The global obesity epidemic highlights the need to understand the molecular mechanisms that regulate energy metabolism. Among emerging research areas, fat browning-the transformation of white adipose tissue into beige fat-has gained significant attention. This review explores the molecular pathways involved in fat browning triggered by fasting, physical exercise, and cold exposure, emphasizing both shared and distinct regulatory mechanisms. These stimuli consistently induce physiological responses such as lipolysis, mitochondrial biogenesis, and improved insulin sensitivity. Notably, PGC-1α and SIRT3 are upregulated across all three conditions, underscoring their central roles in mitochondrial function and energy metabolism and identifying them as promising therapeutic targets. In contrast, UCP1 and PRDM16 exhibit condition-specific regulation, suggesting they may not be universally essential for fat browning. In addition, the review discusses species-specific differences in brown adipose tissue (BAT) activation, particularly between rodents and humans, highlighting the challenges of translating animal model findings to human therapies. Future research should aim to develop selective pharmacological activators of PGC-1α and SIRT3 to enhance therapeutic outcomes while minimizing adverse effects. This review also proposes that integrating fasting, exercise, and cold exposure could provide innovative strategies to promote metabolic health.

Pregnancy requires the coordination of metabolically active organs to support maternal nutrition and fetal growth. However, the metabolic cross-talk between adipose tissue and liver in females during pregnancy is still less clear. In this study, we evaluated the metabolic adaptations and phenotypes of liver in response to pregnancy-associated metabolic stress, particularly in the context of genetic ablation of Uncoupling protein 1 (Ucp1)-mediated catabolic circuit. Our results revealed that Ucp1 deficiency (UCP1 knockout, KO) mice during late pregnancy exhibited significantly deteriorated metabolic phenotypes, including hepatic steatosis and whole-body glucose and lipid homeostasis, as compared to Ucp1 deficiency or normal pregnancy mice. However, non-pregnant Ucp1 deficiency mice displayed nearly normal metabolic phenotypes and structure alterations similar to those of littermate controls. Moreover, transcriptomic analyses by RNA sequencing (RNA-seq) clearly revealed that Ucp1 deficiency led to a significant liver metabolic remodeling of differentially express genes (DEGs) before and especially during pregnancy. Consistently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the potential altered functions and signaling pathways, including metabolic dysfunctions in ribosome, oxidative phosphorylation, etc. Importantly, as derived from trend analyses of DEGs, our results further revealed the distinct expression pattern of each subcluster, which coincided with potential biological functions and relevant signaling pathways. The findings in the present study might provide valuable insights into the molecular mechanism of metabolic dysfunction-associated fatty liver disease (MAFLD) during pregnancy. Additionally, our data may provide a novel animal model of MAFLD, thus facilitating its potential therapies. NEW & NOTEWORTHY: Genetic ablation of Ucp1 during pregnancy increases hepatic steatosis and deteriorated whole-body glucose and lipid homeostasis. Moreover, changes in hepatic gene expression are closely associated with metabolic dysfunctions in ribosome and oxidative phosphorylation. This work highlights the therapeutic potential of targeting UCP1- mediated catabolic circuit between adipose and liver during pregnancy, and the utility of RNA-seq analysis to reveal valuable information for the distinct expression pattern of each subcluster that contribute to pregnancy-dependent MASLD progression.

STRA13, a basic helix-loop-helix protein superfamily member, is a CLOCK gene. Previous studies have reported the role of STRA13 in regulating blood pressure. However, the role of STRA13 in diabetic cardiomyopathy (DCM) has not been fully elucidated. In this study, STRA13 full knockout mice were subjected to a high-fat diet (HFD) to induce DCM. We found that STRA13 was upregulated in both heart tissue and cardiomyocytes undergoing metabolic disorders. STRA13 knockout ameliorated HFD-induced cardiac dysfunction, fibrosis, mitochondrial dysfunction and cell apoptosis. STRA13 deficiency also protected against HFD-induced glucose and lipid metabolism disorders. STRA13 overexpression in mice worsened HFD-induced cardiac dysfunction, fibrosis, and injury. STRA13 overexpression in cardiomyocytes worsened high glucose-induced cell injury, mitochondrial dysfunction and oxidative stress. STRA13 silencing in cardiomyocytes protected against the high glucose (HG)-induced alterations described above. Moreover, STRA13 was found to downregulate retinoid X receptor alpha (RXRα), resulting in reduced expression of uncoupling protein 1 (UCP-1). Co-IP confirmed that STRA13 interacted with RXRα. A luciferase assay confirmed that RXRα regulated the transcription of UCP-1. Silencing of STRA13 did not protect cardiomyocytes from HG-induced injury caused by RXRα or UCP-1 knockdown. Cardiac overexpression of UCP-1 also blunted the deteriorating effects of STRA13. However, STRA13 inhibited RXRα nuclear expression, which hampered the protective effects of RXRα overexpression in vivo. Taken together, our findings demonstrate that STRA13 exacerbates diabetic cardiomyopathy by impairing mitochondrial function through the disruption of RXRα-UCP-1 signaling. Therefore, targeting the STRA13-RXRα-UCP-1 axis may represent a promising therapeutic strategy for mitigating mitochondrial dysfunction and cardiac injury in the context of DCM.

The escalating global obesity crisis and its associated metabolic disorders have posed a significant threat to public health, increasing the risk of major health issues such as cardiovascular diseases and type 2 diabetes. Central to metabolic regulation are the liver and brown adipose tissue (BAT), which orchestrate glycolipid metabolism, thermogenesis, and energy homeostasis. Emerging evidence highlights the role of natural bioactive compounds-such as polyphenols (e.g., resveratrol, curcumin), alkaloids (e.g., berberine), and terpenoids (e.g., paeoniflorin, shikonin)-in modulating liver-BAT crosstalk. These compounds influence critical pathways, including AMPK activation, PPAR signaling, and UCP1-mediated thermogenesis, to enhance lipid oxidation, suppress gluconeogenesis, and improve insulin sensitivity. This review systematically examines how these natural agents regulate metabolic interplay between the liver and BAT, addressing their effects on energy expenditure, carbohydrate utilization, and lipid mobilization. Key mechanisms involve the suppression of hepatic lipogenesis, promotion of BAT-mediated thermogenesis, and secretion of hepatokines (e.g., FGF21) and batokines that coordinate interorgan communication. By synthesizing preclinical and clinical findings, we highlight the translational potential of dietary interventions and nutraceuticals targeting liver-BAT axis dysfunction. Future research should prioritize mechanistic studies, dose optimization, and personalized approaches to harness these compounds for combating obesity-related diseases. These insights underscore the promise of natural bioactive molecules as adjuvants to lifestyle modifications, offering innovative strategies for metabolic health restoration.

Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.

Background: Inflammation is one of the most important pathways in innate immunity and its relationship with redox biology is becoming increasingly clear in the last decades. However, the specific redox modes and pathways by which inflammation is produced are not yet well defined. Significance: In this review, we provide a general explanation of the reactive oxygen species (ROS) production and quenching modes occurring in mammalian mitochondria, as well as a summary of the most recent advances in mitochondrial redox biology and bioenergetics regarding sodium (Na+) homeostasis. In addition, we provide a collection of examples in which several inflammatory pathways have been associated with specific modes of either mitochondrial ROS production or quenching. Innovation: The role of Na+ in mitochondrial biology is being developed. Since its discovery as a second messenger, the research of its role in the immune system has emerged. Now, the role of Na+ in mitochondrial bioenergetics has recently been identified, which owns unprecedented applications. The potential implication of Na+ in inflammatory mechanisms grows as its role does not only cover ROS production and respiration but also the control through the management of mitochondrial membrane potential. Future directions: Na+ is becoming relevant for mitochondrial biology. Thus, processes regarding mitochondrial bioenergetics, redox state, or metabolism may probably need to include the study of Na+ in their road map. Some of these pathways are involved in inflammation and more are possibly to come. This review is expected to serve as a bridge between both fields. Antioxid. Redox Signal. 00, 000-000.

Trichinella spiralis (Ts) is known to cause cardiac fibrosis, which is a critical precursor to various heart diseases, and its progression is influenced by metabolic changes. However, the metabolic mechanisms remain unclear. Here, we observed that Ts-infected mice exhibited cardiac fibrosis along with elevated succinate levels in the heart using metabolomic analysis. Administration of succinate exacerbated fibrosis during Ts infection, while deficiency in succinate receptor 1 (Sucnr1) alleviated the condition, highlighting the role of the succinate-Sucnr1 axis in fibrosis development. Furthermore, metagenomics sequencing showed that Ts-infected mice had a higher abundance ratio of succinate-producing bacteria to succinate-consuming bacteria in the intestines. Notably, the succinate-producer Bacteroides vulgatus was enriched in Ts group. Oral supplementation with B. vulgatus aggravated Ts-induced cardiac fibrosis. In summary, our findings underscore the succinate-Sucnr1 axis as a critical pathway in helminth-induced cardiac fibrosis and highlight the potential of targeting this axis for therapeutic interventions. This study presents novel insights into the gut-heart axis, revealing innovative strategies for managing cardiovascular complications associated with helminth infections.

Solute carrier (SLC) family transporters are crucial transmembrane proteins responsible for transporting various molecules, including amino acids, electrolytes, fatty acids, and nucleotides. To date, more than fifty SLC transporter subfamilies have been identified, many of which are linked to the progression of hepatic steatosis and fibrosis. These conditions are often caused by factors such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which are major contributors to the global liver disease burden. The activity of SLC members regulates the transport of substrates across biological membranes, playing key roles in lipid synthesis and metabolism, mitochondrial function, and ferroptosis. These processes, in turn, influence the function of hepatocytes, hepatic stellate cells, and macrophages, thereby contributing to the development of hepatic steatosis and fibrosis. Additionally, some SLC transporters are involved in drug transport, acting as critical regulators of drug-induced hepatic steatosis. Beyond substrate transport, certain SLC members also exhibit additional functions. Given the pivotal role of the SLC family in hepatic steatosis and fibrosis, this review aimed to summarize the molecular mechanisms through which SLC transporters influence these conditions.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting reproductive-age women, characterized primarily by hyperandrogenism, ovulatory dysfunction, and metabolic abnormalities. In recent years, the gut microbiota has garnered widespread attention for its potential role as a key regulator of host metabolism in the pathogenesis of PCOS. Studies have shown that PCOS patients exhibit dysbiosis in their gut microbiota, characterized by reduced microbial diversity, an imbalance in the ratio of Firmicutes to Bacteroidetes, changes in the abundance of specific taxa, and abnormal levels of metabolic products. These alterations may exacerbate metabolic dysfunction in PCOS through multiple mechanisms, including influencing host energy metabolism, disrupting lipid and bile acid metabolism, and inducing chronic inflammation. Addressing gut dysbiosis through the modulation of patients' microbiomes-such the use of, prebiotics, fecal microbiota transplantation, and optimizing diet lifestyle-may offer strategies for improving metabolic abnormalities and alleviating clinical symptoms in PCOS. Additionally, the gut microbiome promises as a potential marker, aiding in the precise diagnosis and personalization of PCOS. Although our current understanding of how the gut microbiota influences PCOS is still limited, research is needed to explore the causal relationships and mechanisms involved, providing a more reliable theoretical basis for clinical. This review aims summarize the research progress on the relationship between gut microbiota and PCOS, and to suggest future directions to promote the development of prevention and treatment strategies for PCOS.

Gut microbiota-derived metabolites play a crucial role in modulating the inflammatory response in inflammatory bowel disease (IBD). In this study, we identify gut microbiota-derived succinate as a driver of inflammation in ulcerative colitis (UC) by activating succinate-responsive, colitogenic helper T (Th) cells that secrete interleukin (IL)-9. We demonstrate that colitis is associated with an increase in succinate-producing gut bacteria and decrease in succinate-metabolizing gut bacteria. Similarly, UC patients exhibit elevated levels of succinate-producing gut bacteria and luminal succinate. Intestinal colonization by succinate-producing gut bacteria or increased succinate availability, exacerbates colonic inflammation by activating colitogenic Th9 cells. In contrast, intestinal colonization by succinate-metabolizing gut bacteria, blocking succinate receptor signaling with an antagonist, or neutralizing IL-9 with an anti-IL-9 antibody alleviates inflammation by reducing colitogenic Th9 cells. Our findings underscore the role of gut microbiota-derived succinate in driving colitogenic Th9 cells and suggesting its potential as a therapeutic target for treating IBD.

Rotator cuff injury (RCI), a prevalent cause of shoulder pain and disability, often leads to significant functional impairments due to adipocyte infiltration into the damaged tissue. Caveolin-1 (Cav-1), a critical membrane protein, plays a significant role in adipocyte differentiation and lipid metabolism. This study utilized single-cell RNA sequencing (scRNA-seq) to investigate the heterogeneity of cell subpopulations in RCI tissues and assess the regulatory effects of Cav-1. The findings revealed that Cav-1 expression negatively correlates with adipogenic activity, and its modulation through exercise or targeted therapies can significantly reduce adipocyte infiltration and enhance tissue repair. Further, Cav-1 knockout and overexpression models demonstrated the protein's impact on key genes involved in adipocyte differentiation and lipid metabolism, such as Scd1, fatty acid synthase (FASN), and peroxisome proliferator-activated receptor gamma (Pparg). Animal studies corroborated these results, showing that exercise intervention increased Cav-1 expression, decreased adipocyte infiltration, and promoted structural repair. These insights suggest that targeting Cav-1 could offer a novel therapeutic strategy for improving RCI outcomes.

Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.

Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease and inflammatory disorders. In these conditions, perturbed TCA cycle and subsequent succinate accumulation have been reported. The role of succinate as a regulator of immunological responses and inflammation is increasingly being recognized. Nevertheless, how endothelial cell function and phenotype are altered by elevated intracellular succinate has not been addressed yet. Thus, we employed numerous in vitro functional assays using primary HUVECs and diethyl succinate (DES), a cell membrane-permeable succinate analogue. An MTS assay 1 h post stimulation with DES suggested reduced metabolic activity in HUVECs. Concurrently, elevated production of ROS, including mitochondrial superoxide, and a reduction in mitochondrial membrane potential were observed. These findings were corroborated by Seahorse mito-stress testing, which revealed that DES acutely lowered the OCR, maximal respiration and ATP production. Given the link between mitochondrial stress and apoptosis, we examined important survival signalling pathways. DES transiently reduced ERK1/2 phosphorylation, a response that was followed by a skewed pro-apoptotic shift in the BAX to BCL2L1 gene expression ratio, which coincided with upregulating VEGF gene expression. This indicated an induction of mixed pro-apoptotic and pro-survival signals in the cell. However, the BAX/BCL-XL protein ratio was unchanged, suggesting that the cells did not commit themselves to apoptosis. An MTS assay, caspase 3/7 activity assay and annexin V/propidium iodide staining confirmed this finding. By contrast, stimulation with DES induced acute endothelial barrier permeability, forming intercellular gaps, altering cell size and associated actin filaments without affecting cell count. Notably, during overnight DES exposure gradual recovery of the endothelial barrier and cell sprouting was observed, alongside mitochondrial membrane potential restoration, albeit with sustained ROS production. COX-2 inhibition and EP4 receptor blockade hindered barrier restoration, implicating a role of COX-2/PGE2/EP4 signalling in this process. Interestingly, ascorbic acid pre-treatment prevented DES-induced acute barrier disruption independently from ROS modulation. In conclusion, succinate acts as a significant regulator of endothelial mitochondrial function and barrier integrity, a response that is counterbalanced by upregulated VEGF and prostaglandin production by the endothelial cells.

Glucagon-like peptide 1 (GLP-1) is an incretin hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic agent. We demonstrated previously that supaglutide, a novel long-acting GLP-1 analog, exerted hypoglycemic, hypolipidemic, and weight loss effects in type 2 diabetic db/db mice, DIO mice, and diabetic monkeys. In the present study, we investigated supaglutide's therapeutic efficacy in rhesus monkeys with spontaneous metabolic dysfunction-associated steatohepatitis (MASH).

15 rhesus monkeys with biopsy-confirmed MASH were divided into three groups, receiving supaglutide 50 µg/kg, supaglutide 150 µg/kg, and placebo, respectively, by weekly subcutaneous injection for 3 months. Liver fat content quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), liver pathology, and metabolic parameters were assessed.

We found that once-weekly subcutaneous injections of supaglutide for 3 months significantly reduced hepatic fat accumulation, with a 40% percentage decrease in MRI-PDFF from baseline (P < 0.001 vs. Placebo). Treatment with supaglutide alleviated hepatic histological steatosis (nonalcoholic fatty liver disease activity score P < 0.001 vs. Placebo) without worsening of fibrosis, as assessed by ultrasound-guided liver biopsy. Supaglutide concomitantly ameliorated liver injury exemplified by a lowering tendency of hepatic alanine aminotransferase levels. Supaglutide also decreased body weight in a dose-dependent fashion accompanied by decreased food intake, improved lipid profile and glycemic control.

Supaglutide exerts beneficial effects on hepatic and metabolic outcomes in spontaneous MASH monkeys.

Acetaminophen (APAP) has emerged as a predominant contributor to acute liver failure (ALF) in United States. Alismatis rhizoma, a commonly used traditional herbal medicine, contains small molecular components with extensive hepatoprotective activity. However, the specific role of Alismatis rhizoma polysaccharide (ARP) in liver protection remains unclear. ARP50 and ARP70, derived through graded alcohol precipitation and refinement, predominantly consisted of varying proportions of glucose, galactose, and arabinose. In vitro experiments on free radical scavenging demonstrated notable antioxidant capabilities of ARP50 and ARP70. To investigate the hepatoprotective effects, an APAP-induced acute liver injury (ALI) model was established in mice. ARP50 and ARP70 exerted dose-dependent therapeutic effects on APAP-induced liver injury. Further analysis of liver metabolites revealed that ARPs facilitated the reconstruction of the liver antioxidant system by modulating the metabolism network centered on l-glutamine. In addition, the abundance of gut microbiota was altered under the influence of ARPs. ARP50 significantly reduced the levels of Pseudarthrobacter and markedly increased the levels of Faecalibacterium，At the same time, ARP50 could increase the levels of acetic acid in the liver and serum. Meanwhile, ARP70 significantly increased the abundance of Dubosiella, Muribaculum, Ileibacterium, and Prevotellaceae UCG 001, while reducing the abundance of Escherichia Shigella and Pseudarthrobacter. The results indicated that ARPs could exert a protective effect against APAP-induced acute liver injury by reshaping the liver metabolic profile and modulating the gut microbiota.

Succinic acid plays a crucial role as an essential intermediate in the mitochondrial tricarboxylic acid cycle in mitochondria. In recent years, growing evidence has supported the the important role of succinic acid in fat metabolism. Therefore, we aimed to investigate the effects of succinic acid on adipose tissue metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice and try to explore its potential mechanism. We found that the addition of succinic acid (40 mM) to drinking water inhibited the hypertrophy of inguinal white adipose tissue (iWAT) in HFD-induced mice. Furthermore, succinic acid supplementation enhanced insulin sensitivity and improved their glucose tolerance in obese mice. Interestingly, succinic acid supplementation improved lipid metabolism in HFD-fed mice, as shown by decreased serum levels of TG, TC, LDL-C, and increased HDL-C. In addition, succinic acid supplementation increased the expression of browning markers and mitochondria-related genes in iWAT. Further studies showed that the addition of succinic acid to drinking water promotes the browning of iWAT by activating the PI3K-AKT/MAPK signaling pathway. These results suggest that succinic acid has the potential to be used as an effective component for dietary intervention and may, therefore, play an important role in ameliorating and preventing obesity and associated metabolic diseases caused by HFD.

Previously characterized as inert fat depots, adipocytes are now recognized as dynamic mediators of inflammatory tone, metabolic health, and nutrient homeostasis. As endocrine organs, specialized depots of adipose tissue engage in crosstalk between the gut, liver, pancreas, and brain to coordinate appetite, thermogenesis, and ultimately body weight. These functions are tightly linked to the inflammatory status of adipose tissue, which is in turn influenced by the health of the gut microbiome. Here, we review recent findings linking specific gut microbes and their secreted factors, including recently identified elements such as bacterial extracellular vesicles, to the functional status of adipocytes. We conclude that further study may generate novel approaches for treating obesity and metabolic disease.

Uncoupling protein 1 (UCP1) is located at the inner membrane of mitochondria and mediates nonshivering thermogenesis. Its abnormal expression is associated with metabolic diseases, cancer, and acute kidney injury. Myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity accumulate in the tumor microenvironment (TME). Here, decreased UCP1 expression in MDSCs was observed in the peripheral blood of patients with colorectal cancer and transplanted mouse tumors. Aggravated tumor progression was observed in UCP1-knockout mice and conditional knockout mice (UCP1fl/fl-S100A8cre). The number of G-MDSCs and M-MDSCs increased in the transplanted tumor tissues from UCP1-deficient mice compared with those from wild-type mice. The tumor-promoting effect disappeared when the tumor-bearing mice were depleted of MDSCs by the α-DR5 administration. Adoptive transfer of tumor-derived MDSCs sharply promoted the tumor growth in vivo. Furthermore, these tumor-derived MDSCs enhanced the proliferation, reduced death, inhibited IFN-γ production of CD4+ and CD8+T cells, and induced Treg cells ex vivo. In conclusion, MDSCs in the TME alter the metabolic pattern by decreasing UCP1 expression to enhance immunosuppressive activity for tumor escape.

Weaning causes redox dyshomeostasis in piglets, which leads to hepatic oxidative damage. Microbe-derived antioxidants (MA) have great potential for anti-oxidation. This study aimed to investigate changes in hepatic redox system, mitochondrial function and apoptosis after weaning, and effects of MA on growth performance and liver health in weaning piglets.

This study consisted of 2 experiments. In the both experiments, piglets were weaned at 21 days of age. In Exp. 1, at 21 (W0), 22 (W1), 25 (W4), 28 (W7), and 35 (W14) days of age, 6 piglets were slaughtered at each timepoint. In Exp. 2, piglets were divided into 2 groups: one received MA gavage (MA) and the other received saline gavage (CON). At 25 days of age, 6 piglets from each group were sacrificed.

In Exp. 1, weaning caused growth inhibition and liver developmental retardation from W0 to W4. The mRNA sequencing between W0 and W4 revealed that pathways related to "regulation of apoptotic process" and "reactive oxygen species metabolic process" were enriched. Further study showed that weaning led to higher hepatic content of reactive oxygen species (ROS), H2O2 and O2-. Weaning enhanced mitochondrial fission and suppressed their fusion, activated mitophagy, thus triggering cell apoptosis. In Exp. 2, MA improved growth performance of piglets with higher average daily gain (ADG) and average daily feed intake (ADFI). The hepatic ROS, as well as products of oxidative damage malonaldehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the MA group decreased significantly than that of the CON group. The MA elevated mitochondrial membrane potential, increased activity of mitochondrial respiratory chain complexes (MRC) I and IV, enhanced mitochondrial fusion and reduced mitophagy, thus decreasing cell apoptosis.

The present study showed that MA improved the growth performance of weaning piglets and reversed weaning-induced oxidative damage, mitochondrial dysfunction, and apoptosis. Our results suggested that MA had promising prospects for maintaining liver health in weaning piglets and provided a reference for studies of liver diseases in humans.

Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated OR on a HFD and the role of the IRX3 gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.

Succinate is an important metabolite and a critical chemical with diverse applications in the food, pharmaceutical, and agriculture industries. Recent studies have demonstrated several protective or detrimental functions of succinate in diseases; however, the effect of succinate on lipid metabolism is still unclear. Here, we identified a role of succinate in nonobese nonalcoholic fatty liver disease (NAFLD). Specifically, the level of succinate is increased in the livers and serum of mice with hepatic steatosis. The administration of succinate promotes triglyceride (TG) deposition and hepatic steatosis by suppressing fatty acid oxidation (FAO) in nonobese NAFLD mouse models. RNA-Seq revealed that succinate suppressed fibroblast growth factor 21 (FGF21) expression. Then, the restoration of FGF21 was sufficient to alleviate hepatic steatosis and FAO inhibition induced by succinate treatment in vitro and in vivo. Furthermore, the inhibition of FGF21 expression and FAO mediated by succinate was dependent on the AMPK/PPARα axis. This study provides evidence linking succinate exposure to abnormal hepatic lipid metabolism and the progression of nonobese NAFLD.

Exercise has multiple beneficial effects on human metabolic health and is regarded as a "polypill" for various diseases. At present, the lack of physical activity usually causes an epidemic of chronic metabolic syndromes, including obesity, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Remarkably, NAFLD is emerging as a serious public health issue and is associated with the development of cirrhosis and hepatocellular carcinoma. Unfortunately, specific drug therapies for NAFLD and its more severe form, non-alcoholic steatohepatitis (NASH), are currently unavailable. Lifestyle modification is the foundation of treatment recommendations for NAFLD and NASH, especially for exercise. There are under-appreciated organs that crosstalk to the liver during exercise such as muscle-liver crosstalk. Previous studies have reported that certain exerkines, such as FGF21, GDF15, irisin, and adiponectin, are beneficial for liver metabolism and have the potential to be targeted for NAFLD treatment. In addition, some of exerkines can be modified for the new proteins and get enhanced functions, like IL-6/IC7Fc. Another importance of exercise is the physiological adaptation that combats metabolic diseases. Thus, this review aims to summarize the known exerkines and utilize a multi-omics mining tool to identify more exerkines for the future research. Overall, understanding the mechanisms by which exercise-induced exerkines exert their beneficial effects on metabolic health holds promise for the development of novel therapeutic strategies for NAFLD and related diseases.

In this study, we investigated the effects of glycoprotein (PG)-mediated regulation of Porphyra haitanensis on liver glucose metabolism in hyperglycemic mouse models, and sought to establish the underlying mechanism, as determined by the changes in liver gene expression and metabolic profiles. The results showed that 30-300 mg kg-1 PG upregulated the expression of the liver genes Ins1, Ins2, Insr, Gys2, Gpi1, Gck, and downregulated the expression of G6pc, G6pc2, and G6pc3, in a concentration-dependent manner. 300 mg kg-1 PG downregulated the concentrations of glucose-related metabolites in the liver, but upregulated lactic acid, 2-aminoacetic acid, and glucose-1-phosphate concentrations. It was assumed that PG regulated liver glucose metabolism by enriching insulin secretion, glycolysis/gluconeogenesis, and the AMPK signaling pathway, and promoting insulin secretion, glycogen synthesis, and glycolysis. Our findings supported the development of P. haitanensis and its glycoproteins as novel natural antidiabetic compounds that regulated blood glucose homeostasis.

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.

Redox signaling, a mode of signal transduction that involves the transfer of electrons from a nucleophilic to electrophilic molecule, has emerged as an essential regulator of inflammatory macrophages. Redox reactions are driven by reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites such as fumarate and itaconate, which can post-translationally modify specific cysteine residues in target proteins. In the past decade our understanding of how ROS, RNS, and redox-sensitive metabolites control macrophage function has expanded dramatically. In this review, we discuss the latest evidence of how ROS, RNS, and metabolites regulate macrophage function and how this is dysregulated with disease. We highlight the key tools to assess redox signaling and important questions that remain.

Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and succinate receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI).

The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 μg, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated.

The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1α (HIF-1α) expression, inhibitory κB-α (IκB-α) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1α expression and IκB-α phosphorylation.

The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury.

Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β cells. Mice with β cell-specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

In diabetic liver injury, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Rutin is a bioflavonoid produced by the hydrolysis of glucosidases to quercetin. Its biological activities include lowering blood glucose, regulating insulin secretion, regulating dyslipidemia, and exerting anti-inflammatory effects have been demonstrated. However, its effect on diabetic NAFLD is rarely reported.

Our study aimed to investigate the protective effects of Rutin on diabetic NAFLD and potential pharmacological mechanism.

We used db/db mice as the animal model to investigate diabetic NAFLD. Oleic acid-treated (OA) HeLa cells were examined whether Rutin had the ability to ameliorate lipid accumulation. HepG2 cells treated with 30 mM/l d-glucose and palmitic acid (PA) were used as diabetic NAFLD in vitro models. Total cholesterol (TC) and Triglycerides (TG) levels were determined. Oil red O staining and BODIPY 493/503 were used to detect lipid deposition within cells. The indicators of inflammation and oxidative stress were detected. The mechanism of Rutin in diabetic liver injury with NAFLD was analyzed using RNA-sequence and 16S rRNA, and the expression of fat-synthesizing proteins in the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway was investigated. Compound C inhibitors were used to further verify the relationship between AMPK and Rutin in diabetic NAFLD.

Rutin ameliorated lipid accumulation in OA-treated HeLa. In in vitro and in vivo models of diabetic NAFLD, Rutin alleviated lipid accumulation, inflammation, and oxidative stress. 16S analysis showed that Rutin could reduce gut microbiota dysregulation, such as the ratio of Firmicutes to Bacteroidetes. RNA-seq showed that the significantly differentially genes were mainly related to liver lipid metabolism. And the ameliorating effect of Rutin on diabetic NAFLD was through AMPK/SREBP1 pathway and the related lipid synthesis proteins was involved in this process.

Rutin ameliorated diabetic NAFLD by activating the AMPK pathway and Rutin might be a potential new drug ingredient for diabetic NAFLD.

Transplantation of brown adipose tissue (BAT) is a promising approach for treating obesity and metabolic disorders. However, obtaining sufficient amounts of functional BAT or brown adipocytes for transplantation remains a major challenge. In this study, we developed a hydrogel that combining adipose acellular matrix (AAM) and GelMA and HAMA that can be adjusted for stiffness by modulating the duration of light-crosslinking. We used human white adipose tissue-derived microvascular fragments to create beige adipose organoids (BAO) that were encapsulated in either a soft or stiff AAM hydrogel. We found that BAOs cultivated in AAM hydrogels with high stiffness demonstrated increased metabolic activity and upregulation of thermogenesis-related genes. When transplanted into obese and type 2 diabetes mice, the HFD + BAO group showed sustained improvements in metabolic rate, resulting in significant weight loss and decreased blood glucose levels. Furthermore, the mice showed a marked reduction in nonalcoholic liver steatosis, indicating improved liver function. In contrast, transplantation of 2D-cultured beige adipocytes failed to produce these beneficial effects. Our findings demonstrate the feasibility of fabricating beige adipose organoids in vitro and administering them by injection, which may represent a promising therapeutic approach for obesity and diabetes.

Aging-associated hepatic fatty acid (FA) oxidation dysfunction contributes to impaired adaptive thermogenesis. 5-Heptadecylresorcinol (AR-C17) is a prominent functional component of whole wheat and rye, and has been demonstrated to improve the thermogenic capacity of aged mice via the regulation of Sirt3. However, the effect of AR-C17 on aging-associated hepatic FA oxidation dysfunction remains unclear. Here, 18-month-old C57BL/6J mice were orally administered with AR-C17 at a dose of 150 mg/kg/day for 8 weeks. Systemic glucose and lipid metabolism, hepatic FA oxidation, and the lipolysis of white adipose tissues (WAT) were measured. The results showed that AR-C17 improved the hepatic FA oxidation, and especially acylcarnitine metabolism, of aged mice during cold stimulation, with the enhancement of systemic glucose and lipid metabolism. Meanwhile, AR-C17 improved the WAT lipolysis of aged mice, promoting hepatic acylcarnitine production. Furthermore, the adipose-specific Sirt3 knockout mice were used to investigate and verify the regulation mechanism of AR-C17 on aging-associated hepatic FA oxidation dysfunction. The results showed that AR-C17 failed to improve the WAT lipolysis and hepatic FA oxidation of aged mice in the absence of adipose Sirt3, indicating that AR-C17 might indirectly influence hepatic FA oxidation via regulating WAT Sirt3. Our findings suggest that AR-C17 might improve aging-associated hepatic FA oxidation dysfunction via regulating adipose Sirt3.

SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a "sequential" or "bypassing" mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.

That uncoupling protein 1 (UCP1) is the sole mediator of adipocyte thermogenesis is a conventional viewpoint that has primarily been inferred from the attenuation of the thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue. To mitigate these potentially confounding ancillary changes, we constructed mice with inducible adipocyte-selective Ucp1 disruption. We find that, although germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with the inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase b (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold intolerance. Following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature brown adipocytes that coordinately restore UCP1 and CKB expression. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy-through UCP1 and CKB-to promote cold-induced energy dissipation.