Single-Cell Transcriptomics Identifies Pituitary Gland Population Changes in Diet-Induced Obesity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240022 | GEO | 2024/01/24
REPOSITORIES: GEO
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Project description:Anterior pituitary cells are highly active with regards to protein synthesis and secretion, processes which depend heavily on mitochondrial ATP production and functional endoplasmic reticula. It is well known that obesity adds an allostatic overload to tissues, requiring them to adapt to inflammation and oxidative stress. Therefore, we hypothesized that the pituitary is highly vulnerable to the stress of high fat diet-induced weight gain. In this study, we utilized a 10-15 week high fat diet (HFD, 60%) plus a thermoneutral housing paradigm, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-seq. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin, Il-6, resistin, MCP-1, and TNFα. HFD males had increased insulin; both HFD males and females had increased TSH, and HFD females had decreased serum prolactin and growth hormone (GH) pulse amplitude. Pituitary scRNA-seq revealed modest or no changes in pituitary cell gene expression in the different cell types from HFD males after 10 or 15 weeks or HFD females after 10 weeks. However, females exposed to a HFD for 15 weeks showed significant numbers of differentially expressed genes in lactotropes and stem cells. Pathway analyses identified a reduction in pathways that supported protein translation, ribosome biogenesis, and oxidative phosphorylation, indicating mitochondrial dysfunction. Collectively, these studies reveal that pituitary cells from males are more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females.
2024-01-04 | GSE244595 | GEO
Project description:Inter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we found that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a novel mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism.
2023-01-11 | GSE216096 | GEO
Project description:Overproduction of adrenal hormones causes obesity and hypertension, whereas adrenalectomy (ADX) leads to weight loss and hypotension. The pituitary gland is a major target organ for the adrenal hormones. To identify potential mediators for the effect of ADX on pituitary system regulating weight loss and hypotension, we investigated the effect of ADX on pituitary gene expression using serial analysis of gene expression (SAGE). The numbers of analyzed SAGE tag were 126688 tags for intact mice (n = 51) and 59482 tags for ADX mice (n = 12), which corresponded to 45151 and 21790 distinct tag species, respectively. Thirty-three pituitary genes were differentially expressed between intact and ADX mice. Three genes encoding for pro-opiomelanocortin have been upregulated by ADX. The ADX has induced the gene expression of growth hormone while downregulating an expressed sequence tag similar to (EST) growth hormone. The ADX reduced the expression of genes involved in mitochondrial oxidative phosphorylation, such as NADH dehydrogenase 3 and cytochrome c oxidase 3, whereas neuromedin B gene were dramatically induced. In addition, the ADX increased the expression levels of other three genes involved in hormone release (response to metastatic cancers 1), extracellular matrix (matrix gamma-carboxyglutamate gla protein), and cation transport (solute carrier family member 17). Moreover, one functionally-uncharacterized and 20 novel transcripts were significantly modulated by ADX. Thus the current study has revealed the alterations in the pituitary gene expression that may play key roles in the mechanisms of ADX-induced weight loss and hypotension. Keywords: adrenalectomy, serial analysis of gene expression Rodents and pituitary gland sampling. Male C57BL6 mice were obtained from Charles River Laboratories (St. Constant, QC, Canada), at 12-14 weeks of age. Mice were housed in an air-conditioned room (19-25?) with controlled lighting from 07:15 to 19:15 h and were given free access to food (Lab Rodent Diet No. 5002) and water. One week prior to sampling of pituitary gland, adrenalectomy was performed in mice of ADX groups (n = 12). The ADX mice received sodium chloride (0.9g/dl) in their drinking water after the surgery. All mice were killed between 08:30 and 12:30 by decapitation under isoflurane anesthesia. Brain was removed from the skull and the pituitary gland was immediately dissected. The pituitary gland was immediately frozen in liquid nitrogen, pooled together for each group, and stored at -80? until RNA extraction.
2007-12-18 | E-GEOD-5879 | biostudies-arrayexpress
Project description:The anterior pituitary gland drives a set of highly conserved physiologic processes in mammalian species. These hormonally controlled processes are central to somatic growth, pubertal transformation, fertility, lactation, and metabolism. Current models, largely based on candidate gene based immuno-histochemical and mRNA analyses, suggest that each of the seven hormones synthesized by the pituitary is produced by a specific and exclusive cell-lineage. However, emerging evidence suggests more complex relationship between hormone specificity and cell plasticity. Here we have applied massively parallel single-cell RNA sequencing (scRNA-seq), in conjunction with complementary imaging-based single-cell analyses of mRNAs and proteins, to systematically map both cell-type diversity and functional state heterogeneity in adult male and female mouse pituitaries at single-cell resolution and in the context of major physiologic demands. These quantitative single-cell analyses reveal sex-specific cell-type composition under normal pituitary homeostasis, identify an array of cells associated with complex complements of hormone-enrichment, and undercover non-hormone producing interstitial and supporting cell-types. Interestingly, we also identified a Pou1f1-expressing cell population that is characterized by a unique multi-hormone gene expression profile. In response to two well-defined physiologic stresses, dynamic shifts in cellular diversity and transcriptome profiles were observed for major hormone producing and the putative multi-hormone cells. These studies reveal unanticipated cellular complexity and plasticity in adult pituitary, and provide a rich resource for further validating and expanding our molecular understanding of pituitary gene expression programs and hormone production.
2020-03-31 | GSE146619 | GEO
Project description:An 8-week high fat palm oil diet causes obesity and insulin resistance in C57BL/6J mice, but induces only small changes in the muscle transcriptome. Introduction: The metabolic syndrome (MS) is a cluster of metabolic abnormalities linked to an increased risk of type 2 diabetes and cardiovascular diseases. Two major characteristics of the MS are obesity and insulin resistance. In the present study we investigated the effect of obesity and insulin resistance on the mouse muscle transcriptome. Methods: C57BL/6J mice were fed a palm oil-based low fat diet (LFD) or high fat diet (HFD) for eight weeks. Microarray analysis was performed by using two complementary strategies: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Results: HFD mice develop obesity and whole-body insulin resistance. Despite these metabolic disturbances we found that HFD induces relatively small changes in gene expression (< 1.3 fold). Only the up-regulation of FA oxidation and the down-regulation of the MAPK cascade were specific for the HFD intervention. Eight-weeks of aging induced more changed gene expression levels than the HFD, including genes involved in cell-cell interaction and development. Conclusion: Eight weeks of aging induce more pronounced changes in the muscle transcriptome than an HFD. Since only one strategy revealed the transcriptional down-regulation of the MAPK cascade, whereas both strategies showed the up-regulation of FA oxidation we suggest the use of complementary analysis strategies by the genome-wide search of gene expression changes induced by mild interventions, such as an HFD. Keywords: diet intervention and time course In this study, C57BL/6J mice were fed a high fat (HF) diet for 8 weeks to induce obesity and insulin resistance. Plasma levels of the adipokines leptin and adiponectin were measured. To investigate how these metabolic disturbances will influence the skeletal muscle transcriptome we performed whole-genome microarray analysis. Functional implications were assessed by analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways.
2010-08-10 | E-GEOD-17576 | biostudies-arrayexpress
Project description:Obesity and diabetes associated visual impairment and vascular dysfunctions are increasing reasons for vision loss. The detailed mechanisms in these diseases are still largely unknown, but mice models have been useful to study these mechanisms and explore the detailed effects of potential compounds. Such compounds usually have antioxidant and anti-inflammatory properties. These properties are found in anthocyanins and a major source of dietary anthocyanins in Nordic diet is bilberries (European wild blueberries, Vaccinium myrtillus). In this explorative study we show results with differentially expressed genes in retina using a high-fat diet (HFD) mouse model. Our findings displayed differential regulation of genes in pathways for apoptosis, inflammation and oxidative stress, especially systemic lupus erythematosus (SLE), mitogen activated protein kinase (MAPK) and glutathione metabolism. Mice fed with HFD had increased retinal gene expression of several crystallins, which was reduced in the retina of mice fed with bilberries. Bilberries seem to reduce the expression of genes in MAPK and to increase the expression of genes in glutathione metabolism pathway. All together despite minor effects in the mouse phenotype, a diet rich in bilberries may prevent the retinal gene expression changes in the early stages of obesity. Mice were fed ad libitum with normal control diet (NCD, 10% kcal fat), high-fat diet (HFD, 45% kcal fat), 5% (w/w) freeze-dried biberries (Vaccinium myrtillus) in NCD (NCD+BB) or HFD (HFD+BB) for 12 weeks. Diets were prepared in Research Diets Inc. Feed consumption and weight gain were measured during the feeding trial, and blood pressure and serum markers of obesity at the end. Retinas were collected and RNA extracted from all 24 mice samples, and pooled retinas from 4 mice per group were hybridized with standard Illumina protocols. The expression in retinas was analyzed using R, Pathvisio and DAVID to screen for differences between high-fat and berry induced changes to control diets and further bilberry induced changes to HFD up- or downregulated transcripts. diet: NCD, HFD, NCD+BB, HFD+BB
2012-09-08 | E-GEOD-34154 | biostudies-arrayexpress
Project description:The purpose of this research is to determine whether the drug, Bevacizumab (a monoclonal anti VEGF-A antibody), which is approved to treat patients with metastatic colon cancer induces hyperprolactinemia (increased prolactin secretion) in humans with intact pituitary function. Past studies have shown Bevacizumab to shrink tumor size and also increase prolactin levels. The mechanism of the hyperprolactinemia might be inhibition of pituitary portal vein transport, suggesting that Bevacizumab induces prolactin secretion from normal lactotrophs in the pituitary gland.
Patients who have been treated with Bevacizumab for at least one month will be recruited to participate.
The subjects who are being treated with Bevacizumab by Dr. Stephen Wolin (a sub-investigator) will be screened by him for study eligibility. Dr. Wolin will approach eligible patients with all the information and background of the study and see if they have an interest in being consented.
If consented, there will be 2 blood draws for the research that is not part of their standard care in which 10 ml of blood is collected and prolactin, growth hormone, IGF-I, TSH, thyroxine, ACTH, and cortisol will be measured. One 5ml blood draw will occur before the administration of Bevacizumab and the second 5 ml blood draw will occur after the administration of the Bevacizumab. The investigators will then review the laboratory results. The blood tests are of the hormones of the pituitary gland to test pituitary function and see if there are any abnormalities with the secretions of the gland. Pituitary function abnormalities and hyperprolactinemia are diagnosed by looking at hormone levels in the blood and comparing them to the normal reference ranges.
This study will only involve 10 subjects and will be conducted entirely at Cedars-Sinai Medical Center.
| 2077752 | ecrin-mdr-crc
Project description:The anterior pituitary is comprised of distinct cell types that each secrete specific hormones to control a variety of biological processes including growth, metabolism, reproduction and stress responses. The anterior pituitary shows a remarkable level of cell type plasticity that allows shifts in hormone producing populations to meet organismal demands. Pituitary cell plasticity is tightly regulated and both deficiency in cell plasticity and excessive cell plasticity are associated with common pituitary pathologies. The molecular mechanisms underlying this plasticity are not well characterized but recent work has implicated the stem cell determinants and sequence-specific mRNA binding proteins of the Musashi family as regulators of adult pituitary hormone production. In this study we have sought to identify the full range of Musashi target mRNAs in the adult mouse pituitary. Using Musashi RNA immunoprecipitation we identify a cohort of 1192 mRNAs that show specific Musashi binding. These include mRNAs restricted to discrete hormone-producing cell lineages as well as mRNAs associated with stem and progenitor cells. The processes influenced by the proteins encoded by the Musashi-associated mRNAs include cellular homeostasis, protein trafficking and secretion, unfolded protein response, endocrine processes and female pregnancy. Functional analysis of validated mRNA regulatory 3' untranslated regions (3’ UTRs) reveals UTR-specific positive or negative control by the Musashi proteins within the same cellular context. Together, our findings indicate a broad role for Musashi proteins in the control of pituitary function.
2023-07-31 | GSE199098 | GEO
Project description:Obesity is tightly associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of obesity-induced fatty liver remain largely unknown.In order to identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, we performed a clustering analysis of Affymetrix arrays,which revealed that a number of mRNAs were dys-regulated in the livers of mice fed a high-fat diet (HFD), compared with mice fed a normal chow diet (ND). To identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, male C57BL/6 mice aged 8 weeks were fed a normal diet (ND) or high-fat-diet (HFD) containing 60 Kcal% of fat for 12 weeks. Then mice were sacrificed and total RNAs were isoloated from hepatic tissues. Affymetrix array hybridisation and scanning were performed using Mouse Genome 430 2.0 chips.Total RNA samples obtained from six mice per group (ND and HFD) and pooled by each of the two were used for microarray analysis.
2014-05-09 | E-GEOD-57425 | biostudies-arrayexpress
Project description:The pituitary is the vertebrate endocrine gland responsible for the production and secretion of several essential peptide hormones. These, in turn, control many aspects of an animal’s physiology and development, including growth, reproduction, homeostasis, metabolism and stress responses. In teleost fish, each hormone is presumably produced by a specific cell type. However, key details on the regulation of, and communication between these cell types are still poorly understood. We have therefore generated gene expression profiles for 2592 and 3804 individual cells from the pituitaries of female and male adult medaka (Oryzias latipes), respectively. Based on expression profile clustering, we define 15 and 16 distinct cell types in the female and male pituitary, respectively, of which nine are involved in the exclusive production of a single peptide hormone. Collectively, our data provide a high-quality reference for studies on pituitary biology and the regulation of hormone production, both in fish and in vertebrates in general.
2021-07-29 | GSE162787 | GEO