Metabolism: clinical and experimental最新文献

Background and aims: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity.

Methods: A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators.

Results: Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [-4.81, -2.29]), fat mass (MD -2.95 kg, 95 %-CI [-4.11, -1.79]), and lean mass (MD -0.86 kg, 95 %-CI [-1.30, -0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass.

Conclusions: Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.

Aims: NAD⁺ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD⁺ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD⁺ synthesis.

Methods: Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD⁺ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.

Results: NRH entered tissues unassisted and was rapidly metabolized for NAD⁺ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD⁺ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.

Conclusion: This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD⁺ enhancement.

Background & aims: Abnormal regulation of lncRNA is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (Rock2) axis and the NORAD/ROCK2 interaction in the development of MASLD.

Methods: In vitro and in vivo models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis.

Results: NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate Rock2 mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/Rock2 axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis.

Conclusions: The NORAD/miR-511-3p/Rock2 axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.

Background: Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions.

Methods: In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index.

Results: We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (ABO, AOC1, FTO, GCKR, MTOR, POLK, PPARG, and APEH), with MTOR and PPARG categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles.

Conclusions: Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.

Skeletal muscle is a crucial tissue for physical activity and energy metabolism. Muscle atrophy, characterized by the loss of muscle mass and strength, contributes to adverse outcomes among individuals. This study elucidated the involvement of the nuclear lamina component PRR14 in transmitting mechanical signals and mediating the impact of exercise on skeletal muscle. The expression of PRR14 demonstrated a positive correlation with exercise, while a decline in adult skeletal muscle is evident in disuse muscle conditions. Genetically, multiple single nucleotide polymorphisms (SNPs) within PRR14's genomic locus were linked with muscle mass and function. Specific knockout (KO) of skeletal muscle Prr14 in mice lead to muscle atrophy, validating the genetic association. By employing biochemical analysis and high-throughput sequencing techniques, including transcriptome profile and epigenome investigations such as Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and Transposase-Accessible Chromatin sequencing (ATAC-seq), we discovered that PRR14's deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, ultimately causing muscle atrophy. Our finding highlights the crucial role of PRR14 in mechanotransduction and epigenetic regulation, offering new therapeutic avenues for skeletal muscle pathologies related to these mechanisms.

Background: Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration.

Methods: This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet. The therapeutic potential was evaluated from a metabolic perspective, including ocular pathologies such as retinal lesions, neovascularization, and vascular leakage.

Results: We discovered that inhibition or genetic ablation of HDAC6 markedly alleviates DR symptoms by dampening NLRP3 inflammasome activation and mitigating retinal damage. Moreover, bone marrow transplantation from HDAC6-deficient mice into wild-type counterparts reversed DR symptoms, underscoring the significance of HDAC6 in systemic immune regulation. The study introduces a novel HDAC6 inhibitor, noted for superior bioavailability and blood-retinal barrier permeability, further highlights the therapeutic promise of targeting HDAC6 in DR.

Conclusions: Our findings not only underscore the crucial role of HDAC6 in the immune regulatory mechanisms underlying DR pathogenesis through NLRP3 inflammasome activation but also position HDAC6 inhibition as a promising strategy for addressing diabetic complications beyond DR.

Neurodegenerative disorders are straining public health worldwide. During neurodegenerative disease progression, aberrant neuronal network activity, bioenergetic impairment, adaptive neural plasticity impairment, dysregulation of neuronal Ca²⁺ homeostasis, oxidative stress, and immune inflammation manifest as characteristic pathological changes in the cellular milieu of the brain. There is no drug for the treatment of neurodegenerative disorders, and therefore, strategies/treatments for the prevention or treatment of neurodegenerative disorders are urgently needed. Intermittent fasting (IF) is characterized as an eating pattern that alternates between periods of fasting and eating, requiring fasting durations that vary depending on the specific protocol implemented. During IF, depletion of liver glycogen stores leads to the production of ketone bodies from fatty acids derived from adipocytes, thereby inducing an altered metabolic state accompanied by cellular and molecular adaptive responses within neural networks in the brain. At the cellular level, adaptive responses can promote the generation of synapses and neurons. At the molecular level, IF triggers the activation of associated transcription factors, thereby eliciting the expression of protective proteins. Consequently, this regulatory process governs central and peripheral metabolism, oxidative stress, inflammation, mitochondrial function, autophagy, and the gut microbiota, all of which contribute to the amelioration of neurodegenerative disorders. Emerging evidence suggests that weight regulation significantly contributes to the neuroprotective effects of IF. By alleviating obesity-related factors such as blood-brain barrier dysfunction, neuroinflammation, and β-amyloid accumulation, IF enhances metabolic flexibility and insulin sensitivity, further supporting its potential in mitigating neurodegenerative disorders. The present review summarizes animal and human studies investigating the role and underlying mechanisms of IF in physiology and pathology, with an emphasis on its therapeutic potential. Furthermore, we provide an overview of the cellular and molecular mechanisms involved in regulating brain energy metabolism through IF, highlighting its potential applications in neurodegenerative disorders. Ultimately, our findings offer novel insights into the preventive and therapeutic applications of IF for neurodegenerative disorders.