Nucleobindin-2 controls insulin-sensitivity in obesity without impacting food intake and adiposity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97309 | GEO | 2018/11/14
REPOSITORIES: GEO
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Project description:Inducers of satiety are drug targets for weight loss to mitigate obesity-associated diseases. Nucleobindin-2 (Nucb2) is thought to be post-translationally processed into bioactive nesfatin-1 peptide, which reportedly induces satiety, causes weight loss, and thus improves insulin sensitivity. Here, we show that deletion of Nucb2 did not affect food intake or adiposity and, instead, caused insulin resistance in mice fed a high-fat diet. In addition, ablation of Nucb2 in orexigenic hypothalamic Agrp neurons did not affect food intake, and nesfatin-1 was detectable in serum, despite global deletion of Nucb2 protein. Upon high-fat diet feeding, the loss of Nucb2 exacerbated metabolic inflammation in adipose tissue macrophages in an NF?B-dependent manner without inducing classical M1 or alternative M2-like macrophage polarization. Furthermore, the loss of Nucb2 in myeloid cells but not in adipocytes mediated the insulin resistance in response to a high-fat diet. Our study reveals that Nucb2 links metabolic inflammation to insulin resistance without affecting weight gain and food intake.
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Project description:Adipose tissue gene expression was profiled from perigonadal adipose tissue of mice whose body mass and insulin sensitivity varied as a function of diet, gender, monogenic mutations and insulin sensitizing therapies. Mice were 22-24 weeks of age and sacrificed between 2-3 hours into the light portion of a 12/12 dark-light cycle. The goal was to identify transcripts whose adipose tissue expression is correlated with adiposity, insulin sensitivity and other measures of metabolic function. Experiment Overall Design: Mice on the C57BL/6J strain were housed in groups of 3-5 and fed ad libitum. 2-4 days prior to collection of adipose tissue fasting blood glucose and serum insulin concentrations were measured. Mice were sacrificed 2-3 hours into the light cycle. RNA was extracted from perigonadal adipose tissue and used to generate labed cRNA for hybridization to Affymetrix Mu74Av2 microarrays.
2008-11-13 | E-GEOD-8831 | biostudies-arrayexpress
Project description:Adipose tissue gene expression was profiled from perigonadal adipose tissue of mice whose body mass and insulin sensitivity varied as a function of diet, gender, monogenic mutations and insulin sensitizing therapies. Mice were 22-24 weeks of age and sacrificed between 2-3 hours into the light portion of a 12/12 dark-light cycle. The goal was to identify transcripts whose adipose tissue expression is correlated with adiposity, insulin sensitivity and other measures of metabolic function. Keywords: population
2008-11-01 | GSE8831 | GEO
Project description:While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies, and predisposition of miR-33-/- mice to obesity and metabolic dysfunction, exemplify the possible pitfalls of miRNA based therapies. Our work provides an in-depth characterization of miR-33-/- mice, and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1 mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33-/- mice we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals.
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Project description:ObjectivesInsulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla.MethodsTo address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis.ResultsBy specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity.ConclusionsTaken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases.
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Project description:BackgroundDisruption of the gut microbiota homeostasis may induce low-grade inflammation leading to obesity-associated diseases. A major protective mechanism is to use the multi-layered mucus structures to keep a safe distance between gut epithelial cells and microbiota. To investigate whether pesticides would induce insulin resistance/obesity through interfering with mucus-bacterial interactions, we conducted a study to determine how long-term exposure to chlorpyrifos affected C57Bl/6 and CD-1 (ICR) mice fed high- or normal-fat diets. To further investigate the effects of chlorpyrifos-altered microbiota, antibiotic treatment and microbiota transplantation experiments were conducted.ResultsThe results showed that chlorpyrifos caused broken integrity of the gut barrier, leading to increased lipopolysaccharide entry into the body and finally low-grade inflammation, while genetic background and diet pattern have limited influence on the chlorpyrifos-induced results. Moreover, the mice given chlorpyrifos-altered microbiota had gained more fat and lower insulin sensitivity.ConclusionsOur results suggest that widespread use of pesticides may contribute to the worldwide epidemic of inflammation-related diseases.
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Project description:In mammals, insulin regulates blood glucose levels and plays a key regulatory role in appetite via the hypothalamus. In contrast, chickens are characterized by atypical glucose homeostasis, with relatively high blood glucose levels, reduced glucose sensitivity of pancreatic beta cells, and large resistance to exogenous insulin. The aim of the present study was to investigate in chickens the effects of 5 h fasting and 5 h insulin immuno-neutralization on hypothalamic mRNA levels of 23 genes associated with food intake, energy balance, and glucose metabolism. We observed that insulin immune-neutralization by administration of anti-porcine insulin guinea pig serum (AI) significantly decreased food intake and increased plasma glucose levels in chickens, while 5 h fasting produced a limited and non-significant reduction in plasma glucose. In addition, 5 h fasting increased levels of NPY, TAS1R1, DIO2, LEPR, GLUT1, GLUT3, GLUT8, and GCK mRNA. In contrast, AI had no impact on the levels of any selected mRNA. Therefore, our results demonstrate that in chickens, food intake inhibition or satiety mechanisms induced by insulin immuno-neutralization do not rely on hypothalamic abundance of the 23 transcripts analyzed. The hypothalamic transcripts that were increased in the fasted group are likely components of a mechanism of adaptation to fasting in chickens.
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Project description:Oxidation of cysteines by reactive oxygen species (ROS) initiates thermogenesis in brown and beige adipose tissues. Cellular selenols, where sulfur is replaced with selenium, exhibit enhanced reactivity with ROS. Here we developed a mass spectrometric method to interrogate incorporation of selenols into proteins. Unexpectedly, this approach revealed facultative incorporation of selenium into proteins that lack canonical encoding for selenium-containing amino acids. Selenium was selectively incorporated into regulatory sites on key metabolic proteins, including as selenocysteine replacing cysteine at position 253 in UCP1. Remarkably, dietary selenium supplementation elevated facultative incorporation into UCP1, elevated energy expenditure through thermogenic adipose tissue, and protected against obesity. Together, these findings reveal the existence of facultative protein selenation, which correlates with impacts on thermogenic adipocyte function.
2021-09-09 | PXD018225 | Pride