Kidney fibrosis is the final common pathway of virtually all chronic kidney diseases (CKDs) and is therefore considered to be a promising therapeutic target for these conditions. However, despite great progress in recent years, no targeted antifibrotic therapies for the kidney have been approved, likely because the complex mechanisms that initiate and drive fibrosis are not yet completely understood

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, influencing numerous regulatory axes and extrahepatic vital organs. The molecular mechanisms that lead to the progression of NAFLD remain unclear and knowledge on the pathways causing hepatocellular damage followed by lipid accumulation is limited. Recently, a number of studies have shown that mRNA N6-methyladenosine

Metabolic abnormalities are a hallmark of cancer cells and are essential to tumor progression. Oncometabolites have pleiotropic effects on cancer biology and affect a plethora of processes, from oncogenesis and metabolism to therapeutic resistance. Targeting oncometabolites, therefore, could offer promising therapeutic avenues against tumor growth and resistance to treatments. Recent advances in characterizing

Exercise has systemic health benefits through effects on multiple tissues, with intertissue communication. Recent studies indicate that exercise may improve breastmilk composition and thereby reduce the intergenerational transmission of obesity. Even if breastmilk is considered optimal infant nutrition, there is evidence for variations in its composition between mothers who are normal weight, those

The number of patients with type 2 diabetes mellitus (T2DM) is rising at an alarming rate. Regular physical activity and exercise are cornerstones in the therapy of T2DM. While a one-size-fits-all approach fails to account for many between-subject differences, the use of personalized exercise medicine has the potential of optimizing health outcomes. Here, a road map for personalized exercise therapy

Aggression is a well-studied social behavior that is universally exhibited by animals across a wide range of contexts. Prevailing knowledge suggests gonadal steroids primarily mediate aggression; however, this is based mainly on studies of male–male aggression in laboratory rodents. When males and females of other species, including humans, are examined, a positive relationship between gonadal steroids

A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism

Thyroid hormone replacement is paramount in overt hypothyroidism; recently, however, thyroid hormone substitution is increasingly prescribed to patients with normal thyroid hormone levels. This forum article discusses the complex causes and the possible negative effects of overusing thyroid hormone replacement drugs.

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The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their

Cytoplasmic mitochondrial DNA (mtDNA) can trigger the interferon response to promote disease progression, but mtDNA sensing mechanisms remain elusive. Lei et al. have shown that Z-DNA binding protein1 (ZBP1) cooperates with cyclic GMP-AMP synthase (cGAS) to sense Z-form mtDNA and transmit mtDNA stress signals to promote diseases such as cardiotoxicity, providing an important piece of the mtDNA stress

White adipose tissue (WAT) plays an important role in the integration of whole-body metabolism by storing fat and mobilizing triacylglycerol when needed. The released free fatty acids can then be oxidized by other tissues to provide ATP. AMP-activated protein kinase (AMPK) is a key regulator of metabolic pathways, and can be targeted by a new generation of direct, small-molecule activators. AMPK activation

Obesity is an independent risk factor for severe COVID-19, yet there remains a lack of consensus on the mechanisms underlying this relationship. A hypothesis that has garnered considerable attention suggests that SARS-CoV-2 disrupts adipose tissue function, either through direct infection or by indirect mechanisms. Indeed, recent reports have begun to shed some light on the important role that the

Precise diagnoses are essential for defining appropriate treatments. This is particularly true for polycystic ovary syndrome (PCOS), whose phenotypical manifestations have recently suggested a possible diversity of etiological factors. PCOS is defined on the basis of gynecological and endocrinological alterations, but the patients often display considerable metabolic impairments, such as insulin resistance

The prevailing COVID-19 pandemic and climate change-mediated wildfires can combine to impact maternal–child health, yet this connection remains understudied. To shape policies and design interventions to mitigate the combined effects of future global catastrophes, it is vital to holistically evaluate the impact of syndemics on maternal–child health.

The effects of bile acids (BAs) on liver, enteroendocrine function, small intestine, and brown adipose tissue have been described extensively. Outside the liver, BAs in the peripheral circulation system represent a specific but underappreciated physiological compartment. We discuss how systemic BAs can be regarded as specific steroidal hormones that act on white adipocytes, and suggest the name 'bilokines'

Ferroptosis holds promise for cancer therapy. A recent study by Yang et al. in Cell Metabolism reveals that VKORC1L1-mediated reduction of vitamin K inhibits ferroptosis and establishes a direct p53-VKORC1L1 link in its regulation. As warfarin can inhibit VKORC1L1, the study further underscores this drug’s potential as a cancer therapy.

Understanding how obesity rewires the brain, triggers neuroinflammation and neurodegeneration relies on research using animal models. There is, however, a disconnect between the timeline of human obesity and typical preclinical protocols. We emphasize here the need to adopt models of chronic obesity to study the pathophysiology of human obesity.

Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the ‘exercise IL-6 enigma’. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory

Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism

Increasing evidence suggests that the brain plays a key role in glucose homeostasis, making it a potential target for the treatment of type 2 diabetes (T2D). Sun et al. recently reported that intracerebroventricular (ICV) administration of a single dose of fibroblast growth factor 4 (FGF4) can induce sustained T2D remission in mouse models in the absence of any risk of hypoglycemia.

Cellular crosstalk plays a vital role in maintaining pancreas homeostasis. Recently, in Cell Metabolism, Basile et al. demonstrated that aberrant upregulation of acinar-cell-specific pancreatic elastase CELA3B within endocrine islets reduces β-cell viability in type 2 diabetes (T2D). This identifies detrimental acinar–β-cell crosstalk as a novel pathogenic mechanism in diabetes.

Skeletal muscle and adipose tissues (ATs) are secretory organs that release secretory factors including cytokines and exosomes. These factors mediate muscle–adipose crosstalk to regulate systemic metabolism via paracrine and endocrine pathways. Myokines and adipokines are cytokines secreted by skeletal muscle and ATs, respectively. Exosomes loaded with nucleic acids, proteins, lipid droplets, and organelles

The past two decades have been characterized by a substantial global increase in cardiometabolic diseases, but the prevalence and incidence of these diseases and related traits differ across populations. African ancestry populations are among the most affected yet least included in research. Populations of African descent manifest significant genetic and environmental diversity and this under-representation

Many aspects of metabolism are sex-biased, from gene expression in metabolic tissues to the prevalence and presentation of cardiometabolic diseases. The influence of hormones produced by male and female gonads has been widely documented, but recent studies have begun to elucidate the impact of genetic sex (XX or XY chromosomes) on cellular and organismal metabolism. XX and XY cells have differential

The peripheral nervous system (PNS) relays information between organs and tissues and the brain and spine to maintain homeostasis, regulate tissue functions, and respond to interoceptive and exteroceptive signals. Glial cells perform support roles to maintain nerve function, plasticity, and survival. The glia of the central nervous system (CNS) are well characterized, but PNS glia (PNSG) populations

Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients with concurrent IDDM and SPS often manifest insulin resistance, and SPS-associated IDDM probably has heterogeneous causes. Some patients manifest IDDM associated only with high titers of anti-GAD65 caused by SPS. By contrast, other patients

Bariatric surgery is a powerful therapy for type 2 diabetes in patients with obesity. The mechanism of insulin sensitization by surgery has been extensively investigated in weight loss-dependent and weight loss-independent conditions. However, a consensus remains to be established regarding the underlying mechanisms. Energy deficit induced by calorie restriction (CR), that occurs both before and after

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Epigenetic drugs induce ATP depletion, promoting a glycolysis-to-oxidative phosphorylation (OXPHOS) shift which sometimes favors tumor growth by promoting necroptosis over apoptosis. To restore effective apoptosis in tumors, we propose that the administration of citrate could inhibit ATP production, activate caspase-8 (a key necroptosis inhibitor), and downregulate key anti-apoptotic proteins (Bcl-xL

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Metabolomics holds great promise for uncovering insights around biological processes impacting disease in human epidemiological studies. Metabolites can be measured across biological samples, including plasma, serum, saliva, urine, stool, and whole organs and tissues, offering a means to characterize metabolic processes relevant to disease etiology and traits of interest. Metabolomic epidemiology studies

Changes in maternal nutrient availability due to diet or disease significantly increase the risk of neural tube defects (NTDs). Because the incidence of metabolic disease continues to rise, it is urgent that we better understand how altered maternal nutrient levels can influence embryonic neural tube development. Furthermore, primary neurulation occurs before placental function during a period of histiotrophic

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Mitochondria operate as hubs of cellular metabolism that execute important regulatory functions. Damaged/dysfunctional mitochondria are recognized as major pathogenic contributors to many common human diseases. Assessment of mitochondrial function relies upon invasive tissue biopsies; peripheral blood cells, specifically platelets, have emerged as an ideal candidate for mitochondrial function assessment

The body partially maintains metabolic homeostasis through interorgan communication between metabolic organs under physiological conditions. This crosstalk is known to be mediated by hormones or metabolites, and has recently been expanding to include extracellular vesicles (EVs). EVs participate in interorgan communication under physiological and pathological conditions by encapsulating various bioactive

Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the

Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated

In biology, there are no good or evil molecules. There is limited or no evidence to support the consumption of antioxidants or (super)foods rich in antioxidants, for the intended purpose of an antioxidant effect, because there is risk of interfering with free radicals and deoptimizing the regulation of fundamental processes.

p62 is an important multifunctional adaptor protein participating in autophagy and many other activities. Many studies have revealed that p62 is highly expressed in multiple cancers and decreasing its level can effectively lower the proliferation ability of cancer cells. Moreover, much research has highlighted the significant role of the regulation of cancer cell metabolism in helping to treat tumors

Cancer remains the second leading cause of mortality, with nearly 10 million deaths worldwide in 2020. In many cases, radiotherapy is used for its anticancer effects. However, radiation causes healthy tissue toxicity as a side effect. In intra-abdominal and pelvic malignancies, the healthy bowel is inevitably included in the radiation field, causing radiation-induced enteritis and dramatically affecting

Wolffian ducts (WDs) are the paired embryonic structures that give rise to internal male reproductive tract organs. WDs are initially formed in both sexes but have sex-specific fates during sexual differentiation. Understanding WD differentiation requires insights into the process of fate decisions of epithelial and mesenchymal cells, which are tightly coordinated by endocrine, paracrine, and autocrine

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Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently

Integrity of the microbiome is an essential element for human gut health. 3-Hydroxybutyrate (3HB) secreted into the gut lumen has gained attention as a regulator of gut physiology, including stem cell expansion. In this opinion, I propose new prebiotics leading to gut health by use of a ketone (3HB) donor. When exogenous 3HB is supplied through ketone donation, it has the potential to markedly improve

Doxorubicin (Dox) is a highly potent chemotherapy drug. Despite its efficacy, Dox’s clinical application is limited due to its association with significant complications, namely cardiotoxicity and the risk of heart failure. Recent intriguing findings by Ozcan et al. indicate that alternate-day fasting (ADF) significantly exacerbates the cardiotoxicity of Dox.

Despite several decades of study, whether iron is involved in the development of atherosclerosis remains a controversial and unresolved issue. Here, we focus on the up-to-date advances in studies on role of iron in atherosclerosis and discuss possible reasons why patients with hereditary hemochromatosis (HH) do not show any increased incidence of atherosclerosis. In addition, we analyze conflicting

Effective pharmacological treatments to achieve significant and sustained weight loss in obese individuals remain limited. Here, we apply a ‘reverse engineering’ approach to cancer cachexia, an extreme form of dysregulated energy balance resulting in net catabolism. We discuss three phenotypic features of the disease, summarize the underlying molecular checkpoints, and explore their translation to

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Ovarian estradiol and leptin are important modulators of whole-body energy homeostasis that act in the hypothalamus. In a recent paper in Cell Metabolism, González-García et al. demonstrate that CITED1 acts as a key hypothalamic cofactor that mediates the antiobesity effects of estradiol through potentiation of the anorectic actions of leptin.

Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation

Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with

Distance running requires a high absolute oxygen consumption, while for a breath-hold diver the opposite is preferable. We compared physiological exercise parameters and mitochondrial function in a competitive triathlete with those seen in an accomplished breath-hold diver and notice some remarkable differences, possibly explaining why both have become successful.

CD4+ T cells are effector T cells (Teffs) produced by the differentiation of initial T cells in peripheral lymphoid tissue after being attacked by antigens, and have an indispensable role in the development and activation of B cells and CD8+ T cells to regulate and assist immunity. In this review, we provide a new perspective on the relationship between CD4+ T cell glycolysis and its function. We summarize

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