Effect of leptin deficiency in Bmal1 knockout mice across different tissues
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA631168 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR11732500_1.fastq.gz | Fastqsanger.gz | |||
| SRR11732500_2.fastq.gz | Fastqsanger.gz | |||
| SRR11732600_1.fastq.gz | Fastqsanger.gz | |||
| SRR11732600_2.fastq.gz | Fastqsanger.gz | |||
| SRR11732700_1.fastq.gz | Fastqsanger.gz |
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Project description:Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. We show here that the activity of the circadian clock regulator BMAL1 is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition to direct transcriptional regulation of metabolic programs by BMAL1, we show that adaptation disruption of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans, but were absent in hepatocyte specific Bmal1 knockout mice. This suggestsing that systemic endocrine perturbation associated with circadian disruptionthe disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases.
2022-01-26 | GSE150102 | GEO
Project description:Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. We show here that the activity of the circadian clock regulator BMAL1 is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition to direct transcriptional regulation of metabolic programs by BMAL1, we show that adaptation of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans, suggesting that endocrine perturbation associated with circadian disruption is critical for the pathogenesis of metabolic and liver diseases.
2022-01-26 | GSE190221 | GEO
Project description:Mice without cardiac Bmal1 function develop severe progressive heart failure with age. To examine the mechanism underlying the failing heart phenotype observed in heart-specific Bmal1 knockout mice, microarray analyses were performed. The analyses revealed that broad classes of genes regulating cellular energy metabolism were upregulated or downregulated in the heart tissues of heart-specific Bmal1 knockout mice compared with those of control animals. Heart total RNA extracted from six animals per genotype (control and heart-specific Bmal1 knockout) was pooled and then used for a microarray analysis.
2014-09-27 | E-GEOD-61787 | biostudies-arrayexpress
Project description:Mice without cardiac Bmal1 function develop severe progressive heart failure with age. To examine the mechanism underlying the failing heart phenotype observed in heart-specific Bmal1 knockout mice, microarray analyses were performed. The analyses revealed that broad classes of genes regulating cellular energy metabolism were upregulated or downregulated in the heart tissues of heart-specific Bmal1 knockout mice compared with those of control animals.
2014-09-27 | GSE61787 | GEO
Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.
2011-04-29 | E-GEOD-16790 | biostudies-arrayexpress
Project description:Skeletal mandibular hypoplasia (SMH), one of the common types of craniofacial deformities, seriously affects appearance, chewing, pronunciation, and breathing. Moreover, SMH is prone to inducing obstructive sleep apnea syndrome. We found that brain and muscle ARNT-like 1 (BMAL1), the core component of the molecular circadian oscillator, was significantly decreased in mandibles of juvenile SMH patients. Accordingly, SMH was observed in circadian rhythm-disrupted or BMAL1-deficiency mice. RNA sequencing and protein chip analyses suggested that matrix metallopeptidase 3 (MMP3) is the potential target of BMAL1 during the mandibular developmental process. Interestingly, in juvenile SMH patients, we observed that MMP3 level was increased obviously. Consistently, MMP3 was upregulated during the whole growth period of 3 to 10 weeks in Bmal1-/- mice. Given these findings, we set to characterize the underlying mechanism and found that BMAL1-deficiency enhanced Mmp3 transcription through activating p65 phosphorylation. Together our results provide new insight into the mechanism by which BMAL1 is implicated in the pathogenesis of SMH
2017-11-07 | GSE106586 | GEO
Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1-alpha and PPAR-alpha to wild type levels; CR paradoxically further suppressed cardiac PPAR-alpha. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction.
2011-04-29 | GSE16790 | GEO
Project description:BMAL1-deficiency contributes to mandibular dysplasia by upregulating MMP3
| PRJNA417294 | ENA
Project description:To define regulation of tissue proteomes by Bmal1, daily feeding rhythm, and the interaction, we employed Bmal1-stopFL mice, which do not express the main transcriptional activator of the molecular clock, Bmal1, except in cre recombinase-expressing cells1,2 (Figure 1A). Bmal1-stopFL mice lacking cre (Bmal1 knockout, KO) are analogous to Bmal1-null mice and display severely impaired behavioral and molecular rhythms1-3. Hepatocyte-specific Alfp-cre and skeletal muscle-specific Hsa-cre genes were introduced to generate a single line wherein both hepatocyte and skeletal muscle Bmal1 were reconstituted (Liver+Muscle-RE), i.e., rescued (Smith, Koronowski et al. 2023). This approach had the benefit of analyzing liver and muscle from the same mice but comes with the qualification that the abundance of some proteins may be influenced by Bmal1 function in the other tissue, or by a synergistic effect of Bmal1 in both tissues, rather than through rescue of local Bmal1 function alone. Proteomic anlaysis was performed in liver and skeletal muscle.
2024-01-26 | PXD040362 | Pride
Project description:Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening public health, however its natural history is poorly understood. Unlike ob/ob mice, Lep∆I14/∆I14 rats develop unique NASH phenotype with an inflection point of inflammation at postnatal week 16. Using Lep∆I14/∆I14 rats, we studied the natural history of NASH progression by performing an integrated analysis of hepatic transcriptome from postnatal week 4 to 48. Leptin deficiency leads to the precipitously increasing expression of genes encoding rate-limiting enzymes in lipid metabolism. However, hepatic inflammation related genes, pathways and immune-cell infiltration are restricted after week 16, implying an essential role of LEPTIN in regulating hepatic inflammation. Lep∆I14/∆I14 rats share more genes with NASH patients than known mouse models, therefore will provide a better genetic platform for studying NASH than mice.
2019-12-31 | GSE124002 | GEO