COVER: Wang et al. revealed that elevated WTAP in interscapular brown adipose tissue (iBAT) during postnatal development promotes iBAT development and thermogenesis by stabilizing METTL3, indicating that WTAP and METTL3 together control iBAT development and thermogenesis by catalyzing m6A mRNA modification. In the cover image, you can see one of Chinese myths and legends “Sui drilling wood to make a fire”. On a cold snowy day, Sui is making a fire by using hardwood, stick that is straight for the drill piece, and tinder bundle. He is holding stick (WTAP) to drill hardwood (METTL3) to generate sparks (m6A), and then making a fire with a tinder bundle (heat production). This fire (heat) can protect Sui and others from the cold weather. Stick (WTAP) and hardwood (METTL3) work together to generate sparks (m6A), which is essential for making a fire (iBAT development and thermogenesis). See pages 269−283 for details.
Understanding the mechanisms underlying brown fat development and metabolism can provide unique insights into the regulation of energy homeostasis. In a recent study published in Life Metabolism, Wang et al. established Wilms’ tumor 1-associating protein (WTAP), a key component in m6A methyltransferase complex, as a new and essential regulator in the postnatal development and maturation of interscapular brown adipose tissue (iBAT).
Enrica Baldelli, Amedeo Lonardo·06 Dec 2022
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“Maybe you are searching among the branches for what only appears in the roots”—Rumi.
Substantiating the paradigm of disease heterogeneity, nonalcoholic fatty liver disease (NAFLD) has a remarkably variable natural history in the individual patient which legitimates personalized medicine approaches. Why some individuals follow a benign indolent course while others progress from simple steatosis to ongoing liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) remains a fundamental (though unanswered) clinical and research question. In this context, although it is hepatic fibrosis, not nonalcoholic steatohepatitis (NASH), that dictates the prognosis and the clinical course of NAFLD, NASH is recognized as the critical link triggering the deterioration toward the most severe hepato-histological pictures in a proportion of NAFLD patients.
The Warburg effect is critical for tumor growth. A new study showed that cold acclimatization activates brown adipose tissue (BAT), reduces blood glucose levels, and subsequently blunts aerobic glycolysis in cancer and tumor growth.
In a recent study published in Nature, Zhang et al. employed an innovative approach by reprogramming and engineering yeast strain for combined biosynthesis of vindoline and catharanthine, followed by an additional in vitro chemical step for the successful synthesis of the anti-cancer vinblastine.
In a tour-de-force study by Zhang et al. recently published in Nature Metabolism, a newly identified aldolase inhibitor, Aldometanib, is shown to activate lysosomal AMP-activated protein kinase (AMPK). Remarkably, mice treated with Aldometanib have increased insulin sensitivity, lowered blood glucose, and decreased hepatic steatosis and fibrosis, and are long-lived, effects of which all appear to be mediated via activation of lysosomal AMPK.
Xin-Yu Ke, Miaowen Zou, Chenqi Xu·15 Dec 2022
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As an essential part of adaptive immunity, T cells coordinate the immune responses against pathogens and cancer cells. Lipid metabolism has emerged as a key regulator for the activation, differentiation and effector functions of T cells. Therefore, uncovering the molecular mechanisms by which lipid metabolism dictates T cell biology is of vital importance. The tumor microenvironment is a hostile milieu that is often characterized by nutrient restriction. In this environment, various cells, such as T cells and cancer cells, reprogram their metabolism, including their lipid metabolism, to meet their energy and functional needs. Here, we review the participation of fatty acid and cholesterol metabolism homeostasis in orchestrating T cell biology. We demonstrate how the tumor microenvironment reshapes the lipid metabolism in T cells. Importantly, we highlight the current cancer therapeutic interventions that target fatty acid and cholesterol metabolism of T cells. By offering a holistic understanding of how lipid metabolic adaption by T cells facilitates their immunosurveillance in the tumor microenvironment, we believe this review and the future studies might inspire the next-generation immunotherapies.
Yulong Sun, Wenjiao Jiang, Tiffany Horng·09 Dec 2022
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Macrophages are an integral part of the innate immune system and coordinate host defense to microbial infections, as well as shaping the remodeling response after tissue injury. Metabolism is now appreciated to be a powerful and pervasive regulator of the identity and function of macrophages. Upon exposure to microbial ligands, macrophage inflammatory activation and the associated induction of phagocytosis, inflammatory responses, and other host defense activities are supported by dynamic changes to cellular metabolism. Of note, metabolic activity is robustly regulated in a circadian fashion, with many metabolic processes displaying peak activity in one phase of the circadian cycle and trough activity in an antiphase manner. Here, we review recent findings suggesting that circadian metabolism influences macrophage activities and particularly the inflammatory response. First, we summarize macrophage activities known to display time-of-day–dependent variation and their mechanistic basis. Second, we review metabolic processes that have been shown to be rhythmically regulated in macrophages and discuss how such circadian metabolism affects or is likely to affect macrophage activities. Third, we discuss the concept of entrainment of the macrophage clock, and consider how loss of rhythmic regulation of macrophage activities may contribute to pathophysiological conditions like shift work, obesity, and aging. Finally, we propose that circadian metabolism can be used to understand the rationale and mechanistic basis of dynamic regulation of inflammatory responses during infection.
Xin Du, Yisi Hu, Guangping Huang, Fuwen Wei·28 Dec 2022
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Metabolism is the basis for sustaining life and essential to the adaptive evolution of organisms. With the development of high-throughput sequencing technology, genetic mechanisms of adaptive evolution, including metabolic adaptation, have been extensively resolved by omics approaches, but a deep understanding of genetic and epigenetic metabolic adaptation is still lacking. Exploring metabolic adaptations from genetic and epigenetic perspectives in wild vertebrates is vital to understanding species evolution, especially for the early stages of adaptative evolution. Herein, we summarize the advances in our understanding of metabolic adaptations via omics approaches in wild vertebrates based on three types of cases: extreme environment, periodically changing environment, and changes of species characteristics. We conclude that the understanding of the formation of metabolic adaptations at the genetic level alone can well identify the adaptive genetic variation that has developed during evolution, but cannot resolve the potential impact of metabolic adaptations on the adaptative evolution in the future. Thus, it seems imperative to include epigenomics and metabolomics in the study of adaptation, and that in the future genomic and epigenetic data should be integrated to understand the formation of metabolic adaptation of wild vertebrate organisms.Metabolism is the basis for sustaining life and essential to the adaptive evolution of organisms. With the development of high-throughput sequencing technology, genetic mechanisms of adaptive evolution, including metabolic adaptation, have been extensively resolved by omics approaches, but a deep understanding of genetic and epigenetic metabolic adaptation is still lacking. Exploring metabolic adaptations from genetic and epigenetic perspectives in wild vertebrates is vital to understanding species evolution, especially for the early stages of adaptative evolution. Herein, we summarize the advances in our understanding of metabolic adaptations via omics approaches in wild vertebrates based on three types of cases: extreme environment, periodically changing environment, and changes of species characteristics. We conclude that the understanding of the formation of metabolic adaptations at the genetic level alone can well identify the adaptive genetic variation that has developed during evolution, but cannot resolve the potential impact of metabolic adaptations on the adaptative evolution in the future. Thus, it seems imperative to include epigenomics and metabolomics in the study of adaptation, and that in the future genomic and epigenetic data should be integrated to understand the formation of metabolic adaptation of wild vertebrate organisms.
Liping Xiang, Xiaoyan Li, Yunchen Luo, Bing Zhou, Yuejun Liu, Yao Li, Duojiao Wu, Lijing Jia, Pei-Wu Zhu, Ming-Hua Zheng, Hua Wang, Yan Lu·01 Dec 2022
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Nonalcoholic steatohepatitis (NASH) has emerged as a major cause of liver failure and hepatocellular carcinoma. Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology. Here, we present comprehensive multi-omic profiles of preclinical animal models to identify genes, non-coding RNAs, proteins, and plasma metabolites involved in this progression. In particular, by transcriptomics analysis, we identified Growth Differentiation Factor 3 (GDF3) as a candidate noninvasive biomarker in NASH. Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH, and differences in these levels provide a high diagnostic accuracy of NASH diagnosis (AUROC = 0.90; 95% confidence interval: 0.85−0.95) with a good sensitivity (90.7%) and specificity (86.4%). In addition, by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH, we show that ferroptosis may be a potential target to treat NASH. Moreover, by using competing endogenous RNAs network analysis, we found that several miRNAs, including miR-582-5p and miR-292a-3p, and lncRNAs, including XLOC-085738 and XLOC-041531, are associated with steatosis-to-NASH progression. Collectively, our data provide a valuable resource into the molecular characterization of NASH progression, leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.
Nicole Aaron, Tarik Zahr, Ying He, Lexiang Yu, Brent Mayfield, Utpal B Pajvani, Li Qiang·11 Nov 2022
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Obesity is characterized by chronic, low-grade inflammation, which is driven by macrophage infiltration of adipose tissue. PPARγ is well established to have an anti-inflammatory function in macrophages, but the mechanism that regulates its function in these cells remains to be fully elucidated. PPARγ undergoes post-translational modifications (PTMs), including acetylation, to mediate ligand responses, including on metabolic functions. Here, we report that PPARγ acetylation in macrophages promotes their infiltration into adipose tissue, exacerbating metabolic dysregulation. We generated a mouse line that expresses a macrophage-specific, constitutive acetylation-mimetic form of PPARγ (K293Qflox/flox:LysM-cre, mK293Q) to dissect the role of PPARγ acetylation in macrophages. Upon high-fat diet feeding to stimulate macrophage infiltration into adipose tissue, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice, including responses to the PPARγ agonist Rosiglitazone. Macrophage-specific PPARγ K293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue, but not in subcutaneous or brown adipose tissue, leading to decreased energy expenditure, insulin sensitivity, glucose tolerance, and adipose tissue function. Furthermore, mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling. Our study reveals that acetylation is a new layer of PPARγ regulation in macrophage activation, and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.
Yuqin Wang, Xinzhi Li, Cenxi Liu, Liying Zhou, Lei Shi, Zhiguo Zhang, Long Chen, Ming Gao, Lanyue Gao, Yuanyuan Xu, He Huang, Jin Li, Zheng Chen·10 Oct 2022
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Brown adipocyte maturation during postnatal development is essential for brown adipose tissue (BAT) to protect animals against cold. Impaired maturation of brown adipocytes leads to cold intolerance. However, the molecular mechanisms that determine the maturation of brown adipocytes during postnatal development are not fully understood. Here, we identify Wilms’ tumor 1-associating protein (WTAP) as an essential regulator in the postnatal development and maturation of BAT. BAT-specific knockout of Wtap (Wtap-BKO) severely impairs maturation of BAT in vivo by decreasing the expression of BAT-selective genes, leading to the whitening of interscapular BAT (iBAT). Single nucleus RNA-sequencing analysis shows the dynamic changes of cell heterogeneity in iBAT of Wtap-BKO mice. Adult mice with WTAP deficiency in BAT display hypothermic and succumb to acute cold challenge. Mechanistically, WTAP deficiency decreases m6A mRNA modification by reducing the protein stability of METTL3. BAT-specific overexpression of Mettl3 partially rescues the phenotypes observed in Wtap-BKO mice. These data demonstrate that WTAP/METTL3 plays an essential role in iBAT postnatal development and thermogenesis.
In response to contraction during exercise, skeletal muscle growth and metabolism are dynamically regulated by nerve action, blood flow and metabolic feedback. α-ketoglutarate (AKG), a bioactive intermediate in the tricarboxylic acid cycle released during exercise, has been shown to promote skeletal muscle hypertrophy. However, the underlying mechanism of AKG in regulating skeletal muscle development and metabolism is still less known. 2-Oxoglutarate receptor 1 (OXGR1), the endogenous AKG receptor, is found to be distributed in the vascular smooth muscle (VSM) of skeletal muscles. OXGR1 knockout results in skeletal muscle atrophy, accompanied by decreased expression of myosin heavy chain I (MyHC I), capillary density, and endurance exercise capacity. Furthermore, the study found that dietary AKG supplementation increased mice endurance exercise distance, MyHC I/MyHC IIb ratio, arteriole and capillary densities in skeletal muscle. Meanwhile, acute AKG administration gradually increased the blood flow in the lower limbs. Further, by using OXGR1 global knock-out and OXGR1 VSM specific (MYH11-Cre × OXGR1-FloxP) knockdown models, we found that OXGR1 in VSM is essential for AKG-induced improvement of skeletal muscle performances. According to the in vitro study, AKG expanded the cell area in VSM with a decreased intracellular pH (pHi) by OXGR1. Our results demonstrated a novel role of AKG/OXGR1 in VSM of skeletal muscle to regulate blood flow and then enhance slow muscle fiber conversion and capillarization. These findings provide a theoretical basis for the AKG/OXGR1 signaling pathway to maintain human muscle function and improve meat production and livestock and poultry meat quality.
