Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

Abstract

We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ϳ50% increase in serine de novo synthesis. Pyruvate was the primary (ϳ90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/Sadenosylhomocysteine ratio and lower cystathione ␤-synthase and cystathionine ␥-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.The metabolic and biochemical impact of qualitative and quantitative changes in dietary protein intake continues to be of interest because of their implications for public health and because of a number of studies showing a strong relationship between protein intake during pregnancy with cardiovascular function, hypertension, and glucose intolerance in the offspring (1-3). Studies in humans, primarily focused on whole body protein, nitrogen metabolism, and protein accretion, show that both high and low protein intake can impact these processes (4 -7). However, how humans adapt to protein deprivation or the biochemical mechanisms involved has not been examined. In the context of pregnancy, both high protein intake (in humans) and protein restriction in rodents have been shown to cause fetal metabolic programming and consequently altered physiological response in the offspring in adulthood (8 -11). In the rodent, dietary protein restriction during pregnancy results in growth retardation, impaired beta cell function and mass, impaired insulin sensitivity, hypertension, and other pathological responses in the offspring (1, 2). These have been associated with a change in the hypothalamic-pituitary-adrenal axis, changes in the renin-angiotensin system, and ...

FGF21 is an endocrine signal of protein restriction

“…The underlying reason for this differential regulation remains unclear, but it seems likely that hepatic metabolism is uniquely different in settings of protein versus energy restriction. For instance, our data are consistent with previous work (33) demonstrating that protein restriction triggers adaptive increases in hepatic amino acid synthesis and decreases in hepatic amino Figure 4. LP-induced increases in circulating FGF21 depend on both GCN2 and PPARα signaling.…”

“…Although there was no effect of diet on final body weight or body weight gain, 14 days of LP diet increased body adiposity (control: 18.2% ± 0.005%; LP: 20.3% ± 0.008% fat, P = 0.034). Consistent with a state of dietary protein restriction (33), LP diet altered circulating amino acid concentrations, reduced hepatic leucine oxidation, Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction.…”

Premature Birth and Disease Programming. Contribution of Neonatal Intensive Care

“…Это также сопровождается нарушением связей в системе гипофиз -гипоталамус -кора надпочечников, что способствует изменению активности ренин-ангиотензи-новой системы, концентрации циркулирующих катехолами-нов и плотности адренорецепторов в тканях [12,28]. Более того, у небеременных крыс изокалорическое ограничение белка в диете приводит к изменению экспрессии генов, связанных с клеточной дифференциацией, транспортом и метаболическими процессами в печени [29]. Эти наблю-дения указывают на важность преконцепционного програм-мирования, доказанного на крысах.…”

“…Эти наблю-дения указывают на важность преконцепционного програм-мирования, доказанного на крысах. Существуют данные, что изокалорическое ограничение поступления белка к матери может повлиять на синтез серина, который также является важным источником поступления метильных групп in vivo [29]. Пока не ясно, могут ли новорожденные отвечать подоб-ным образом на ограничение поступления белка.…”

0476 Low protein diets produce divergent effects on energy balance

“…These include imbalances in plasma and brain amino acid concentrations in rats [15][16][17] , modulation of energy sensors in the hypothalamus and anterior piriform cortex in rats 18 , and increased activity in the reward areas such as the orbitofrontal cortex and striatum in humans 11 . Low protein diets also enhance energy expenditure in rodents 17,[19][20][21][22] , however, the underlying mechanisms are poorly understood.…”