Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria
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PROVIDER: PRJNA780798 | ENA |
REPOSITORIES: ENA
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Project description:Maintenance of energetic homeostasis during periods of limited supply requires metabolic adaptation. Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to this homeostasis by disrupting energetic pathways. To better understand the systemic and cellular responses to long-term energy shortage, we investigated a hemizygous mouse model of MMAuria that has a knock-in (ki) missense allele combined with a knock-out (ko) allele (Mmut-ko/ki) and shows typical clinical features including reduced growth. We found that Mmut-ko/ki (mutant) mice, compared to their Mmut-ki/wt (control) littermates, have reduced body mass along with a relative reduction in lean mass but increase in fat mass. White adipose tissue appears histologically normal, but brown adipose tissue show a process of whitening, in line with their lower body surface temperature and lesser ability to cope with cold challenge. Ad libitum fed mice show constitutive hypometabolism: they have reduced food intake, reduced energy expenditure, and reduced plasma glucose, but elevated lactate and fibroblast growth factor 21 (Fgf21). Together, these changes culminate in a loss of metabolic flexibility in mutant mice. This is manifested in lesser ability to regulate energy sources when switching from the fed to fasted state, and in a delayed glucose clearance in response to exogenous glucose and insulin. Liver investigations find multi-metabolite accumulation and suggest upregulation of peroxisome proliferator-activated receptor (Ppar)- and Fgf21-controlled metabolic pathways, including beta-oxidation, and downregulation of oxidative phosphorylation, as molecular consequences. Altogether, this study identifies a multi-faceted metabolic response to chronic energy shortage in MMAuria and suggests hypometabolism combined with dysregulated adaptive capability to be underlying features.
2023-06-26 | GSE188931 | GEO
Project description:Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)-type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.
| S-EPMC10460489 | biostudies-literature
Project description:Gene expression atlas of energy balance brain regions
| PRJNA738366 | ENA
Project description:Granulosa cells of dominant follicles originating from dairy cows with severe negative energy balance (BHBH) or mild negative energy balance (BHBL) were compared. Mild negative energy balance (BHBL) is the reference. Two conditions experiment (BHBH and BHBL); Four pools of 3 biological replicates for each group (total = 12 cows for each group); Two technical replicates per pool (dye-swap).
2015-07-31 | E-GEOD-66116 | biostudies-arrayexpress
Project description:This project involved bulk-RNAseq analysis of mouse brain regions involved in energy balance. Two mouse embryonic stem cell controls were included
2021-06-17 | GSE178290 | GEO
Project description:Granulosa cells of dominant follicles originating from dairy cows with severe negative energy balance (BHBH) or mild negative energy balance (BHBL) were compared. Mild negative energy balance (BHBL) is the reference.
2015-07-31 | GSE66116 | GEO
Project description:Energy Balance Drives Diurnal and Nocturnal Brain Transcriptome Rhythms
| PRJNA952252 | ENA
Project description:Our objectives were to compare gene expression profiles in neutrophils (PMN) during a Streptococcus uberis mastitis challenge between lactating cows subjected to feed restriction to induce negative energy balance (NEB; n = 5) and cows fed ad libitum to maintain positive energy balance (PEB; n = 5). The NEB cows were feed-restricted to 60% of calculated net energy for lactation requirements for 7 d, whereas PEB cows were fed the same diet for ad libitum intake. After 5 d of feed restriction, one rear mammary quarter of each cow was inoculated with 5,000 cfu of Streptococcus uberis (strain O140J). Blood PMN were isolated at 24 h post-inoculation from all cows for RNA extraction and microarray analysis. NEB resulted in 94 differentially expressed genes compared with PEB. Of these, 51 genes were down-regulated, including genes involved with antigen presentation (HLADRA and HLAA), respiratory burst (SOD1), and the pro-inflammatory response (TNFA and IRAK-1). The most affected genes up-regulated by NEB (n = 43) included IL1R2 and IL6, toll-like receptors (TLR2 and TLR4), and THY1. Network analysis by Ingenuity Pathway Analysis ® revealed that TNFA was associated with the expression of numerous differentially expressed genes involved with immune response in NEB cows compared with PEB cows. Energy balance alters PMN expression of several genes involved with immune response, which provides new information on transcriptomic mechanisms associated with post-partal NEB and immune response during early lactation. Briefly, 10 multiparous Holstein cows in PEB and past peak lactation were used for this study. The NEB cows were feed-restricted to 60% of calculated NEL requirements for 7 d, whereas PEB cows were fed the same diet for ad libitum intake. After 5 d of feed restriction, one rear mammary quarter of each cow was inoculated with 5,000 cfu of Streptococcus uberis (strain O140J). Blood PMN were isolated at 24 h post-inoculation from all cows. A 13,257-oligonucleotide (70-mers) array was used for transcript profiling. Cy3- and Cy5 labelled cDNA from PMN and a reference standard were used for hybridizations. All samples were hybridized to duplicate slides with reverse labeling (20 microarrays total).
2010-05-16 | E-GEOD-15364 | biostudies-arrayexpress
Project description:The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that trigger the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element–binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction—Crtc1-/- mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice; leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin’s effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.
2008-09-04 | GSE12209 | GEO
Project description:Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. The goal of this study is to isolate ‘diet/energy balance’ effects independent from ‘body weight’ effects on various metabolic and behavioral parameters using the Diet Switch feeding paradigm in mice. [We conducted] unbiased gene expression analysis of the nutrient-sensing circumventricular hypothalamus [using RNA-seq]. Remarkably, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight. Furthermore, linear regression models revealed that npy and agrp showed similar modifiability by diet/energy balance and body weight compared to electroencephalographic-measured sleep/wake behavior.
2018-05-17 | GSE104709 | GEO