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The effects of exercise on gene expression in abdominal subcutaneous adipose tissue

ABSTRACT: Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise on health can lead to new therapies for disease. We find that exercise training in humans causes profound changes in subcutaneous adipose tissue (scWAT) gene expression, including genes encoding secreted proteins. In addition, we used our previously published microarray dataset derived from scWAT from mice housed in static cages (sedentary controls) or mice housed in cages with running wheels for 11 days. Genes that were significantly changed by exercise training in humans and mice were further selected by annotation for Extracellular Space in Gene Ontology. Of these genes, the most significantly correlated with the total wheel running distance in the trained mice was Tgfb2. We validated that exercise training increased TGFB2 mRNA in scWAT of human subjects using RT-qPCR. This led us to hypothesize that TGF-β2 is an exercise-induced adipokine. To determine the therapeutic potential and mechanism for increased TGF-β2, we investigated mouse models of exercise training and obesity. Our findings indicate that exercise training improves metabolism through inter-organ communication with fat via a TGF-β2 signaling, providing a novel mechanism for counteracting metabolic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116801 | GEO | 2018/11/21

REPOSITORIES: GEO

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Project description:Exercise improves brain function enhancing neuronal plasticity and cognitive enhancement. For voluntary resistance wheel running (RWR) exercise, with a load of 30% of body weight, we reported enhancement of neurogenesis and spatial memory associated with hippocampal brain-derived neurotrophic factor (BDNF) signaling compared to wheel running (WR) without a load (Lee et al., 2012; Lee et al., 2013). Despite these new evidences, mechanisms for RWR-induced improvement of hippocampal function remained to be clarified. In the present study, we have utilized the high-throughput DNA microarray approach to gain deep insight into molecular mechanisms underlying these changes that could be novel targets of RWR-induced hippocampal plasticity. To do so, whole genome (4x44K) high-density oligonucleotide microarrays were used to monitor the expression level of gene transcripts in the hippocampus of rats voluntary running for 4 weeks in comparison with sedentary animals. These rats showed a significant decrease in average running distance although average work levels immensely increased 12-fold in the RWR group, resulting in muscular adaptation for the fast-twitch plantaris muscle. DNA microarray analysis revealed that 122 (sedentary x WR) and 157 (sedentary x RWR) genes were up-regulated (> 1.5-fold change) as compared with 97 (sedentary x WR) and 467 (sedentary x RWR) down-regulated genes (< 0.75-fold change). Functional categorization using the Ingenuity Pathway Analysis (IPA) revealed expression pattern changes in the major categories of disease and disorders, molecular functions and physiological system development and function. Among these, RWR up-regulated genes such as NFATc1, AVPR1A and FGFR4, which are crucial role for neuronal development and its functions. The down-regulated inflammatory cytokines (IL1B, IL10, IL2RA, TNF) and chemokines (CXCL1, CXCL9, CXCL10, CCL2, CCL13, CCR4) might be important to neuronal dysfunction and vulnerability. Taken together, these gene candidates are suggested to play a critical role in hippocampal plasticity. This is a first study presenting not only new information into the voluntary RWR influenced transcriptome in the rat hippocampus, but also provides a hypothesis for the RWR influenced enhancement in brain function. 10-week-old male Wistar rats were randomly allocated to three groups: (1) housed in standard cages and used as non-active controls (sedentary, n = 10), (2) wheel running with no resistance (WR, n = 8), and (3) housed in cages with resistance running wheels with an adjustable resistance (RWR, n = 8). Rats of both running wheel groups (WR and RWR) were housed individually and had free access to a specially designed running wheel apparatus for 24 h/day. Between 08:00 and 12:00 on the day after the final day of exercise, the animals were immediately decapitated using a guillotine. The hippocampi were rapidly dissected, snap frozen in liquid nitrogen and stored at —80°C prior to further analysis. The deep-frozen hippocampi were transferred to a precooled (in liquid nitrogen) mortar and ground with a pestle to a very fine powder with liquid nitrogen. Total RNA was extracted and validated followed by checking subsequently synthesized cDNA by RT-PCR. A rat 4x44K whole genome oligo DNA microarray chip was used for global gene expression analysis using the hippocampi. Fluorescently labeled targets of Sed, WR and RWR samples were hybridized to the same microarray slide with 60-mer probes. A flip labeling (dye swap or reverse labeling with Cy3 and Cy5 dyes) procedure was followed to nullify the dye bias associated with unequal incorporation of the two Cy dyes into cDNA. Briefly, to select differentially expressed genes, we identified genes that were up regulated in chip 1 (Cy3/Cy5 label for sedentary and WR, respectively) but down regulated in chip 2 (Cy3/Cy5 label for WR and sedentary, respectively) for the hippocampus. The same selection criteria were applied for chips 3-4 (sedentary and RWR). Hybridization and wash processes were performed according to the manufacturer’s instructions, and hybridized microarrays were scanned using an agilent microarray scanner. The functional and network analysis were generated through the use of IPA (Ingenuity® Systems, www.ingenuity.com). To validate gene changes in array data and test the BDNF signaling-related molecules and expression of select transcripts were determined by quantitative real-time RT-PCR.

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The effects of exercise on gene expression in abdominal subcutaneous adipose tissue

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