Nutritional Status, Cognition, and Survival

Although adequate nutrition is essential for optimal neural activity and survival, mild energy restriction may improve cognition and prolong longevity. Energy status is monitored by the cellular AMP-activated protein kinase (AMPK) system, whereas leptin regulates total energy balance. We investigated the roles of AMPK and leptin in cognition and survival under diet restriction (DR). Hippocampal AMPK activity increases with energy restriction. Modest activation (DR to 60%) induces neurogenesis and improves cognition. However, DR to 40% augmented AMPK activity, reduced cognition and catecholamines, and increased neural apoptosis and mortality. Leptin signaling is preserved only in DR to 60%, countering the effects of AMPK “overactivation” by preventing neuroapoptosis, restoring noradrenergic activity and behavioral performance, and increasing longevity. The balance between leptin and AMPK is crucial in determining neuronal fate, cognitive ability, and survival. Should these findings extend to Man, then controlled activation of AMPK may improve neurodegenerative diseases, and leptin may have a new role in treating stress-associated malnutrition. Although adequate nutrition is essential for optimal neural activity and survival, mild energy restriction may improve cognition and prolong longevity. Energy status is monitored by the cellular AMP-activated protein kinase (AMPK) system, whereas leptin regulates total energy balance. We investigated the roles of AMPK and leptin in cognition and survival under diet restriction (DR). Hippocampal AMPK activity increases with energy restriction. Modest activation (DR to 60%) induces neurogenesis and improves cognition. However, DR to 40% augmented AMPK activity, reduced cognition and catecholamines, and increased neural apoptosis and mortality. Leptin signaling is preserved only in DR to 60%, countering the effects of AMPK “overactivation” by preventing neuroapoptosis, restoring noradrenergic activity and behavioral performance, and increasing longevity. The balance between leptin and AMPK is crucial in determining neuronal fate, cognitive ability, and survival. Should these findings extend to Man, then controlled activation of AMPK may improve neurodegenerative diseases, and leptin may have a new role in treating stress-associated malnutrition. Since the Garden of Eden and the trees of knowledge and life, the connection between food, cognition, and survival has been recognized. Today, nutritional status is a well accepted regulator of neural function and longevity. Studies have shown that mild energy restriction (to 60% of control) improves cognitive function, whereas severe restriction (to 40%) prejudices it (1Pitsikas N. Algeri S. Neurobiol. Aging. 1992; 13: 369-373Crossref PubMed Scopus (121) Google Scholar, 2Avraham Y. 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Cellular energy status is monitored and controlled by the 5′-AMP-activated protein kinase (AMPK) 2The abbreviations used are: AMPKAMP-activated protein kinaseALad libitumDRdiet restrictionHPLChigh performance liquid chromatographyAICAR5-aminoimidazole-4-carboxamide ribonucleoside.2The abbreviations used are: AMPKAMP-activated protein kinaseALad libitumDRdiet restrictionHPLChigh performance liquid chromatographyAICAR5-aminoimidazole-4-carboxamide ribonucleoside. system. AMPK is allosterically activated by 5′-AMP, which accumulates following ATP hydrolysis (18Hardie D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (960) Google Scholar, 19Hardie D.G. Carling D. Eur. J. Biochem. 1997; 246: 259-273Crossref PubMed Scopus (1138) Google Scholar). Recent studies have demonstrated that this activation regulates intracellular signaling pathways involved in cellular survival and apoptotic cell death (20Campas C. Lopez J.M. Santidrian A.F. Barragan M. Bellosillo B. Colomer D. Gil J. 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Nature. 2004; 428: 569-574Crossref PubMed Scopus (1332) Google Scholar). AMP-activated protein kinase ad libitum diet restriction high performance liquid chromatography 5-aminoimidazole-4-carboxamide ribonucleoside. AMP-activated protein kinase ad libitum diet restriction high performance liquid chromatography 5-aminoimidazole-4-carboxamide ribonucleoside. Leptin is an adipokinin hormone that plays a central role in food intake and energy balance, mainly through its hypothalamic receptors (25Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2108) Google Scholar, 26Chua Jr., S.C. Chung W.K. Wu-Peng X.S. Zhang Y. Liu S.M. Tartaglia L. Leibel R.L. Science. 1996; 271: 994-996Crossref PubMed Scopus (1033) Google Scholar, 27Montague C.T. Farooqi I.S. Whitehead J.P. Soos M.A. Rau H. Wareham N.J. Sewter C.P. Digby J.E. Mohammed S.N. Hurst J.A. Cheetham C.H. Earley A.R. Barnett A.H. Prins J.B. O'Rahilly S. 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Linking systemic energy balance (appetite and autonomic nervous activity) with cellular AMP concentrations makes obvious “biological sense.” There are also leptin receptors in the hippocampus, suggesting a possible role for leptin signaling in cognition. The involvement of leptin and AMPK in brain function has heretofore not been addressed and is the subject of this report. We have used diet restriction (DR) tools to define the processes underlying the effects of nutrition on cognition and survival. Our results indicate that AMP kinase responds to nutritional status and modulates cognitive ability by affecting the balance between neurogenesis and neuroapoptosis. Leptin reverses the deleterious effects of severe DR, consistent with its role as a “survival” (anti-apoptotic) hormone under such stress conditions. Cells and Reagents—PC12 cells were kindly provided by O. Meyuhas, Department of Biochemistry, Faculty of Medicine, Hebrew University-Hadassah Medical School, Jerusalem. These cells were grown either in Dulbecco's modified Eagle's medium supplemented with 8% horse serum, 8% fetal bovine serum, glutamine, and gentamicin or with 1% horse serum in the presence of nerve growth factor (50 ng/ml), which causes the cells to differentiate. Murine leptin was provided by A. Gertler. AICAR was obtained from Toronto Research Chemicals. Mice—The experimental protocol was approved by the institutional committee for the use of animals, number MD-89.52-4. 8-10-week-old female Sabra mice (29-32g) were assigned at random to different groups of 10 mice. The food provided was Purina chow. Diet Restriction—Control mice received food ad libitum (AL). Diet-restricted mice received a diet of 57 kCal/week/mouse (2.16 g/day/mouse) as 60% of the requirement or 38 kCal/week/mouse (1.44 g/day/mouse) for 40% DR. DR was carried out for 10 days. Behavioral tests were performed using the eight-arm spatial maze during the second week of the experiment. During the behavioral tests, half the animals in each group were treated with AICAR (1-2 mm equal to 258-516 mg/kg) or leptin (1 mg/kg) and the other half with saline. The mice were treated with a dose of 1 mg/kg leptin based on previous experiments. We have evaluated the effect of 100-2000 μg/kg of body weight (intraperitoneal) on cognitive function and found that 1000-2000 μg/kg were the optimal dosages, whereas lower concentrations impaired it. 3E. M. Berry and Y. Avraham, unpublished observations. This dose is likely to lead to leptin concentrations in the high physiological range (∼100 ng/ml) in the injected animals (characteristic of obese subjects), which declined to lower concentrations after 24 h (29Dridi S. Williams J. Bruggeman V. Onagbesan M. Raver N. Decuypere E. Djiane J. Gertler A. Taouis M. Domest. Anim. Endocrinol. 2000; 18: 325-335Crossref PubMed Scopus (35) Google Scholar). AICAR and leptin were dissolved and diluted in saline. All administrations were given intraperitoneally in a volume of 0.1 ml/mouse. Mice were sacrificed by decapitation after the behavioral tests, and the hippocampi were frozen at -70 °C. RT-PCR Analysis—Total hippocampal RNA was extracted using Tri-Fast reagent according to the manufacturer's instructions and reverse transcribed. Primers specific for OBRlong were GATGTTCCAAACCCCAAGAA and CATAGCTGCTGGGACCATCT, for OBRshort ATCTGCCGGTGTGAGTTTTC and CCAGTCTCTTGCTCCTCACC, for BAX CTGAGCTGACCTTGGAGC and GACTCCAGCCACAAAGATG, for BCL-2 GACAGAAGATCATGCCGTCC and GGTACCAATGGCACTTCAAG, and for actin and All were by Analysis—Total hippocampal protein was extracted using Tri-Fast of the of protein were in mm and mm at for The were by and in a was by the in in for h at The were then to the diluted for 1 h at and were obtained from Cell and actin were from The were in and then with for 1 h at were by with Cell were grown in and treated with AICAR for was evaluated using the Research and cells were with at a of in of Dulbecco's modified Eagle's for and by were with in saline. were and in the on the were and through in mm in a at for into and to for of in were with activated diluted in for h at with for with and with for were as Y. Bonne O. Berry E.M. Brain Res. 1996; 732: 133-144Crossref PubMed Scopus (50) Google Scholar). The for and were performed by and using are as a animals were in an eight-arm maze that is a of that for D.S. R.J. J. Anim. 1976; 2: Scopus Google Scholar, J. J. Neurosci. PubMed Scopus Google Scholar). We used by and a of of at the of each The mice were of during into or 24 the lower the the the cognitive performance was each for days. were as under the the of in for each and the were for each the group was are as and or were evaluated by of and was carried out using the Hippocampal AMPK nutrition may cognitive function, hippocampal AMPK activity in to DR. Mice were assigned at random to different of DR for and then DR led to of AMPK phosphorylation in a a AMPK activation DR to 40% of the mice with mm AICAR a specific of this the hippocampal AMPK phosphorylation for by severe DR whereas a range of lower AICAR concentrations AMPK activation not AMPK and We the function of AMPK activation in the results that can AMPK a used which was demonstrated to hippocampal AMPK in a to these nutritional Mice were treated with and either or AICAR for 10 days. The number of cells in the dentate gyrus the of new cells and was increased from to following the performed behavioral using the eight-arm maze to was a in cognition. Mice treated with AICAR performed the and the effect of of hippocampal AMPK activation, mice were injected with of AICAR (1-2 for 10 days. Such concentrations for the dosages, of We also these findings were with in hippocampal-dependent spatial Mice given high dose AICAR a in maze performance with the group and in a to mice under DR to 40% the cellular mechanisms involved in these AMPK by RT-PCR and the with AICAR of BAX apoptosis AMPK an Cell in the cellular effects of AMPK in the hippocampus, also performed in studies using This cell is from cells and can be into a for these studies L.A. Proc. Natl. Acad. Sci. U. S. A. 1976; 73: PubMed Scopus Google Scholar). of cells with the of AICAR to a in the number of cells for mm and for total after h We also evaluated the apoptotic at h by cell that AICAR induces apoptotic cell death and for and 1 in a Leptin and is a key hormone in the of energy balance and is to AMPK activity in other C.T. Farooqi I.S. Whitehead J.P. Soos M.A. Rau H. Wareham N.J. Sewter C.P. Digby J.E. Mohammed S.N. Hurst J.A. Cheetham C.H. Earley A.R. Barnett A.H. Prins J.B. O'Rahilly S. Nature. 1997; 387: 903-908Crossref PubMed Scopus (2440) Google Scholar, Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1670) Google Scholar). We considered leptin may with AMPK in brain We leptin under different of diet restriction. Mice were assigned at random to groups and DR to 60%, or DR to 40% for 10 days. leptin concentrations after of DR and were after of leptin by RT-PCR demonstrated an increasing of the with the of diet restriction. However, DR to 60% of the of the this was not in to 40% DR these the effects of leptin on hippocampal AMPK of 40% mice for h with 1 mg/kg leptin reduced the AMPK phosphorylation Leptin the of DR on and investigated the effects of leptin on neural function in mice. Mice were assigned at random to The groups were under or DR to 40% for 10 and injected with either 1 mg/kg leptin or for during the second with leptin the impaired eight-arm maze performance with DR to 40% the group was not by leptin performance was also in the not We then evaluated the effects on the concentrations of and in the with leptin the of following DR Leptin concentrations in the group not in the DR group in which concentrations were reduced the cellular mechanisms involved in leptin by RT-PCR and the between and Although leptin not hippocampal and of the it and reduced of DR mice. Although this effect was in RNA and protein BCL-2 was only in the protein suggesting the involvement of of demonstrated a in the following leptin suggesting an in the of survival We the effect of leptin by of activated as of apoptotic cell not be in the hippocampi of Leptin reduced the of the activated following 40% DR Leptin under Energy energy restriction to of neural function and leptin improves cognitive function following DR to 40% and neural investigated it may also mice survival under these severe conditions. mice were or DR to 40% for and leptin was by during the second week of the mice with leptin with in the group results using to leptin or continuously for animals in each of the or groups whereas in the DR groups a weight mice The survival in the treated group increased from to days. During the of survival on the ability to body when food was these also be the ability to and to stress The crucial of cognitive function under such of We these mechanisms were to survival of the We the of cellular energy nutritional balance, and cognitive function through the cellular and systemic actions of AMPK and actions survival. cellular AMPK activity, which is of the in the This activity has a on cell We that AMPK may cellular changes in the of these mechanisms in the hippocampus that AMPK is of cell neurogenesis and neuroapoptosis. The function of AMPK as a neurogenesis is in with its role in neural J.A. C. M. K. G. D. J. 2002; PubMed Scopus Google Scholar). It a for neuronal and cognitive function during mild energy restriction. these findings may the effects of DR found in neurodegenerative (6Duan W. Mattson M.P. J. Neurosci. Res. 1999; 57: 195-206Crossref PubMed Scopus (396) Google Scholar, 7Love R. Lancet Neurol. 2005; 4: 84Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) and in the suppression of deficits in learning and memory (6Duan W. Mattson M.P. J. Neurosci. Res. 1999; 57: 195-206Crossref PubMed Scopus (396) Google Scholar). The is that the actions of AMPK are to of mild energy it and increases cellular ATP. However, energy intake is as in severe diet cell are not to reverse the and AMPK activation to apoptosis R.J. M. N. R.L. L.A. R.A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar). This of AMPK function the effects of and severe DR on cognitive function of hippocampal cell Leptin concentrations were not different and declined following or 40% DR. the of leptin was in the hippocampus only when energy was to This is in with other the in hypothalamic leptin receptors under energy restriction and reduced leptin activity C. T. C. S. C. A. J.M. M. 2002; PubMed Scopus Google Scholar). The leptin to the of receptors and the of mice are to of the of the C. C.M. Jr., J.E. M. Friedman J.M. Nat. 1996; PubMed Scopus Google Scholar). this is by the is J. J. Endocrinol. 2004; PubMed Scopus Google Scholar). under energy restriction to 60%, leptin signaling is preserved by mechanisms of severe DR this The that leptin inhibit the phosphorylation of AMPK and the and behavioral deficits following 40% DR the of its signaling in the effects of severe energy restriction. This a role for leptin as a to AMPK in the hippocampus in to neural function under such conditions. AMPK of a of neural Diet restriction concentrations AMPK as a to impaired learning and However, of leptin function AMPK activation, increases and improves cognitive function C.T. D. M. B. Science. PubMed Scopus Google Scholar). the involvement of in the apoptotic effects of as of has been found to apoptosis and survival I. E. N. D. A. D. A. Neurosci. Lett. PubMed Scopus Google Scholar). leptin and induces neural survival. The from is that AMPK to neural energy to hippocampal function, it However, when AMPK is to the as in severe diet it neuronal AMPK is a factor in the balance between neuronal growth and death in to nutritional status and The of these results is that a of AMPK activation is whereas a is AMPK is a may be benefits to dose of AMPK in the of cognitive the function of leptin as a is crucial for the of neuronal activity during in energy status results leptin the survival of mice under severe diet restriction by stimulating is information leptin and the effects of and energy balance, is its function during It that following mild leptin may improve brain function, an obvious to the However, under severe diet restriction these effects The in to its other leptin cognitive function and survival under these results are found to be to Man, then leptin may be used in the of disease by or energy balance. These and stress and the weight loss with severe found in or which was considered to be a for may in a new role in the of stress with and We N. B. and H. for the

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