BACKGROUND: The American Heart Association (AHA) introduced the concept of cardiovascular-kidney-metabolic (CKM) health and stage, reflecting the interaction among metabolism, chronic kidney disease (CKD), and the cardiovascular system. However, the association between CKM stage and the long-term risk of cardiovascular disease (CVD) has not been validated. This study aimed to evaluate the long-term CVD risk associated with CKM health metrics and CKM stage using data from a population-based cohort study. METHODS: In total, 5293 CVD-free participants were followed up to around 13 years in the Chinese Multi-provincial Cohort Study (CMCS). Considering the pathophysiologic progression of CKM health metrics abnormalities (comprising obesity, central adiposity, prediabetes, diabetes, hypertriglyceridemia, CKD, and metabolic syndrome), participants were divided into CKM stages 0, 1, and 2. The time-dependent Cox regression models were used to estimate the cardiovascular risk associated with CKM health metrics and stage. Additionally, broader CVD outcomes were examined, with a specific assessment of the impact of stage 3 in 2581 participants from the CMCS-Beijing subcohort. RESULTS: Among participants, 91.2% (4825/5293) had at least one abnormal CKM health metric, 8.8% (468/5293), 13.3% (704/5293), and 77.9% (4121/5293) were in CKM stages 0, 1, and 2, respectively; and 710 incident CVD cases occurred during a median follow-up time of 13.3 years (interquartile range: 12.1 to 13.6 years). Participants with each poor CKM health metric exhibited significantly higher CVD risk. Compared with stage 0, the hazard ratio (HR) (95% confidence interval [CI]) for CVD incidence was 1.31 (0.84-2.04) in stage 1 and 2.27 (1.57-3.28) in stage 2. Significant interactive impacts existed between CKM stage and age or sex, with higher CVD risk related to increased CKM stages in participants aged <60 years or females. CONCLUSION These findings highlight the contribution of CKM health metrics and CKM stage to the long-term risk of CVD, suggesting the importance of multi-component recognition and management of poor CKM health in CVD prevention.
Humans ; Female ; Male ; Cardiovascular Diseases/etiology* ; Middle Aged ; Adult ; Cohort Studies ; Renal Insufficiency, Chronic/metabolism* ; Aged ; Risk Factors ; Metabolic Syndrome/metabolism* ; China ; East Asian People

BACKGROUND: Studies on the impact of blood glucose indicators on metabolism remain relatively scarce. The aim of this study was to investigate the associations between blood glucose indicators and metabolic disorders in China. METHODS: Data were from the Thyroid disorders, Iodine status and Diabetes Epidemiological survey (TIDE survey), which randomly selected 31 cities from 31 provinces in the Chinese mainland. A total of 68,383 participants without preexisting diabetes and have complete data on blood glucose, lipids, and blood pressure were included in the analysis. The diabetic population was divided into seven groups based on different types of elevated blood glucose levels, including fasting plasma glucose (FPG), postprandial glucose (PPG), and hemoglobin A1c (HbA1c): FPG ≥7 mmol/L; PPG ≥11.1 mmol/L; HbA1c ≥6.5%; FPG ≥7 mmol/L and PPG ≥11.1 mmol/L; FPG ≥7 mmol/L and HbA1c ≥6.5%; PPG ≥11.1 mmol/L and HbA1c ≥6.5%; FPG ≥7 mmol/L, PPG ≥11.1 mmol/L, and HbA1c ≥6.5%. The effects of each blood glucose indicator on metabolism were investigated separately. Weighted calculation was applied during the analysis, with the weighting coefficient based on the number of people corresponding to the population characteristics of each sample in the 2010 Chinese Census. A logistic regression model with restricted cubic splines (RCS) was employed to characterize the nonlinear associations of age and body mass index (BMI) with the risk of diabetes subtypes defined by distinct blood glucose indicators elevations, as well as the relationships between different blood glucose indicators (FPG, PPG, HbA1c) and the risk of metabolic disorders such as hypertension, hypertriglyceridemia, hypercholesterolemia, high low-density lipoprotein cholesterol (high LDL-C) and low high-density lipoprotein cholesterol (low HDL-C). RESULTS: Among individuals with diabetes, elevated PPG alone was the most common abnormality, affecting 26.96% (1382/5127) of the population. Among the seven groups with only one elevated blood glucose indicator, individuals with elevated PPG alone exhibited the highest mean levels of triglycerides (TG) at 2.11 mmol/L (95% confidence interval [CI]: 1.97-2.25 mmol/L, P = 0.004), total cholesterol (TC) at 5.26 mmol/L (95% CI: 5.18-5.33 mmol/L, P <0.001), and low-density lipoprotein cholesterol (LDL-C) at 3.12 mmol/L, (95% CI: 3.06-3.19 mmol/L, P = 0.001). Individuals with elevated PPG alone showed a high prevalence of hypertension (806/1382, 58.32%), hypertriglyceridemia (676/1382, 48.91%), hypercholesterolemia (694/1382, 50.22%), High LDL-C (525/1382, 37.94%), and Low HDL-C (364/1382, 26.34%). The association of age and BMI with the risk of diabetes revealed that the older the patient, the steeper the RCS curve for the odds ratio (OR) of diabetes with elevated PPG alone (age = 60, OR = 2.79, 95% CI [2.49-3.12], P <0.01). Similarly, as BMI increased, the RCS curve for the OR of diabetes with elevated HbA1c alone also steepened (BMI = 35, OR = 3.75, 95% CI [3.23-4.35], P <0.001). Additionally, the RCS yielded a positive association between blood glucose indicators and metabolic diseases risk. In individuals with diabetes, RCS for both the ORs of metabolic diseases (hypertension, hypertriglyceridemia, hypercholesterolemia, high LDL-C, low HDL-C) and the levels of metabolic indicators (TG, TC, LDL-C, HDL-C) revealed some inflection points within the ranges of FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%. CONCLUSIONS PPG is more closely related to metabolic disorders than FPG and HbA1c in people with diabetes. For patients with diabetes and metabolic disorders, it may be necessary to monitor blood glucose fluctuations within specific ranges (FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%).
Humans ; Female ; Cross-Sectional Studies ; Male ; Blood Glucose/metabolism* ; Middle Aged ; Glycated Hemoglobin/metabolism* ; Adult ; Metabolic Diseases/epidemiology* ; Aged ; China ; Diabetes Mellitus/blood* ; East Asian People

Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) is a core member of the PGC-1 family and serves as a transcriptional coactivator, playing a crucial regulatory role in various diseases. Mitochondria, the main site of cellular energy metabolism, are essential for maintaining cell growth and function. Their function is regulated by various transcription factors and coactivators. PGC-1α regulates the biogenesis, dynamics, energy metabolism, calcium homeostasis, and autophagy processes of mitochondria by interacting with multiple nuclear transcription factors, thereby exerting significant effects on mitochondrial function. This review explores the biological functions of PGC-1α and its regulatory effects and related mechanisms on mitochondria, providing important information for our in-depth understanding of the role of PGC-1α in cellular metabolism. The potential role of PGC-1α in metabolic diseases, cardiovascular diseases, and neurodegenerative diseases was also discussed, providing a theoretical basis for the development of new treatment strategies.
Humans ; Mitochondria/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/physiology* ; Animals ; Energy Metabolism/physiology* ; Neurodegenerative Diseases/physiopathology* ; Autophagy/physiology* ; Transcription Factors/physiology* ; Metabolic Diseases/physiopathology* ; Cardiovascular Diseases/physiopathology*

Obesity is a worldwide health problem. An imbalance in energy metabolism is an important cause of obesity and related metabolic diseases. Our previous studies showed that inhibition of miR-429 increased the protein level of uncoupling protein 1 (UCP1) in beige adipocytes; however, whether local inhibition of miR-429 in subcutaneous adipose tissue affects diet-induced obesity and related metabolic disorders remains unclear. The aim of this study was to investigate the effect of local overexpression of miR-429 sponge in subcutaneous adipose tissue on obesity and related metabolic disorders. The control adeno-associated virus (AAV) or AAV expressing the miR-429 sponge was injected into mouse inguinal white adipose tissue. Seven days later, the mice were fed a high-fat diet for 10 weeks to induce obesity. The effects of the miR-429 sponge on body weight, adipose tissue weight, plasma glucose and lipid levels, and hepatic lipid content were explored. The results showed that the overexpression of miR-429 sponge in subcutaneous white adipose tissue reduced body weight and fat mass, decreased fasting blood glucose and plasma cholesterol levels, improved glucose tolerance, and alleviated hepatic lipid deposition in mice. Mechanistic investigation showed that the inhibition of miR-429 significantly upregulated the expression of UCP1 in adipocytes and adipose tissue. These results suggest that local inhibition of miR-429 in subcutaneous white adipose tissue ameliorates obesity and related metabolic disorders potentially by upregulating UCP1, and miR-429 is a potential therapeutic target for the treatment of obesity and related metabolic disorders.
Animals ; MicroRNAs/physiology* ; Obesity/metabolism* ; Mice ; Adipose Tissue, White/metabolism* ; Metabolic Diseases ; Subcutaneous Fat/metabolism* ; Male ; Uncoupling Protein 1/metabolism* ; Diet, High-Fat ; Mice, Inbred C57BL

Metabolic diseases characterized by an imbalance in energy homeostasis represent a significant global health challenge. Individuals with metabolic diseases often suffer from complications related to disorders in lipid metabolism, such as obesity and non-alcoholic fatty liver disease (NAFLD). Understanding core genes involved in lipid metabolism can advance strategies for the prevention and treatment of these conditions. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in lipid metabolism that converts saturated fatty acids into monounsaturated fatty acids. SCD1 plays a crucial regulatory role in numerous physiological and pathological processes, including energy homeostasis, glycolipid metabolism, autophagy, and inflammation. Abnormal transcription and epigenetic activation of Scd1 contribute to abnormal lipid accumulation by regulating multiple signaling axes, thereby promoting the development of obesity, NAFLD, diabetes, and cancer. This review comprehensively summarizes the key role of SCD1 as a metabolic hub gene in various (patho)physiological contexts. Further it explores potential translational avenues, focusing on the development of novel SCD1 inhibitors across interdisciplinary fields, aiming to provide new insights and approaches for targeting SCD1 in the prevention and treatment of metabolic diseases.
Stearoyl-CoA Desaturase/metabolism* ; Humans ; Metabolic Diseases/physiopathology* ; Lipid Metabolism/physiology* ; Animals ; Obesity/enzymology* ; Non-alcoholic Fatty Liver Disease

The circadian rhythm regulates the 24-hour physiological and behavioral cycles through endogenous molecular clocks governed by core clock genes via the transcription-translation feedback loop (TTFL). In mammals, the suprachiasmatic nucleus (SCN) serves as the central pacemaker, coordinating the timing of physiological processes throughout the body by regulating clock genes such as CLOCK, BMAL1, PER, and CRY. The molecular clocks of peripheral tissues and cells are synchronized by the SCN through TTFLs to regulate metabolism, immunity, and energy homeostasis. Numerous studies indicate that circadian rhythm disruption is closely related to obesity, type 2 diabetes, metabolic syndrome and other diseases, and the mechanism involves the dysregulation of glucose and lipid metabolism, abnormal insulin signaling and low-grade inflammation. In recent years, small-molecule compounds targeting the core clock components such as CRY, REV-ERB, and ROR have been identified and shown potential to modulate metabolic diseases by stabilizing or inhibiting the activity of key clock proteins. This review summarizes the mechanisms and advances in these compounds, and explores the challenges and future directions for their clinical translation, providing insights for chronotherapy-based metabolic disease interventions.
Humans ; Metabolic Diseases/physiopathology* ; Animals ; Circadian Rhythm/physiology* ; Biological Clocks/drug effects* ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Suprachiasmatic Nucleus/physiology*

Most of the life forms on Earth have gradually evolved an endogenous biological clock under the long-term influence of periodic daily light-dark cycles. This biological clock system plays a crucial role in the orderly progression of life activities. In mammals, central circadian clock is located in the suprachiasmatic nucleus of the hypothalamus and the function of the biological clock relies on a transcription-translation negative feedback loop. As a negative regulator in this loop, the function of CHRONO is less known. To deeply explore the role of the Chrono gene in rhythm entrainment and physiology, we constructed a Chrono gene knockout mouse strain using the CRISPR/Cas9 technology and analyzed its entrainment ability under different T cycles. Running wheel tests and glucose tolerance tests were also performed. The results showed that the period of the endogenous biological clock of Chrono knockout mice was prolonged, and the entrainment rate under the T21 cycle was decreased. In addition, metabolic abnormalities, including weight gain and impaired glucose tolerance, were observed in the non-entrained mice. Overall, this study reveals a crucial role of the Chrono gene in maintaining circadian rhythms and metabolic balance, providing a new perspective for understanding the relationship between the biological clock and metabolism. Further research is needed to fully understand the underlying molecular mechanisms.
Animals ; Mice, Knockout ; Mice ; Circadian Rhythm/genetics* ; Metabolic Diseases/physiopathology* ; Photoperiod ; Male ; Period Circadian Proteins/physiology* ; Light ; Circadian Clocks/physiology*

Child ; Humans ; China ; Consensus ; Fatty Liver/therapy* ; Metabolic Diseases/therapy* ; Systematic Reviews as Topic

Metabolic diseases have seen a steady increase in incidence in recent years, becoming one of the main causes of sub-health status globally. Neutrophil extracellular traps(NETs) are reticular complexes containing DNA, which trap foreign microorganisms or induce an immune response. Current research indicates that NETs are widely active in various metabolic diseases and can cause severe damage to the body through multiple mechanisms, including promoting blood glucose elevation, damaging vascular endothelial cells, forming vascular embolisms, triggering intense inflammation, and promoting lipid accumulation. Therefore, intervening in NETs is an important approach to treating metabolic diseases. Research has shown a close relationship between the theory of spleen heat-turbid toxin theory and metabolic diseases-NETs mechanism. The basic pathogenesis include the internal accumulation of phlegm-dampness, qi stagnation and blood stasis, internal accumulation of dampness-heat, phlegm and blood stasis, and flourishing toxic heat. Various Chinese herbal medicines with the functions of dispelling dampness, resolving phlegm, promoting blood circulation to remove blood stasis, and clearing heat and toxins, along with their extracts and compound prescriptions, can treat metabolic diseases by regulating NETs and delaying disease progression. This paper systematically outlined the formation mechanisms of NETs, their connection to metabolic diseases, the theoretical basis in TCM, their roles in numerous metabolic diseases, and the current research status of TCM in regulating NETs to prevent and control metabolic diseases, aiming to provide effective reference ideas for developing therapeutic strategies for metabolic diseases.
Humans ; Extracellular Traps/metabolism* ; Metabolic Diseases/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Neutrophils/metabolism* ; Medicine, Chinese Traditional

Macrophages are the crucial immune cells integral to host defense and the regulation of homeostasis, exhibiting remarkable plasticity across various tissues. Upon exposure to different stimuli, they can polarize into functional subsets. The reorganization process of cellular metabolism, known as metabolic reprogramming, involves the comprehensive adjustment of intracellular metabolites, enzymes, and metabolic pathways. Recent studies have revealed the critical role of metabolic reprogramming in shaping the phenotypes and functions of macrophages. Metabolism drives and regulates macrophages by generating bioenergy and biosynthetic precursors and by altering metabolites that affect gene expression and signal transduction. This review focuses on the immunomodulatory roles of key enzymes and specific products in major metabolic pathways, such as glucose metabolism, lipid metabolism and amino acid metabolism, in macrophages. Additionally, it will highlight recent advancements in targeting metabolic regulation of macrophages in the context of ocular diseases.
Humans ; Macrophages/immunology* ; Animals ; Eye Diseases/immunology* ; Lipid Metabolism ; Glucose/metabolism* ; Metabolic Networks and Pathways ; Signal Transduction ; Metabolic Reprogramming