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Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health

ABSTRACT: Objective Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans. Methods Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks. Results The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting. Conclusions These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE201092 | GEO | 2023/02/23

REPOSITORIES: GEO

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Project description:Although mitochondrial dysfunctions are implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are still not well established. To acquire a comprehensive picture of mitochondrial molecular changes within metabolically active tissues, we focused on hepatic and muscle whole cellular transcriptome and mitochondrial proteome alterations in 16 and 48 weeks old high fat diet (HFD)-feed wild type C57BL/6J and hyperphagic, genetically modified mice with leptin dysfunction (ob/ob and db/db). On transcriptome level, the most discriminative hepatic alterations distinguished between genetically modified and wild type mice, and between overnight fasted and non-fasted mice, while the muscle transcriptional alterations related mainly to the fasting state. The fractions of uniquely different proteins were consistently higher in hyperphagic than in HFD-fed mice and in fasted than non-fasted mice . The liver samples revealed overall higher number of differentially expressed RNAs and proteins than muscle samples. Differentially expressed genes and proteins in the liver, but not in the muscle, could be assigned to several Gene Ontology terms, including oxidation-reduction and several metabolic processes. Thus, altered expression of genes and proteins accompanied the state of obesity and was quantitatively different in the liver and muscle. Our parallel microarray- and quantitative mitochondrial mass spectrometry-based study performed on hepatic and muscle samples identified a higher number of differentially expressed proteins than any other studies investigating obesity-related proteomes. However, even with our integrated transcriptomic and proteomic approach still many details and dynamics of a chain of metabolic events leading to obesity-related mitochondrial dysfunctions remain unresolved . 48 samples each of liver and muscle (total samples: 96). Samples splitted equally according to 3 criterions: age (24 young/24 old), fasting status (24 fasted/24 non fasted), and strain+diet (12 each: B6.V-Lep ob/J+D12450B, B6.BKS(D)-Lep rdb/J+D12450B, C57BL/6J+D12450B, C57BL/6J+D12492). Overall 3 replicates for each strain+diet/age/fasting_status combination. Low fat diet = D12450B; high fat diet = D12492.

Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

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Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health

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