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Nutritional programming of the metabolic syndrome is associated with long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus as revealed by genome-wide DNA microarray analysis

ABSTRACT: Nutrient deficiency during perinatal development is associated with an increased risk to develop obesity, diabetes and hypertension in adulthood. However, the molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown. Given the essential role of the hypothalamus in the integration of nutritional, endocrine and neuronal cues, here we have analyzed the profile of the hypothalamus transcriptome in 180-day-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet throughout pregnancy and lactation. From a total of 26,209 examined genes, 688 were up-regulated and 309 down-regulated (P<0.003) by early protein restriction. Based on the hypothesis that variations in gene expression levels often reflect changes in gene’s activity and that transcriptional networks are at the heart of physiological functions, we identified two gene clusters regulating common cellular processes whose expression is coordinately regulated by perinatal protein restriction. The first one is constituted by several genes of the insulin signaling pathway which, additionally, act as gatekeeper genes for regulation of nutrient sensing. The second cluster encompasses a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel which, in addition, link temporal and nutritional cues to metabolism through their tight interaction with the circadian clock. Collectively, these results indicate that the programming of the hypothalamic circuits regulating energy homeostasis is a key step in the development of obesity associated with malnutrition in early life and provide a valuable starting point for the direct and systematic experimental analysis of the role of the hypothalamus in the physiopathological disturbances associated with the programming of the metabolic syndrome.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE22540 | GEO | 2010/07/02

SECONDARY ACCESSION(S): PRJNA128163

REPOSITORIES: GEO

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Project description:Nutrient deficiency during perinatal development is associated with an increased risk to develop obesity, diabetes and hypertension in adulthood. However, the molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown. Given the essential role of the hypothalamus in the integration of nutritional, endocrine and neuronal cues, here we have analyzed the profile of the hypothalamus transcriptome in 180-day-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet throughout pregnancy and lactation. From a total of 26,209 examined genes, 688 were up-regulated and 309 down-regulated (P<0.003) by early protein restriction. Based on the hypothesis that variations in gene expression levels often reflect changes in gene’s activity and that transcriptional networks are at the heart of physiological functions, we identified two gene clusters regulating common cellular processes whose expression is coordinately regulated by perinatal protein restriction. The first one is constituted by several genes of the insulin signaling pathway which, additionally, act as gatekeeper genes for regulation of nutrient sensing. The second cluster encompasses a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel which, in addition, link temporal and nutritional cues to metabolism through their tight interaction with the circadian clock. Collectively, these results indicate that the programming of the hypothalamic circuits regulating energy homeostasis is a key step in the development of obesity associated with malnutrition in early life and provide a valuable starting point for the direct and systematic experimental analysis of the role of the hypothalamus in the physiopathological disturbances associated with the programming of the metabolic syndrome. Five rats fed a control diet, and five rats fed a low-protein diet. All rats are male.

Project description:A reduction in voluntary feed intake is observed in ruminants consuming nutrient deficient diets, such as those with a low CP or P content, and has been attributed to active metabolic regulation, rather than a physical constraint. The hypothalamus is the key integrator of feed intake regulation in mammals. The objectives of this experiment were to 1) establish a model of metabolic feed intake regulation in ruminants consuming diets of variable CP and P content, and 2) determine key biochemical pathways and influential points of regulation within the hypothalamus. Merino wethers [n = 40; 23.7 ± 1.4 kg liveweight (mean ± SD)] were fed one of five dietary treatments (n = 8/treatment) for 63 days in individual pens. The treatments included targeted combinations of high (H) and low (L) CP (110 and 55 g/kg DM) and high and low P (2.5 and 0.7 g/kg DM) with 9 MJ metabolisable energy (ME) per kg DM which were fed ad libitum (UMEI; unrestricted ME intake) resulting in four experimental diets (HCP-HP-UMEI, LCP-HP-UMEI, HCP-LP-UMEI and LCP-LP-UMEI). An additional nutritional treatment (HCP-HP-RMEI) restricted intake of the HCP-HP diet to an equivalent ME intake of wethers consuming the LCP-LP-UMEI treatment. Wethers offered the LCP-HP-UMEI, HCP-LP-UMEI and LCP-LP-UMEI treatments consumed 42, 32 and 49% less total DM (P ≤ 0.05), respectively than the HCP-HP-UMEI treatment, and this was not attributable to any physical limitation of the rumen. Plasma concentrations of urea nitrogen and inorganic phosphate indicated that these nutrient deficiencies were successfully established. To assess potential mechanisms, RNA-seq was conducted on samples from the arcuate nucleus (ARC), ventromedial hypothalamus and lateral hypothalamus of the wethers, yielding a total of 301, 8 and 148 differentially expressed genes across all pairwise comparisons, respectively. The expression of NPY, AGRP and CARTPT, known for their regulatory role in mammalian feed intake regulation, had a similar transcriptional response in the ARC of wethers consuming nutrient deficient treatments and those consuming a ME restricted treatment, despite these wethers expressing behaviours indicative of satiated and hungry states, respectively. In addition, genes involved with glycolysis (TPI1), the citric acid cycle (CS, OGDH, GLUD1, GOT1) and oxidative phosphorylation (COX5A, ATP5MC1, ATP5F1B, ATP5MC3) were downregulated in the ARC of wethers fed a nutrient deficient (LCP-LP-UMEI) relative to the non-deficient (HCP-HP-UMEI) treatment. In summary, a model for voluntary feed intake restriction was established to determine genome-wide molecular changes in the hypothalamus of young ruminants.

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Nutritional programming of the metabolic syndrome is associated with long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus as revealed by genome-wide DNA microarray analysis

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