Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. Brain cell membranes of vertebrates have high concentrations of long-chain polyunsaturated fatty acids (LCPUFAs) of the n-3 and n-6 series, mainly DHA (22:6 n-3) and arachidonic acid (AA; 20:4 n-6) (1.Alessandri J-M. Guesnet P. Vancassel S. Astorg P. Denis I. Langelier B. Aïd S. Poumès-Ballihaut C. Champeil-Potokar G. Lavialle M. Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life.Reprod. Nutr. Dev. 2004; 44: 509-538Crossref PubMed Scopus (233) Google Scholar). The accretion of DHA during perinatal development is considered to be essential for the proper functioning of the mammalian central nervous system, especially in primates. The functional role of DHA has been mainly investigated in animal models, mainly rodents, deprived of any dietary source of n-3 PUFAs during perinatal development. Dietary deficiency of n-3 PUFAs leads to decreased brain content of DHA, which is accompanied by severe neurosensorial impairments (learning, memory, and anxiety) that have been linked to changes in neurotransmission processes (2.Chalon S. Omega-3 fatty acids and monoamine neurotransmission.Prostaglandins Leukot. Essent. Fatty Acids. 2006; 75: 259-269Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar). Neurotransmission is very energy consuming, particularly the restoration of membrane potential by Na-K-ATPase after an action potential, which consumes about 50% of brain ATP (3.Leybaert L. De Bock M. Van Moorhem M. Decrock E. De Vuyst E. Neurobarrier coupling in the brain: adjusting glucose entry with demand.J. Neurosci. Res. 2007; 85: 3213-3220Crossref PubMed Scopus (43) Google Scholar). Thus, impairment of neurotransmission in animals fed an n-3 PUFA-deficient diet could be due in part to suboptimal brain energy metabolism. Early work relating n-3 PUFAs and brain energy metabolism came from studies by Bourre's group (4.Gerbi A. Zerouga M. Debray M. Durand G. Chanez C. Bourre J.M. Effect of dietary alpha-linolenic acid on functional characteristic of Na+/K(+)-ATPase isoenzymes in whole brain membranes of weaned rats.Biochim. Biophys. Acta. 1993; 1165: 291-298Crossref PubMed Scopus (44) Google Scholar), which demonstrated that activity of brain Na-K-ATPase was 40% lower in nerve terminals of rats made deficient in n-3 PUFAs. This change paralleled significantly lower performance on learning tasks. Later on, Ximenes and colleagues (5.Ximenes da Silva A. Lavialle F. Gendrot G. Guesnet P. Alessandri J-M. Lavialle M. Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids.J. Neurochem. 2002; 81: 1328-1337Crossref PubMed Scopus (130) Google Scholar) demonstrated that animals fed an n-3 PUFA-deficient diet exhibited 50% lower glucose utilization in cerebral cortex and hippocampus by using autoradiographic 2-deoxyglucose method, and 25–30% lower rate of oxidative phosphorylation by measuring cytochrome oxidase activity (5.Ximenes da Silva A. Lavialle F. Gendrot G. Guesnet P. Alessandri J-M. Lavialle M. Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids.J. Neurochem. 2002; 81: 1328-1337Crossref PubMed Scopus (130) Google Scholar). In a recent study, we confirmed that rats on an n-3 PUFA-deficient diet exhibited lower brain uptake of glucose (6.Hennebelle M. Harbeby E. Tremblay S. Chouinard-Watkins R. Pifferi F. Plourde M. Guesnet P. Cunnane S.C. Challenges to determining whether DHA can protect against age-related cognitive decline.Clin. Lipidol. 2015; 10: 91-102Crossref Scopus (10) Google Scholar). Such a decrease can, at least partly, explain the behavioral changes observed during n-3 PUFA deficiency. Brain glucose hypometabolism can occur in healthy older people in the absence of any measurable cognitive decline (7.Nugent S. Tremblay S. Chen K.W. Ayutyanont N. Roontiva A. Castellano C-A. Fortier M. Roy M. Courchesne-Loyer A. Bocti C. et al.Brain glucose and acetoacetate metabolism: a comparison of young and older adults.Neurobiol. Aging. 2014; 35: 1386-1395Crossref PubMed Scopus (82) Google Scholar). This brain glucose hypometabolism seems to be more marked during age-related cognitive decline, such as Alzheimer disease (AD) (8.Kalpouzos G. Eustache F. de la Sayette V. Viader F. Chételat G. Desgranges B. Working memory and FDG-PET dissociate early and late onset Alzheimer disease patients.J. Neurol. 2005; 252: 548-558Crossref PubMed Scopus (66) Google Scholar), and there is a positive association between glucose hypometabolism and cognitive decline during mild cognitive impairment or in AD patients (9.Landau S.M. Harvey D. Madison C.M. Koeppe R.A. Reiman E.M. Foster N.L. Weiner M.W. Jagust W.J. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI.Neurobiol. Aging. 2011; 32: 1207-1218Crossref PubMed Scopus (507) Google Scholar, 10.Habeck C. Risacher S. Lee G.J. Glymour M.M. Mormino E. Mukherjee S. Kim S. Nho K. DeCarli C. Saykin A.J. et al.Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer's disease.Brain Imaging Behav. 2012; 6: 568-583Crossref PubMed Scopus (43) Google Scholar). Brain glucose uptake is highly dependent on glucose transporter (GLUT) activity and especially GLUT1, which is localized in both endothelial cells of the blood-brain barrier and astrocytes. Interestingly, n-3 PUFA-deficient rats have lower expression of GLUT1 at both the gene and protein levels (11.Harbeby E. Jouin M. Alessandri J-M. Lallemand M-S. Linard A. Lavialle M. Huertas A. Cunnane S.C. Guesnet P. n-3 PUFA status affects expression of genes involved in neuroenergetics differently in the fronto-parietal cortex compared to the CA1 area of the hippocampus: effect of rest and neuronal activation in the rat.Prostaglandins Leukot. Essent. Fatty Acids. 2012; 86: 211-220Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 12.Pifferi F. Roux F. Langelier B. Alessandri J-M. Vancassel S. Jouin M. Lavialle M. Guesnet P. (n-3) polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats.J. Nutr. 2005; 135: 2241-2246Crossref PubMed Scopus (103) Google Scholar). The effect was specific to this GLUT because no change in neuronal GLUT3 expression was observed. Altogether, these results suggest an important role of n-3 PUFAs in the regulation of brain glucose in part due to the regulation of the endothelial and Interestingly, in studies on brain endothelial cells of DHA that of DHA to the both glucose transport activity by and GLUT1 F. Jouin M. Alessandri J-M. Roux F. N. Langelier B. Lavialle M. Cunnane S. Guesnet P. n-3 long-chain fatty acids and regulation of glucose transport in of brain endothelial PubMed Scopus Google Scholar, F. Jouin M. Alessandri J.M. Roux F. N. Denis I. Lavialle M. Guesnet P. n-3 Fatty acids brain glucose transport in endothelial cells of the blood-brain Leukot. Essent. Fatty Acids. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). DHA dietary intake may help prevent or correct the glucose hypometabolism observed during age-related cognitive decline E. M. Tremblay S. A. Cunnane S.C. Omega-3 fatty energy and brain function during Leukot. Essent. Fatty Acids. 2006; 75: Full Text Full Text PDF PubMed Scopus Google Scholar). In PUFA supplementation studies confirmed the between PUFA and expression of brain energy metabolism genes and ATP K. A. L. G. The role of n-3 polyunsaturated fatty acids in brain: of brain gene expression by dietary n-3 fatty 2002; PubMed Scopus Google Scholar). In and colleagues D. S. K. acid the age-related impairment of the coupling between neuronal activation and functional cerebral a PET in Res. PubMed Scopus Google Scholar) demonstrated that with DHA for to very dietary to cerebral a linked to neuronal the of these we that a dietary source of n-3 DHA cognitive performance by brain glucose which we tested in nonhuman primates. The mouse (Microcebus is a primate from with a of specific that a to the effects of dietary on behavioral and cognitive in primates. In is is and behavioral and cognitive can be assessed with specific and in S. S. A. G. M. D. et mouse a primate for Res. 2012; PubMed Scopus Google Scholar). is in determining whether dietary PUFAs brain in as the dietary of n-3 in are the levels of in P. N. S. N. P. S. Dietary and of n-6 and n-3 PUFA in adult and 2004; PubMed Scopus Google Scholar). the effect of n-3 LCPUFA supplementation for on cognitive, and performance in adult and mouse lemurs S. F. Pifferi F. Effect of dietary supplementation on the exploratory status and memory of the mouse a Brain Res. 2012; PubMed Scopus Google Scholar, N. Jouin M. A. Guesnet P. Alessandri J-M. F. Pifferi F. Omega-3 fatty acids from lower cognitive and activity in a 2011; 6: PubMed Scopus Google Scholar). for the first time in a nonhuman primate that n-3 PUFA supplementation decreased anxiety and activity and concomitantly cognitive The n-3 diet in the exploratory the memory of these The very effect of PUFA supplementation in animals S. F. Pifferi F. Effect of dietary supplementation on the exploratory status and memory of the mouse a Brain Res. 2012; PubMed Scopus Google Scholar) on and cognitive to at an age in the present on young adult mouse lemurs a of n-3 to the for the adult A. la Scholar). In the present study, we compared the effects of a supplementation with n-3 or with fatty acids on brain glucose metabolism assessed by positron emission tomography In we a memory task from the Barnes to memory and an open-field task to exploratory and both of which we have in mouse lemurs S. S. A. G. M. 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Essent. Fatty Acids. 81: Full Text Full Text PDF PubMed Scopus Google Scholar). The of n-3 PUFAs in n-3 LCPUFA-supplemented animals at the of both n-6 PUFAs and fatty changes to the between n-3 and n-6 PUFAs in the of n-3 LCPUFA-supplemented animals with a of of compared with in the The dietary of PUFAs be to to for of the dietary fatty acid Nutr. PubMed Scopus Google Scholar). Our that n-3 LCPUFA-supplemented mouse lemurs exhibited both lower anxiety in the open-field task and in the Barnes in N. Jouin M. A. Guesnet P. Alessandri J-M. F. Pifferi F. Omega-3 fatty acids from lower cognitive and activity in a 2011; 6: PubMed Scopus Google Scholar) and also that the may be the to higher in the Barnes of the n-3 animals of and lower time to the correct may be due to lower in a higher of in comparison with the Thus, the of performance between the seems to more on anxiety on memory have been made in rodents, which exhibited an of anxiety n-3 PUFA dietary deficiency M. E. of in Res. PubMed Scopus Google Scholar, I. M. de D. Bourre J.M. supplementation behavioral and by n-3 polyunsaturated fatty acid deficiency in Res. Full Text Full Text PDF PubMed Google Scholar) and decreased anxiety DHA supplementation M. E. of in Res. PubMed Scopus Google Scholar). recent that supplementation can in a of C. B. D. S.M. de et and cognitive in Neurosci. 2014; PubMed Scopus Google Scholar). is that lower anxiety cognitive of mouse lemurs on the an that is by a role of DHA in anxiety in R. M. Dietary intake of and and and anxiety in Nutr. PubMed Scopus Google Scholar). The of the present is the that brain glucose uptake is higher during dietary supplementation of n-3 of the brain we This in in F. Jouin M. Alessandri J-M. Roux F. N. Langelier B. Lavialle M. Cunnane S. Guesnet P. n-3 long-chain fatty acids and regulation of glucose transport in of brain endothelial PubMed Scopus Google Scholar, F. Jouin M. Alessandri J.M. Roux F. N. Denis I. Lavialle M. Guesnet P. n-3 Fatty acids brain glucose transport in endothelial cells of the blood-brain Leukot. Essent. Fatty Acids. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) in which higher expression of the isoforms of GLUT1 was linked to higher brain n-3 PUFA also the made by during very supplementation studies in and In and colleagues the cerebral to cognitive in healthy young 2012; PubMed Scopus Google Scholar) that the of a supplementation with in a in the concentrations of and levels of of cerebral during cognitive tasks. In young and and colleagues D. S. K. acid the age-related impairment of the coupling between neuronal activation and functional cerebral a PET in Res. PubMed Scopus Google Scholar) demonstrated that to with a diet in a in cerebral to these studies the of dietary DHA in the coupling between neuronal activation and cerebral The present that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism. is that n-3 on brain glucose uptake and metabolism effects on blood-brain barrier glucose transport on GLUT1 expression and neuronal glucose and brain energy metabolism. we demonstrated in rats that GLUT1, the GLUT for glucose entry the brain at both the endothelial cells and is by dietary n-3 PUFA intake the neuronal transporter of is F. Roux F. Langelier B. Alessandri J-M. Vancassel S. Jouin M. Lavialle M. Guesnet P. (n-3) polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats.J. Nutr. 2005; 135: 2241-2246Crossref PubMed Scopus (103) Google Scholar, F. Jouin M. Alessandri J-M. Roux F. N. Langelier B. Lavialle M. Cunnane S. Guesnet P. n-3 long-chain fatty acids and regulation of glucose transport in of brain endothelial PubMed Scopus Google Scholar, F. Jouin M. Alessandri J.M. Roux F. N. Denis I. Lavialle M. Guesnet P. n-3 Fatty acids brain glucose transport in endothelial cells of the blood-brain Leukot. Essent. Fatty Acids. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). PUFAs are also to the expression of genes in energy metabolism in the brain such as ATP cytochrome cytochrome or K. A. L. G. The role of n-3 polyunsaturated fatty acids in brain: of brain gene expression by dietary n-3 fatty 2002; PubMed Scopus Google Scholar). brain DHA is with lower activity of oxidative such as cytochrome oxidase (5.Ximenes da Silva A. Lavialle F. Gendrot G. Guesnet P. Alessandri J-M. Lavialle M. Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids.J. Neurochem. 2002; 81: 1328-1337Crossref PubMed Scopus (130) Google Scholar). in n-3 PUFA supplementation demonstrated a brain between n-3 PUFA and polyunsaturated fatty acids and cerebral glucose metabolism in Leukot. Essent. Fatty Acids. Full Text Full Text PDF PubMed Scopus Google Scholar), that the between PUFA and glucose metabolism could also in This has been confirmed in a the between and brain of AD in [18F]FDG brain PET and In this study, higher of was with lower brain glucose metabolism a between fatty acids and brain glucose metabolism L. M. S. E. N. et intake and brain of Alzheimer's disease in a 2014; Scholar). this a in S. E. Pifferi F. Fortier M. Tremblay S. E. Cunnane S.C. Brain and glucose metabolism in the healthy Leukot. Essent. Fatty Acids. 2011; 85: Full Text Full Text PDF PubMed Scopus Google Scholar) assessed the effect of a n-3 PUFA supplementation on cerebral glucose metabolism. between healthy and supplemented people was a of this was the of the dietary The present study, during a in a is to the role of n-3 PUFAs in the regulation of brain glucose metabolism. DHA dietary intake may help to prevent the glucose hypometabolism observed during age-related cognitive decline, on the of a and at the onset of glucose In this we demonstrated that the effects of n-3 LCPUFA supplementation on and anxiety) is age dependent S. F. Pifferi F. Effect of dietary supplementation on the exploratory status and memory of the mouse a Brain Res. 2012; PubMed Scopus Google Scholar, N. Jouin M. A. Guesnet P. Alessandri J-M. F. Pifferi F. Omega-3 fatty acids from lower cognitive and activity in a 2011; 6: PubMed Scopus Google Scholar). in lemurs that n-3 PUFA supplementation is with lower anxiety and higher cognitive performance at young age N. Jouin M. A. Guesnet P. Alessandri J-M. F. Pifferi F. Omega-3 fatty acids from lower cognitive and activity in a 2011; 6: PubMed Scopus Google Scholar) the age-related in lemurs at age S. F. Pifferi F. Effect of dietary supplementation on the exploratory status and memory of the mouse a Brain Res. 2012; PubMed Scopus Google Scholar) and functional of the brain during aging could explain effects of fatty acids on in function of animals may from young animals due to age-related changes in n-3 PUFA metabolism as by animal studies a decrease in the and of PUFAs during aging S. S. D. The role of polyunsaturated fatty acids in the aging neuronal Aging. 2002; PubMed Scopus Google Scholar). The present results demonstrate for the first time that n-3 LCPUFA supplementation can to glucose entry and utilization the primate Our suggest that increasing n-3 LCPUFA dietary to for may brain glucose utilization in Thus, n-3 LCPUFA the onset of could help prevent the glucose hypometabolism observed during suggest that and of the supplementation is the the positive and effect of n-3 LCPUFA dietary supplementation on brain particularly brain glucose the supplementation be on a very be early to prevent the effects of as by behavioral studies S. F. Pifferi F. Effect of dietary supplementation on the exploratory status and memory of the mouse a Brain Res. 2012; PubMed Scopus Google Scholar, N. Jouin M. A. Guesnet P. Alessandri J-M. F. Pifferi F. Omega-3 fatty acids from lower cognitive and activity in a 2011; 6: PubMed Scopus Google Scholar).

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