Nuclear Magnetic Resonance-Based Blood Metabolic Profiles of Rats Exposed to Short-Term Caloric Restriction

Abstract

Caloric restriction increases life-span of a number of organisms. The relationship between the increase in life-span and the extent of caloric restriction, however, varies among species. The underlying mechanisms are yet unknown, but appear to be related to changes in metabolism. In order to investigate the metabolic response of caloric restriction of rats, here is presented the first nuclear magnetic resonance (NMR) spectroscopy-based study of how blood metabolite profiles are influenced by graded levels of caloric restriction. The study involved three groups of obese Downloaded by [New York University] at 00:38 06 July 2015 2 rats exposed to 0, 20, and 40 percent caloric restriction for five days. Blood serum from each individual was analyzed by 1 H NMR and the resulting spectra were subjected to multivariate analysis by unsupervised principal component analysis and supervised orthogonal-partial least square discriminant analysis. The analyzes revealed that a response to caloric restriction was present at 20 percent caloric restriction. The metabolites that distinguished the profiles at 20 percent restriction deviated from those at 40 percent restriction. The changes induced by caloric restriction were most clearly observed as an increased level of 3-hydroxybutyrate, and decreased levels of lipids and pyruvate. The metabolic responses of rats exposed to caloric restriction are in good agreement with a switch in metabolism from anabolic pathways towards fatty acid catabolism and gluconeogenesis, which is consistent with previous observations for mice.

Calorie restriction and its impact on gut microbial composition and global metabolism

“…The CR intervention (20% and 40% restricted diet for five days) was associated with elevated plasma levels of trimethylamine-N-oxide (TMAO) and reduced levels of trimethylamine (TMA), choline, and glycerophosphocholine [67]. Consistently, changes in the levels of aliphatic amines, including TMA, dimethylamine (DMA), and TMAO occurred in the urine [22].…”

“…The levels of pyruvate in blood were significantly decreased after CR and fasting intervention [67,90]. Pyruvate kinase enzyme levels decreased in liver samples of mice with 30% restricted CR undergoing a step-down feeding regime [60].…”

“…Alterations in blood lipoproteins has been widely shown in the studies of CR in mouse, rat, dog, and monkey models [13,[69][70][71], as well as in human clinical studies [14,72]. Changes in lipoproteins were manifested by the increase in blood and fecal high density lipoprotein (HDL) levels and reduction in low density lipoprotein (LDL) and very lowdensity lipoprotein (VLDL) levels [13,15,22,48,49,67]. Lower levels of LDL and VLDL are associated with a lowered risk of cardiovascular disease.…”

“…Glyceryl derivatives of lipids and phospholipid choline in liver [60] and serum [16,71] were significantly decreased after CR intervention, such as phosphatidylcholine (PC) (18:0/20:4), sphingomyelin (SM) (d18:0/16:1), and some lysoPCs (C16:1, C16:0, C17:0, C18:2, C18:1, C18:0, C20:4, C20:3, and C22:6). Many of these compounds are involved in fatty acid catabolism, where triacylglycerols and phospholipids become hydrolyzed into non-esterified fatty acids, glycerol, and phosphocholine [67]. Such metabolic phenotypes were observed in some pathological models.…”

“…FFA related metabolites were also altered after CR intervention. FFA oxidation is the major fuel for ketone bodies and increased levels of the circulating ketone bodies, acetoacetate and 3-hydroxybutyrate were observed to be simultaneously elevated after CR and were high in the subjects with higher percentage of weight loss [15,48,67,71,80]. The serum level of carnitine was also increased with CR intervention (40% dietary reduction for 12 weeks), greatly influencing fatty acid oxidation in vivo [70].…”