Fat body-specific reduction of CTPS alleviates HFD-induced obesity
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Abstract
Obesity induced by high-fat diet (HFD) is a multi-factorial disease including genetic, physiological, behavioral, and environmental components. Drosophila has emerged as an effective metabolic disease model. Cytidine 5'-triphosphate synthase (CTPS) is an important enzyme for the de novo synthesis of CTP, governing the cellular level of CTP and the rate of phospholipid synthesis. CTPS is known to form filamentous structures called cytoophidia, which are found in bacteria, archaea, and eukaryotes. Our study demonstrates that CTPS is crucial in regulating body weight and starvation resistance in Drosophila by functioning in the fat body. HFD-induced obesity leads to increased transcription of CTPS and elongates cytoophidia in larval adipocytes. Depleting CTPS in the fat body prevented HFD-induced obesity, including body weight gain, adipocyte expansion, and lipid accumulation, by inhibiting the PI3K-Akt-SREBP axis. Furthermore, a dominant-negative form of CTPS also prevented adipocyte expansion and downregulated lipogenic genes. These findings not only establish a functional link between CTPS and lipid homeostasis but also highlight the potential role of CTPS manipulation in the treatment of HFD-induced obesity.
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This manuscript finds the CTPS enzymes in fat cells to regulate metabolic homeostasis and growth in Drosophila. This enzyme is involved in the de novo synthesis of the CTP and also in the polymerization of filamentous structures called cytoophidia. Whole body knockdown of CTPS led to a body weight reduction along with less starvation resistance in adult flies. The larval body weight was also measured and found to be reduced upon whole-body knockdown of CTPS. Interestingly, fat body-specific knockdown of this enzyme phenocopied the body weight reduction, suggesting an important role of CTPS specifically in adipocytes or fat cells.
A high-fat diet (HFD)-feeding induces obesity in flies. …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7050649.
This manuscript finds the CTPS enzymes in fat cells to regulate metabolic homeostasis and growth in Drosophila. This enzyme is involved in the de novo synthesis of the CTP and also in the polymerization of filamentous structures called cytoophidia. Whole body knockdown of CTPS led to a body weight reduction along with less starvation resistance in adult flies. The larval body weight was also measured and found to be reduced upon whole-body knockdown of CTPS. Interestingly, fat body-specific knockdown of this enzyme phenocopied the body weight reduction, suggesting an important role of CTPS specifically in adipocytes or fat cells.
A high-fat diet (HFD)-feeding induces obesity in flies. Rearing the larvae on a HFD led to an increase in the expression of CTPS mRNA levels and elongation of cytoophidia in the larval fat body compared to a regular diet. The fat body-specific knockdown of CTPS led to enhanced obesity upon HFD feeding compared to control, shown by the increased size of lipid droplets in the fat body and also the total triglyceride (TAG) content. The expression of lipogenic genes was also found to be enhanced as well in the CTPS-depleted larvae.
The authors tried to find the mechanism of growth and lipid homeostasis regulation by the CTPS enzyme. PI3K-AKT signalling is crucial for the regulation of growth and metabolic homeostasis in the fat cells. It was found that the PI3K activity and phosphorylated-AKT level are reduced upon CTPS knockdown in the fat body. Additionally, whether the function of CTPS cytoophidia is involved in this growth regulation was addressed by overexpressing a point-mutatant version of CTPS in the fat cells. Upon HFD-feeding, the overexpression of the normal CTPS enzyme led to an increase in body weight and lipid content, whereas overexpression of the point-mutant CTPS led to the opposite results, i.e., a reduction of body weight and lipid level, compared to control larvae. Thus, the authors concluded that the CTPS activity in the adipocytes alleviates HFD-induced obesity.
Comments:
1. The paper finds a role of CTPS in the regulation of growth and lipid synthesis in Drosophila. However, the mechanism of this regulation by CTPS is not clear. For example, whether the CTP synthesis by CTPS could be important for body weight and lipid homeostasis of the larvae has not been discussed.
2. How the adipocytes cytoophidia is linked with regulation of lipid level and body weight of the larvae is also not discussed in the paper.
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