β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE122361 | GEO | 2019/11/09
REPOSITORIES: GEO
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Project description:Lamin A, lamin C and progerin, produced by alternative RNA processing of LMNA gene, are intermediate filaments involved in nuclear and chromatin architecture. We investigate the ability of LMNALCS/LCS mice to adapt insulin level to physiological and physiopathologic conditions. The metabolic status of young vs old mice shows that old LMNALCS/LCS mice are obese but glucose tolerant due to an increased β cell mass and insulin secretion. By combining RNAseq and RRBS analysis, we observed a transcriptional disregulation of genes related to translation and mitochondria, confirmed by functionnal analysis, suggesting that LMNALCS/LCS mice set up a transcriptional program to adapt β cell mass and function to insulin demand. To investigate this point, we challenged young mice by inducing T1DM and T2DM. In these contexts, we show that LMNALCS/LCS mice are able to normalize their fasting glycemia by both increasing insulin secretion and regenerating β cells.
2019-11-09 | GSE122360 | GEO
Project description:Lamin A, lamin C and progerin, produced by alternative RNA processing of LMNA gene, are intermediate filaments involved in nuclear and chromatin architecture. We investigate the ability of LMNALCS/LCS mice to adapt insulin level to physiological and physiopathologic conditions. The metabolic status of young vs old mice shows that old LMNALCS/LCS mice are obese but glucose tolerant due to an increased β cell mass and insulin secretion. By combining RNAseq and RRBS analysis, we observed a transcriptional disregulation of genes related to translation and mitochondria, confirmed by functionnal analysis, suggesting that LMNALCS/LCS mice set up a transcriptional program to adapt β cell mass and function to insulin demand. To investigate this point, we challenged young mice by inducing T1DM and T2DM. In these contexts, we show that LMNALCS/LCS mice are able to normalize their fasting glycemia by both increasing insulin secretion and regenerating β cells.
2019-11-09 | GSE122359 | GEO
Project description:β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes
| PRJNA504768 | ENA
Project description:β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes (LamineA-C_RNASeq)
| PRJNA504769 | ENA
Project description:β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes (LamineA-C_RRBS)
| PRJNA504770 | ENA
Project description:An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.
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Project description:ObjectiveObesity-related adipose tissue dysfunction has been linked to the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Impaired calcium homeostasis is associated with altered adipose tissue metabolism; however, the molecular mechanisms that link disrupted calcium signaling to metabolic regulation are largely unknown. Here, we investigated the contribution of a calcium-sensing enzyme, calcium/calmodulin-dependent protein kinase II (CAMK2), to adipocyte function, obesity-associated insulin resistance, and glucose intolerance.MethodsTo determine the impact of adipocyte CAMK2 deficiency on metabolic regulation, we generated a conditional knockout mouse model and acutely deleted CAMK2 in mature adipocytes. We further used in vitro differentiated adipocytes to dissect the mechanisms by which CAMK2 regulates adipocyte function.ResultsCAMK2 activity was increased in obese adipose tissue, and depletion of adipocyte CAMK2 in adult mice improved glucose intolerance and insulin resistance without an effect on body weight. Mechanistically, we found that activation of CAMK2 disrupted adipocyte insulin signaling and lowered the amount of insulin receptor. Further, our results revealed that CAMK2 contributed to adipocyte lipolysis, tumor necrosis factor alpha (TNFα)-induced inflammation, and insulin resistance.ConclusionsThese results identify a new link between adipocyte CAMK2 activity, metabolic regulation, and whole-body glucose homeostasis.
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Project description:Depression and use of antidepressant medications are both associated with increased risk of obesity, potentially attributed to a reduced serotonin transporter (SERT) function. However, how SERT deficiency promotes obesity is unknown. Here, we demonstrated that SERT -/- mice display abnormal fat accumulation in both white and brown adipose tissues, glucose intolerance and insulin resistance while exhibiting suppressed aromatase (Cyp19a1) expression and reduced circulating 17β-estradiol levels. 17β-estradiol replacement in SERT -/- mice reversed the obesity and glucose intolerance, supporting a role for estrogen in SERT deficiency-associated obesity and glucose intolerance. Treatment of wild type mice with paroxetine, a chemical inhibitor of SERT, also resulted in Cyp19a1 suppression, decreased circulating 17β-estradiol levels, abnormal fat accumulation, and glucose intolerance. Such effects were not observed in paroxetine-treated SERT -/- mice. Conversely, pregnant SERT -/- mice displayed normalized estrogen levels, markedly reduced fat accumulation, and improved glucose tolerance, which can be eliminated by an antagonist of estrogen receptor α (ERα). Together, these findings support that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance, and suggest approaches to restore 17β-estradiol levels as a novel treatment option for SERT deficiency associated obesity and metabolic abnormalities.
| S-EPMC5430688 | biostudies-literature
Project description:Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
| S-EPMC7537391 | biostudies-literature
Project description:Background Breakthroughs in HIV treatment, especially antiretroviral therapy (ART), have massively reduced mortality. However, ART-treated individuals display elevated rates of obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. These co-morbidities represent a considerable threat to long-term survival and quality of life. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Methods and Results Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. ART-treated mice on a HFD displayed fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. Conclusions The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways in eWAT consistent with macrophage infiltration, resulting in impaired glucose metabolism, energy balance, and metabolic dysfunction.
2018-09-14 | GSE110035 | GEO