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Effects of short-term starvation on the transcriptome and lipid metabolism of epididymal white adipose tissue in mice

ABSTRACT: Beneficial effects have been reported in individuals undergoing fasting to treat excessive weight gain and obesity. To better understand the effects of starvation on the transcriptome and lipid metabolism of white adipose tissue, we established a mouse model of 24-hour fasting using wild type C57BL/6J mice, and performed RNA-seq analysis of the white adipose tissue from the epididymis of fasted mice and control mice. Compared with the control fed mice, these fasted mice showed suppressed lipid synthesis and inhibited insulin signaling, while the lipolysis and gluconeogenesis were enhanced to maintain blood sugar stability. Specifically, the fasted mice had reduced volume of adipose tissues, increased levels of serum NEFA and ANP. In epididymal white adipose tissue, starvation increased the NEFA content, up-regulated the mRNA levels of Atgl, Adrb2, Anp, and Npr1, and promoted the phosphorylation of Hsl. Notably, bioinformatics analysis of the RNA-seq data showed that 24-hour fasting-induced alterations in lipid metabolism was associated with suppressed AMPK signaling and enhanced PPAR signaling in white adipose tissue, which was verified by quantitative PCR. Collectively, these findings supported that starvation promoted the conversion of energy-supplying substrates from glucose to fat. Our work sheds new light on harnessing the plasticity of adipose tissues and the AMPK/PPAR signaling pathways to develop potential strategies to combat obesity and other glucose/lipid metabolisms-associated human diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE207913 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis. 6 week-old male FVB mice were fasted for 0, 12, 24, 48 or 72 hours before sacrifice (N = 5 per group). From each mouse total RNA was isolated from five organs - liver, small intestine, kidney, brain, and calf muscle. Five microarrays per experimental condition (five tissues, five timepoints) were performed. We used a common reference design. The single common-reference sample was a pool of equal amounts of RNA from all the samples investigated, including additional samples from 5 mice that were fasted for 48 hours and supplemented with vitamin B complex after 24 and 36 hours of fasting.

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Effects of short-term starvation on the transcriptome and lipid metabolism of epididymal white adipose tissue in mice

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