Skeletal muscle plays a vital role in the regulation of systemic metabolism, partly through its secretion of endocrine factors which are collectively known as myokines. Altered myokine levels are associated with metabolic diseases, such as type 2 diabetes (T2D). The significance of interorgan crosstalk, particularly through myokines, has emerged as a fundamental aspect of nutrient and energy homeostasis. However, a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge. In this review, we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades, namely interleukin 6 (IL-6), irisin, myostatin (MSTN), growth differentiation factor 11 (GDF11), fibroblast growth factor 21 (FGF21), apelin, brain-derived neurotrophic factor (BDNF), meteorin-like (Metrnl), secreted protein acidic and rich in cysteine (SPARC), β-aminoisobutyric acid (BAIBA), Musclin, and Dickkopf 3 (Dkk3). Related to these, we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease. Despite significant advancements in myokine research, many myokines remain challenging to measure accurately and investigate thoroughly. Hence, new research techniques and detection methods should be developed and rigorously tested. Therefore, developing a comprehensive perspective on myokine biology is crucial, as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.

Pyruvate is an essential fuel for maintaining the tricarboxylic acid (TCA) cycle in the mitochondria. However, the precise molecular mechanism of pyruvate uptake by mitochondrial pyruvate carrier (MPC) is largely unknown. Here, we report that the DNA/RNA-binding protein Y-box binding protein 1 (YBX1) is localized to the mitochondrial inter-membrane space by its C-terminal domain (CTD) in cancer cells. In mitochondria, YBX1 inhibits pyruvate uptake by associating with MPC1/2, thereby suppressing pyruvate-dependent TCA cycle flux. This association, in turn, promotes MPC-mediated glutaminolysis and histone lactylation. Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential, while does not affect cell proliferation in both cultured cells and tumor xenografts. Therefore, the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity, suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.

The “gut-liver axis” is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways, such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut’s influence on liver steatosis remains unknown. Here, we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis. Our study demonstrates that intExos regulate hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.

Atherosclerosis is the major contributor to cardiovascular mortality worldwide. Alternate day fasting (ADF) has gained growing attention due to its metabolic benefits. However, the effects of ADF on atherosclerotic plaque formation remain inconsistent and controversial in atherosclerotic animal models. The present study was designed to investigate the effects of ADF on atherosclerosis in apolipoprotein E-deficient (Apoe^−/−) mice. Eleven-week-old male Apoe^−/− mice fed with Western diet (WD) were randomly grouped into ad libitum (AL) group and ADF group, and ADF aggravated both the early and advanced atherosclerotic lesion formation, which might be due to the disturbed cholesterol profiles caused by ADF intervention. ADF significantly altered cholesterol metabolism pathways and down-regulated integrated stress response (ISR) in the liver. The hepatic expression of activating transcription factor 3 (ATF3) was suppressed in mice treated with ADF and hepatocyte-specific overexpression of Aft3 attenuated the effects of ADF on atherosclerotic plaque formation in Apoe^−/− mice. Moreover, the expression of ATF3 could be regulated by Krüppel-like factor 6 (KLF6) and both the expressions of ATF3 and KLF6 were regulated by hepatic cellular ISR pathway. In conclusion, ADF aggravates atherosclerosis progression in Apoe^−/− mice fed on WD. ADF inhibits the hepatic ISR signaling pathway and decreases the expression of KLF6, subsequently inhibiting ATF3 expression. The suppressed ATF3 expression in the liver mediates the deteriorated effects of ADF on atherosclerosis in Apoe^−/− mice. The findings suggest the potentially harmful effects when ADF intervention is applied to the population at high risk of atherosclerosis.

The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1^IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1^IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1^IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C–C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1^IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1^IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.

Interorgan lipid transport is crucial for organism development and the maintenance of physiological function. Here, we demonstrate that Drosophila long-chain acyl-CoA synthetase (dAcsl), which catalyzes the conversion of fatty acids into acyl-coenzyme As (acyl-CoAs), plays a critical role in regulating systemic lipid homeostasis. dAcsl deficiency in the fat body led to the ectopic accumulation of neutral lipids in the gut, along with significantly reduced lipoprotein contents in both the fat body and hemolymph. The aberrant phenotypes were rescued by fat body-specific overexpression of apolipophorin. A multi-omics investigation comprising lipidomics, metabolomics, and proteomics in conjunction with genetic screening revealed that glycosylation processes were suppressed in dAcsl knockdown flies. Overexpression of CG9035, human ortholog of which is implicated in the congenital disorder of glycosylation, ameliorated gut lipid accumulation in Drosophila. Aberrant lipoprotein glycosylation led to accelerated proteasome-related degradation and induced ER stress in dAcsl knockdown flies, impairing lipoprotein release into the circulation which compromised interorgan lipid transport between the fat body and the gut. Inhibition of ubiquitin-proteasome-dependent degradation alleviated the phenotype of gut ectopic fat accumulation in dAcsl knockdown flies. Finally, we verified that ACSL4, the human homolog of dAcsl, also regulated lipoprotein levels in HepG2 cells, indicating that the role of dAcsl in modulating lipoprotein secretion and systemic lipid homeostasis is possibly conserved in humans.

In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.

In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.

Isocitrate dehydrogenase (IDH) mutations frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) was a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH resulted in the accumulation of α-KG and promoted astrocyte maturation. However, IDH1 mutation significantly reduced α-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-KG and increasing glutaminolysis. Finally, we found that L-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.

Postnatal growth retardation (PGR) frequently occurs during early postnatal development of piglets and induces high mortality. To date, the mechanism of PGR remains poorly understood. Adipose tissue-derived microbes have been documented to be associated with several disorders of metabolism and body growth. However, the connection between microbial disturbance of adipose tissue and pig PGR remains unclear. Here, we investigated piglets with PGR and found that the adipose tissue of PGR piglets was characterized by metabolism impairment, adipose abnormality, and specific enrichment of culturable bacteria from Proteobacteria. Gavage of Sphingomonas paucimobilis, a species of Sphingomonas genus from the alphaproteobacteria, induced PGR in piglets. Moreover, this bacterium could also lead to metabolic disorders and susceptibility to acute stress, resulting in weight loss in mice. Mechanistically, multi-omics analysis indicated the changes in lipid metabolism as a response of adipose tissue to abnormal microbial composition. Further experimental tests proved that one of the altered lipids phosphatidylethanolamines could rescue the metabolism disorder and growth retardation, thereby suppressing the amount of Sphingomonas in the adipose tissue. Together, these results highlight that the microbe–host crosstalk may regulate the metabolic function of adipose tissue in response to PGR.

The endocrine system is a fundamental type of long-range cell–cell communication that is important for maintaining metabolism, physiology, and other aspects of organismal homeostasis. Endocrine signaling is mediated by diverse blood-borne ligands, also called hormones, including metabolites, lipids, steroids, peptides, and proteins. The size and structure of these hormones are fine-tuned to make them bioactive, responsive, and adaptable to meet the demands of changing environments. Why has nature selected such diverse ligand types to mediate communication in the endocrine system? What is the chemical, signaling, or physiologic logic of these ligands? What fundamental principles from our knowledge of endocrine communication can be applied as we continue as a field to uncover additional new circulating molecules that are claimed to mediate long-range cell and tissue crosstalk? This review provides a framework based on the biochemical logic behind this crosstalk with respect to their chemistry, temporal regulation in physiology, specificity, signaling actions, and evolutionary development.

Emerging evidence discloses the involvement of calcium channel protein in the pathological process of liver diseases. Transient receptor potential cation channel subfamily C member 3 (TRPC3), a ubiquitously expressed non-selective cation channel protein, controls proliferation, inflammation, and immune response via operating calcium influx in various organs. However, our understanding on the biofunction of hepatic TRPC3 is still limited. The present study aims to clarify the role and potential mechanism(s) of TRPC3 in alcohol-associated liver disease (ALD). We recently found that TRPC3 expression plays an important role in the disease process of ALD. Alcohol exposure led to a significant reduction of hepatic TRPC3 in patients with alcohol-related hepatitis (AH) and ALD models. Antioxidants (N-acetylcysteine and mitoquinone) intervention improved alcohol-induced suppression of TRPC3 via a miR-339-5p-involved mechanism. TRPC3 loss robustly aggravated the alcohol-induced hepatic steatosis and liver injury in mouse liver; this was associated with the suppression of Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) and dysregulation of genes related to lipid metabolism. TRPC3 loss also enhanced hepatic inflammation and early fibrosis-like change in mice. Replenishing hepatic TRPC3 effectively reversed chronic alcohol-induced detrimental alterations in ALD mice. Briefly, chronic alcohol exposure-induced TRPC3 reduction contributes to the pathological development of ALD via suppression of the CAMKK2/AMPK pathway. Oxidative stress-stimulated miR-339-5p upregulation contributes to alcohol-reduced TRPC3. TRPC3 is the requisite and a potential target to defend alcohol consumption-caused ALD.

Dyslipidemia affects approximately half of all people with gout, and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia (HU), but the underlying mechanisms remain elusive. We hypothesize that dyslipidemia promotes hepatic urate biosynthesis in HU and gout and fatty acid (FA) oxidation (FAO) drives this process. Here we developed a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU, gout, and normaluricemic controls. We found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout groups compared to normouricemic controls, whereas hypoxathine showed opposite trend. Furthermore, the levels of multiple serum FAs were positively correlated with urate, xanthine, and inosine but negatively with hypoxanthine, which was also observed in a murine model of high-fat diet-induced HU. Using a stable isotope-labeled metabolic flux assay, we discovered that exogenous hypoxanthine plays a key role in urate synthesis. Moreover, FAO-induced hypoxia-inducible factor 1 alpha (HIF-1α) activation upregulated 5ʹ-nucleotidase II (NT5C2) and xanthine dehydrogenase (XDH) levels to facilitate hypoxanthine uptake from the blood to the liver and activation of urate biosynthesis. Our findings were further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant donors. Together, this study uncovers a mechanism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways, directly linking lipid metabolism to HU.