Life Metabolism

VOLUME 1 | ISSUE 1 | Aug 2022

COVER:Quan et al. identified a bidirectional regulatory mechanism between myocardial insulin resistance and calcium homeostasis dysregulation in cardiomyocytes mediated by phosphorylation of SERCA2a-Thr484, revealing a novel molecular mechanism in the early pathogenesis of DCM. In the cover image, you can see a “dancing heart” illustrating the mutual dependence between insulin signaling and calcium homeostasis to maintain a healthy heart. A duplicate of an ancient Chinese character of heart ( ) is depicted in red and blue color respectively, representing the two interconnected cellular processes and forming a four-chamber heart in the middle of the dancing figure.


Peng Li, John R Speakman · 29 Apr 2022 loac001

Exactly one hundred years ago, the world was emerging from the ravages of the Spanish flu pandemic that killed 30 million people. Today, we are also emerging from a similar pandemic caused by coronavirus disease (COVID-19). However, the world that survivors of the flu pandemic inherited was very different from the world that will be left after COVID-19 is finally over. Life, of course, has changed enormously in these last 100 years with the advent of air travel, cars, computers, and the internet. But not only healthy life has changed, but what has also changed is the reasons why we get ill and die. After the flu pandemic, the major killers were still infectious diseases and undernutrition. Nowadays, the main health problems are due to over-nutrition and non-communicable diseases such as obesity, Type 2 diabetes, cardiovascular diseases, cancer, and neurological diseases. Moreover, because more people live into old age nowadays, we face many other issues connected with dementia and other disorders of aging.


Qian Shi, Duane D Hall, Long-Sheng Song · 04 Aug 2022 loac014

In a recent study published in Life Metabolism, Quan et al. reported that intracellular Ca2+dysregulation in cardiomyocyte can be both a cause and an effect of cardiac insulin resistance that ultimately leads to diabetic cardiomyopathy. Numerous epidemiologic studies across several decades indicate that insulin-resistant states such as diabetes and obesity are risk factors for congestive heart failure independent of common cardiovascular disease factors such as hypertension and coronary artery diseases [1, 2]. On the other hand, there is evidence that heart failure itself causes the onset and development of insulin resistance [3]. Restoring normal cardiac output in advanced heart failure patients with left ventricular assistance devices improves insulin sensitivity and cardiac metabolism [4]. These observations suggest a bidirectional link exists between insulin resistance and cardiac contractile dysfunction. One common feature of both insulin resistance and heart failure could be abnormal intracellular Ca2+ homeostasis. Ca2+ handling dysfunction is a well-defined hallmark of heart failure [5], and it has long been hypothesized that elevations of cytosolic free Ca2+ in insulin-targeted cells may lead to the development of insulin resistance [6]. However, the mechanism by which a Ca2+ cycling defect could determine insulin resistance has not been pursued. Furthermore, it remains unclear whether the Ca2+ handling processes that are known to be dysfunctional in heart failure are the same as those that contribute to insulin resistance.

Fucheng Dong, Wei Li · 23 Aug 2022 loac015

In a recent study published in Life Metabolism, Xu et al. report that the α-ketoglutaric acid (AKG)/2-oxoglutarate receptor 1 (OXGR1) signaling plays an important role in the regulation of sperm maturation by maintaining epididymal fluid acid–base balance in epididymal smooth muscle cells, suggesting that AKG may provide a new chance for nutritional intervention of some male infertility. With the development of science and technology, the overall health conditions have been greatly improved, but the reproductive health issue is still challenging. Infertility is currently the third most common disease affecting human health, with ~50% of cases being related to male infertility [1]. Considering that the genetic background of populations cannot significantly change within half a century, the changes in environment and the lifestyle should be the major cause for most of the infertility. The effects of environmental pollution on male fertility have been intensively investigated [2], while the mechanism by which lifestyle affects male fertility is still elusive. The lifestyle may affect male fertility by altering our metabolic processes. The tricarboxylic acid cycle (TCA) is a common metabolic pathway in nearly all eukaryotes, and it has been demonstrated that extra-mitochondrial citrate synthase (eCS) is produced in the sperm head, and eCS can suppress age-associated male infertility [3]. As a TCA intermediate, AKG plays a critical role in the regulation of renal HCO3− secretion and salt reabsorption via its receptor, OXGR1 [4]. Considering that pH value and HCO3− concentration are also essential for the maturation of sperm in the epididymis luminal fluid, Xu et al. asked whether the AKG/OXGR1 signaling pathway plays any role in sperm maturation.

Camille Allard, Daniela Cota · 01 Jul 2022 loac010

In the last issue of Cell, Zhang et al. comprehensively pinpointed in male mice how endogenous glucagon-like peptide 1 (GLP-1) production by intestinal L cells triggers a coordinated interorgan crosstalk to mediate stomach distension and appetite suppression. GLP-1 was originally described at the beginning of the 20th century as a peptide deriving from pre-proglucagon, and then officially named in the 1980s [1]. GLP-1 has a large number of metabolic actions, the most studied ones being its capacity to inhibit gastric emptying, suppress food intake, and reduce glycemia [1]. GLP-1 receptor (GLP-1R) agonists are effective drugs for the treatment of type 2 diabetes and obesity [1]. Consequently, there is extensive interest in understanding the precise mechanisms of actions of GLP-1. While initial studies had put forward a prevalent endocrine effect, in part because of the widespread expression of GLP-1R in the organism, subsequent work on GLP-1, by pointing out its very short half-life and very low levels in the blood, has challenged this view [2]. Rather, local action of GLP-1, primarily within the gut, may represent an important conduit of its relevance in physiology [3, 4].

Hao Wu, Ling-Ling Chen · 16 Jun 2022 loac008

In the recent article published in Cell, Zhu and colleagues identified the noncoding RNA, 7S RNA, that couples the homodimer formation of mitochondrial RNA polymerase POLAMT, preventing the latter from interacting with promoter and transcription complex on mitochondrial DNA, leading to suppressed transcription initiation. This negative transcription regulation is modulated by the mitochondrial exoribonuclease complex that can degrade 7S RNA. RNA transcription is the critical biological process by which the genomic DNA is copied into RNA sequence. In eukaryotes, the RNA polymerase II (Pol II) transcribes protein-coding and noncoding genes with the help of transcription factors, including general components like TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH [1]. The Pol II transcribed coding RNAs are m7G capped and polyadenylated, subsequently exported into cytosol, and translated into proteins. Transcription regulation of specific genes is remarkably balanced by enhancer or silencer sequences in cis embedded in DNA sequences, and in trans by auxiliary factors such as promoter-specific activators, suppressors, and co-regulators [2]. For a long time, these regulatory factors are thought to be proteins and protein-containing complexes, but now it is getting increasingly clear that noncoding RNAs (ncRNAs) also play crucial roles in these processes [3, 4].


John R Speakman, Joel K Elmquist · 29 Apr 2022 loac002

People completely lacking body fat (lipodystrophy/lipoatrophy) and those with severe obesity both show profound metabolic and other health issues. Regulating levels of body fat somewhere between these limits would, therefore, appear to be adaptive. Two different models might be contemplated. More traditional is a set point (SP) where the levels are regulated around a fixed level. Alternatively, dual-intervention point (DIP) is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached. The DIP system seems to fit our experience much better than an SP, and models suggest that it is more likely to have evolved. A DIP system may have evolved because of two contrasting selection pressures. At the lower end, we may have been selected to avoid low levels of fat as a buffer against starvation, to avoid disease-induced anorexia, and to support reproduction. At the upper end, we may have been selected to avoid excess storage because of the elevated risks of predation. This upper limit of control seems to have malfunctioned because some of us deposit large fat stores, with important negative health effects. Why has evolution not protected us against this problem? One possibility is that the protective system slowly fell apart due to random mutations after we dramatically reduced the risk of being predated during our evolutionary history. By chance, it fell apart more in some people than others, and these people are now unable to effectively manage their weight in the face of the modern food glut. To understand the evolutionary context of obesity, it is important to separate the adaptive reason for storing some fat (i.e. the lower intervention point), from the nonadaptive reason for storing lots of fat (a broken upper intervention point). The DIP model has several consequences, showing how we understand the obesity problem and what happens when we attempt to treat it.

Jie Luo, Jin-Kai Wang, Bao-Liang Song · 20 Mar 2022 loac004

Low-density lipoprotein (LDL) is the main carrier of cholesterol and cholesteryl ester in circulation. High plasma levels of LDL cholesterol (LDL-C) are a major risk factor of atherosclerotic cardiovascular disease (ASCVD). LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD. Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy. Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments. Here, we review the most recent advances on LDL-C-lowering drugs, focusing on the mechanisms by which they act to reduce LDL-C levels. The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD. Special treatments for those with little or no LDL receptor function then follow. The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein, which are recently approved and still under investigation for LDL-C lowering, respectively, are also included. Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.


Xu Wang, Shen-Ying Liu, Guo-Sheng Hu, Hao-Yan Wang, Guo-Liang Zhang, Xiang Cen, Si-Ting Xiang, Wen Liu, Peng Li, Haobin Ye, Tong-Jin Zhao · 13 Mar 2022 loac003

Brown adipose tissue (BAT) plays a key role in thermogenesis during acute cold exposure. However, it remains unclear how BAT is prepared to rapidly turn on thermogenic genes. Here, we show that damage-specific DNA binding protein 1 (DDB1) mediates the rapid transcription of thermogenic genes upon acute cold exposure. Adipose- or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes. These mice develop hypothermia when subjected to acute cold exposure at 4 °C and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation. Mechanistically, DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b (P-TEFb) to release promoter-proximally paused RNA polymerase II (Pol II), thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure. Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.

Chao Quan, Sangsang Zhu, Ruizhen Wang, Jiamou Chen, Qiaoli Chen, Min Li, Shu Su, Qian Du, Minjun Liu, Hong-Yu Wang, Shuai Chen · 28 Jul 2022 loac013

Diabetic cardiomyopathy (DCM) is currently a progressive and nonstoppable complication in type 2 diabetic patients. Metabolic insults and insulin resistance are involved in its pathogenesis; however, the underlying mechanisms are still not clearly understood. Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM. A western diet induces the development of DCM through at least three phases in mice, among which an early phase depends on impaired Thr484-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr484 to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline. Importantly, this mutation blunts the early phase of DCM, but has no effect on disease progression in the following phases. Interestingly, impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr484 mutation inhibited processing of insulin receptor precursor through FURIN convertase, resulting in cardiac insulin resistance. Collectively, these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis, which may underlie the early pathogenesis of DCM. Our findings have therapeutic implications for early intervention of DCM.

Chang Xu, Yexian Yuan, Cha Zhang, Yuchuan Zhou, Jinping Yang, Huadong Yi, Ishwari Gyawali, Jingyi Lu, Sile Guo, Yunru Ji, Chengquan Tan, Songbo Wang, Yongliang Zhang, Qingyan Jiang, Gang Shu · 14 Jul 2022 loac012

Infertility is a global concern attributed to genetic defects, lifestyle, nutrition, and any other factors that affect the local metabolism and niche microenvironment of the reproductive system. 2-Oxoglutarate receptor 1 (OXGR1) is abundantly expressed in the testis; however, its cellular distribution and biological function of OXGR1 in the male reproductive system remain unclear. In the current study, we demonstrated that OXGR1 is primarily expressed in epididymal smooth muscle cells (SMCs). Aging and heat stress significantly reduced OXGR1 expression in the epididymis. Using OXGR1 global knockout and epididymal-specific OXGR1 knockdown models, we revealed that OXGR1 is essential for epididymal sperm maturation and fluid acid–base balance. Supplementation of α-ketoglutaric acid (AKG), the endogenous ligand of OXGR1, effectively reversed epididymal sperm maturation disorders caused by aging and heat stress. Furthermore, in vitro studies showed that AKG markedly stimulated the release of instantaneous intracellular calcium from epididymal SMCs and substantially reduced the pHi value in the epididymal SMCs via OXGR1. Mechanistically, we discovered that AKG/OXGR1 considerably increased the expression of Na+/HCO3− cotransporter (NBCe1) mRNA in the epididymal SMCs, mediated by intracellular calcium signaling. The local AKG/OXGR1 system changed the epididymal fluid pH value and HCO3− concentration, thereby regulating sperm maturation via intracellular calcium signaling and NBCe1 mRNA expression. This study for the first time reveals the crucial role of OXGR1 in male fertility and sheds light on the applicability of metabolic intermediates in the nutritional intervention of reproduction.

Peixue Xia, Liankui Zhou, Jialiang Guan, Wanqiu Ding, Ying Liu · 24 Jun 2022 loac009

Animals respond to mitochondrial perturbation by activating the mitochondrial unfolded protein response (UPRmt) to induce the transcription of mitochondrial stress response genes. In Caenorhabditis elegans, activation of UPRmt allows the animals to maintain organismal homeostasis, activate the innate immune response, and promote lifespan extension. Here, we show that splicing factors such as Precursor RNA processing 19 (PRP-19) are required for the induction of UPRmt in C. elegans. PRP-19 also modulates mitochondrial perturbation-induced innate immune response and lifespan extension. Knockdown of PRP-19 in mammalian cells suppresses UPRmt activation and disrupts the mitochondrial network. These findings reveal an evolutionarily conserved mechanism that maintains mitochondrial homeostasis and controls innate immunity and lifespan through splicing factors.


Hui Chen, Yang Tao, Min-Dian Li, Yuxuan Gu, Jiaxi Yang, You Wu, Dongmei Yu, Changzheng Yuan · 07 Jul 2022 loac011

Dear Editor, Worldwide, around 55 million people had prevalent dementia in 2019, which is expected to triple by 2050, especially in low- and middle-income countries [1]. Lacking timely diagnosis and limited effective treatment for dementia make identifying risk factors crucial for its early prevention, among which dietary factors have received increasing attention [1]. Recently, accumulating evidence from population-based studies has linked the temporal patterns of energy intake (TPEI), usually defined as the temporal distribution of energy intake during a day, to mortality and metabolic diseases [2], such as diabetes and hypertension. In vitro and in vivo studies also revealed that meal timing could drive metabolic alterations and circadian regulation [3], and disrupted meal timing altered the peripheral circadian clocks in the hippocampus and consequently affected cognitive function [4]. However, population-level evidence on the association between the TPEI and cognitive function remains lacking. We thus aimed to examine this relationship in the China Health and Nutrition Survey from 1997 to 2006, a community-based cohort study with national representativeness [5].