulated by the activation of SERCA-driven futile calcium cycling in adipocytes induced by GIPR.The study further shows that GIPR activation transiently suppresses food intake and increases fat tissue thermogenesis, primarily in white adipose tissue (WAT), while no major effect is observed in other tissues like liver or muscle. In addition, GIPR activation has a metabolic memory effect, meaning that even after the receptor is deactivated, the mice maintain weight loss, suggesting that there might exist a long-lasting alteration in their metabolic state. Moreover, when combined with GLP-1R agonists, the effect of GIPR activation is enhanced, suggesting that multi-receptor therapy could be effective in combating obesity. The study concludes that GIPR activation in adipocytes plays a critical role in increasing energy expenditure, promoting weight loss, and preventing weight regain, with implications for the development of new treatments for obesity and metabolic diseases.In summary, the research demonstrates that GIPR activation can drive weight loss and maintain long-term metabolic improvements through SERCA-mediated futile calcium cycling, providing evidence for the potential of GIPR-based therapies as a promising strategy for obesity treatment. DOI: 10.1016/j.cmet.2024.11.003
Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression![]()
Wortzel Inbal. et al.
Nature Cancer. 2024
This study investigates the role of exosome-derived DNA (EV-DNA) in regulating immune responses and tumor metastasis. The authors have previously showed that EVs contain DNA (EV-DNA) representing the entire genome. In this article, they focus on the molecular mechanisms behind the packaging of DNA into exosomes, particularly how specific genes, such as apoptotic peptidase activating factor 1 (APAF1) and neutrophil cytosolic factor 1 (NCF1), influence this process. They also investigate the impact of EV-DNA on tumor progression, especially liver metastasis in colorectal cancer models.They first find that EV-DNA is associated with uniquely modified histones by treating the EV-DNA with DNase and using quantitative mass spectrometry (MS) analysis. They then identify that APAF1 and NCF1 regulate EV-DNA packaging by performing CRISPR-Cas9 gene knockout screens and RNA sequencing. Using mouse models, the study elucidates that the presence of EV-DNA significantly alters the immune environment in the liver, specifically enhancing the activation of KCs. These activated KCs form tertiary lymphoid structures (TLS), which contribute to an anti-tumor immune response and inhibit metastasis. Conversely, the loss of APAF1 leads to decreased EV-DNA levels, impaired immune activation, and increased metastatic burden, suggesting that EV-DNA plays a critical role in immune surveillance and tumor suppression.Furthermore, the study highlights the correlation between EV-DNA content and cancer progression. Elevated EV-DNA levels are found to be associated with increased metastasis and poor prognosis in CRC patients. The authors conclude that EV-DNA serves as a potential biomarker for predicting tumor metastasis and immune response, offering new therapeutic avenues for targeting the exosome-mediated transfer of DNA in cancer treatment.In summary, this research provides compelling evidence that EV-DNA plays a crucial role in modulating the immune microenvironment, particularly by activating KCs and promoting TLS formation, which collectively enhance anti-tumor immunity and suppress metastasis.DOI: 10.1038/s43018-024-00862-6
Editor & Reviewer: Congci Yu
