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Skeletal glucocorticoid signaling determines aging-related leptin resistance and obesity

ABSTRACT: Aging contributes to many chronic conditions, including central obesity, insulin resistance and osteoporosis, which are also critical features of glucocorticoid excess. To investigate tissue-specific sites of glucocorticoid (GC) action during aging, we disrupted GC signalling in mouse osteoblasts via transgenic overexpression of the GC-inactivating enzyme, 11β-hydroxysteroid-dehydrogenase type 2 (11β-HSD2). Wild-type mice with intact osteoblastic GC signalling developed leptin resistance, obesity and insulin resistance with aging. In contrast, transgenic (HSD2OB-tg) mice remained lean and leptin-sensitive, and were protected against aging-related hyperinsulinaemia, blunted sympathetic responses and loss of thermogenic adipose tissue. These salutary effects were independent of the osteoblast-derived factors osteocalcin and lipocalin-2. Gene expression analysis of bones from HSD2OB-tg mice indicated an early induction of pro-osteogenic and anti-adipogenic factors, and activation of a local pro-inflammatory TLR4-ZBTB16-NR1H3 network in osteoblastic cells. These findings reveal a critical role for skeletal glucocorticoid signaling in central leptin action, and in impaired metabolic function with aging

ORGANISM(S): Mus musculus

PROVIDER: GSE141448 | GEO | 2020/11/09

REPOSITORIES: GEO

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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.

Project description:Mice possessing the lethal yellow (LY) agouti mutation (C57BL/6J Ay/a) exhibit adult-onset obesity, altered metabolic regulation, and early reproductive senescence. The present study was designed to test the hypothesis that aging obese mice possess differences in expression of ovarian genes involved in reproductive function relative to age-matched lean mice. To synchronize ovarian state and exclude gonadotropin-mediated effects, 90- and 180-day old diestrous LY and lean black (C57BL/6J a/a) mice were suppressed with GnRH antagonist (Antide®) for five days, then injected with 5 IU equine chorionic gonadotropin (eCG). Complementary RNA derived from RNA extracts of whole ovarian homogenates collected 36h post eCG were run individually on CodeLink Mouse Whole Genome Bioarrays (Applied Microarrays). Unidentified genes, EST, genes whose expression was below sensitivity limits, and those with less than a 2-fold difference in expression between groups were excluded from analysis. After exclusions, 52 genes had a significant (p<0.05) difference in expression between 180-day-old obese LY and lean black mice. LY exhibited elevated ovarian expression of agouti (350x), leptin (6.5x), and numerous genes involved in cholesterol/lipid transport and metabolism, e.g., lanosterol synthase, CYP51, and steroidogenic acute regulatory protein (StAR). Fewer genes showed lower expression in LY mice, e.g. angiotensinogen. In contrast, none of these genes showed differential expression in 90-day-old LY and black mice, which are of similar body weight. Interestingly, 180-day-old LY mice had a 2-fold greater expression of 11β-hydroxysteroid dehydrogenase (HSD) type 1 and a 2-fold lesser expression of 11β-HSD type 2, differences not seen in 90-day-old mice. Consistent with altered 11β-HSD expression, ovarian concentrations of corticosterone (C) were elevated in aging (180-day) LY mice relative to black mice, but C levels were similar in young (90-day) LY and black mice. The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity, but independent of gonadotropic state.

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Skeletal glucocorticoid signaling determines aging-related leptin resistance and obesity

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