Life Metabolism

VOLUME 1 | ISSUE 2 | Oct 2022

COVER:Wang et al. revealed that elevated levels of systemic ketone bodies in neonatal mice determine the quality and number of follicles within the primordial follicle pool by reducing ROS-induced excessive apoptosis in the ovary, further affecting the reproductive lifespan of female mice. In the cover image, you can see a unique figure painted on a Chinese Dunhuang fresco. This buxom fairy of Dunhuang flying apsaras is both a display of maternal beauty and a symbol of vitality. Her hands touch the sacred Dunhuang sunk panel, indicating a meaning of nurturing her offspring. She provides nutritional support (orange circle, the fat acid in colostrum) to her baby girl who is able to synthesis more ketone bodies to maintain the size of primordial follicle pool. At the center of the Dunhuang sunk panel is the oocyte, surrounded by ketone bodies.


Bin Liang, Jennifer L Watts · 17 Sep 2022 loac023

In a recent paper published in Life Metabolism, Zhu et al. revealed that mutations that reduce phosphatidylcholine (PC) synthesis rescue embryonic lethality but exacerbate lipid droplet (LD) abnormalities in C. elegans seipin mutants, demonstrating distinct roles for Seipin in embryogenesis and LD formation.

Long Yan, Hongmei Wang · 18 Aug 2022 loac018

In a recent study published in Life Metabolism, Wang and colleagues reported that the ketone body was elevated during the neonatal stage to regulate the formation of the primordial follicle pool and affect the subsequent ovarian aging through coordinating ROS-induced follicle apoptosis.

Dongming Zhang, Dongsheng Cai · 03 Jun 2022 loac005

In a recent study published in Nature, Iram et al. reported that treatment with young cerebrospinal fluid can play a rejuvenating function in older mice by promoting the proliferation and differentiation of oligodendrocyte progenitor cells in the hippocampus for cognitive improvement.

Xiu-Fang Xin, Jian-Min Zhou · 01 Sep 2022 loac020

High temperatures adversely affect diverse biological processes, such as disease resistance, in plants. In a recent article published in Nature, Kim et al. found that exposure of Arabidopsis plants to a high ambient temperature (28°C) suppresses the formation of Guanylate Binding Protein-like 3 (GBPL3) defence-activated condensate (GDAC) which in turn leads to the reduction of CBP60g/SARD1 transcription and immune responses at high temperatures.

Fei Mao, Xiaoying Li · 16 Jun 2022 loac007

In a recent study published in Nature, Chen et al. reported a mechanism through which hyperglycemia is transmitted from female mice to their offspring through their eggs and DNA methylation of the paternal-derived pancreatic Gck promoter is increased due to a decrease of maternal effector TET3 dioxygenase.


Shaoqun Zhou, Yongshuo Ma, Yi Shang, Xiaoquan Qi, Sanwen Huang, Jiayang Li · 25 Aug 2022 loac019

Plants are talented biochemists that produce a broad diversity of small molecules. These so-called specialized metabolites (SMs) play critical roles in the adaptive evolution of plants to defend against biotic and abiotic stresses, attract pollinators, and modulate soil microbiota for their own benefits. Many plant SMs have been used as nutrition and flavor compounds in our daily food, as well as drugs for treatment of human diseases. Current multi-omics tools have significantly accelerated the process of biosynthetic pathway elucidation in plants through correlation analyses, genetic mapping, and de novo biosynthetic gene cluster predictions. Understanding the biosynthesis of plant SMs has enabled reconstitution of naturally occurring specialized metabolic pathways in microbial hosts, providing a sustainable supply of these high-value molecules. In this review, we illustrate the general functions of several typical plant SMs in natural ecosystems and for human societies. We then provide an overview of current methods elucidating the biosynthetic pathways of plant SMs, and synthetic biology strategies that optimize the efficiency of heterologous biosynthetic pathways in microbial hosts. Moving forward, dissection of the functions and application of plant SMs by using current multidiscipline approaches would be greatly benefit to the scientific community and human societies.

Charles Brenner · 22 Sep 2022 loac025

It is central to biology that sequence conservation suggests functional conservation. Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity. Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells, this is not a selected trait: SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved. Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals, overexpression of SIR2 homologs was tested in invertebrates for longevity. Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation, a global pursuit of longevity phenotypes was driven by a mixture of framing bias, confirmation bias, and hype. Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes. Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort, we review the data and suggest rejection of the notions that sirtuins (i) have any specific connection to lifespan in animals and (ii) are primary mediators of the beneficial effects of NAD repletion.

Jingyi Guo, Yunhao Zhou, Dingfei Liu, Mengfei Wang, Yi Wu, Daolin Tang, Xingguo Liu · 25 Nov 2022 loac035

Mitochondria are well known to be “energy factories” of the cell as they provide intracellular ATP via oxidative phosphorylation. Interestingly, they also function as a “cellular suicidal weapon store” by acting as a key mediator of various forms of regulated cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis. Ferroptosis, distinct from the other types of regulated cell death, is characterized by iron-dependent lipid peroxidation and subsequent plasma membrane rupture. Growing evidence suggests that an impaired ferroptotic response is implicated in various diseases and pathological conditions, and this impaired response is associated with dramatic changes in mitochondrial morphology and function. Mitochondria are the center of iron metabolism and energy production, leading to altered lipid peroxidation sensitivity. Although a growing number of studies have explored the inextricable link between mitochondria and ferroptosis, the role of this organelle in regulating ferroptosis remains unclear. Here, we review recent advances in our understanding of the role of mitochondria in ferroptosis and summarize the characteristics of this novel iron-based cellular suicide weapon and its arsenal. We also discuss the importance of ferroptosis in pathophysiology, including the need for further understanding of the relationship between mitochondria and ferroptosis to identify combinatorial targets that are essential for the development of successful drug discovery.


Xin-Ying Wang, Xin-Ge Zhang, Yong-Juan Sang, Dan-Yang Chong, Xiao-Qiang Sheng, Hai-Quan Wang, Chao-Fan Yang, GuiJun Yan, Hai-Xiang Sun, Chao-Jun Li · 11 Aug 2022 loac017

Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood; however, the underlying mechanism is still unclear. Herein, we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing. We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum. Reactive oxygen species (ROS) elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles, while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing (POA), which might be related to the activation of cellular endogenous antioxidant system. All these defects could be rescued by ketone body administration, which suppressed ROS-activated follicle apoptosis. Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.

Bing Zhou, Yunchen Luo, Nana Ji, Fei Mao, Liping Xiang, Hua Bian, Ming-Hua Zheng, Cheng Hu, Yao Li, Yan Lu · 10 Jun 2022 loac006

Nonalcoholic steatohepatitis (NASH) has emerged as the major cause of end-stage liver diseases. However, an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies. In the present study, through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis, we identified IGF2BP2, an N6-methyladenosine modification reader, as a key regulator that promotes NASH progression in mice. Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis, inflammation, and fibrosis in mice, at least in part, by increasing Tab2 mRNA stability. Besides, hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers. Of potential clinical significance, IGF2BP2 expression is significantly upregulated in the livers of NASH patients. Moreover, knockdown of IGF2BP2 substantially alleviated liver injury, inflammation, and fibrosis in diet-induced NASH mice. Taken together, our findings reveal an important role of IGF2BP2 in NASH, which may provide a new therapeutic target for the treatment of NASH.

Jinglin Zhu, Sin Man Lam, Leilei Yang, Jingjing Liang, Mei Ding, Guanghou Shui, Xun Huang · 08 Sep 2022 loac021

Seipin plays a vital role in lipid droplet homeostasis, and its deficiency causes congenital generalized lipodystrophy type II in humans. It is not known whether the physiological defects are all caused by cellular lipid droplet defects. Loss-of-function mutation of seip-1, the Caenorhabditis elegans seipin ortholog, causes embryonic lethality and lipid droplet abnormality. We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality. Mechanistically, nhr-114 and spin-4 act in the “B12-one-carbon cycle-phosphatidylcholine (PC)” axis, and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants. Conversely, PC deficiency enhances the lipid droplet abnormality of seip-1 mutants. The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid. In addition, the suppression is enhanced by the knockdown of phospholipid scramblase epg-3. Therefore, seipin and PC exhibit opposite actions in embryogenesis, while they function similarly in lipid droplet homeostasis. Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.

Weizhao Lu, Zhaoping Cheng, Xue Xie, Kun Li, Yanhua Duan, Min Li, Chao Ma, Sijin Liu, Jianfeng Qiu · 27 Oct 2022 loac030

Glucose uptake differs in organs and tissues across the human body. To date, however, there has been no single atlas providing detailed glucose uptake profiles across the entire human body. Therefore, we aimed to generate a detailed profile of glucose uptake across the entire human body using the uEXPLORER positron emission tomography/computed tomography scanner, which offers the opportunity to collect glucose metabolic imaging quickly and simultaneously in all sites of the body. The standardized uptake value normalized by lean body mass (SUL) of 18F-fluorodeoxyglucose was used as a measure of glucose uptake. We developed a fingerprint of glucose uptake reflecting the mean SULs of major organs and parts across the entire human body in 15 healthy-weight and 18 overweight subjects. Using the segmentation of organs and body parts from the atlas, we uncovered the significant impacts of age, sex, and obesity on glucose uptake in organs and parts across the entire body. A difference was recognized between the right and left side of the body. Overall, we generated a total-body glucose uptake atlas that could be used as the reference for the diagnosis and evaluation of disordered states involving dysregulated glucose metabolism.