Saturated fatty acid diet prevents radiation-associated decline in intestinal uptake

“Adult female Sprague-Dawley rats were fed isocaloric semipurified diets containing a high content of either polyunsaturated (P) or saturated (S) fatty acids; these diets were nutritionally adequate, providing for all known essential nutrient requirements. On day 3 after beginning S or P, one group of animals was exposed to a single 6-Gy dose of abdominal radiation, and the other half was sham irradiated. S or P diets were continued for a further 14 days. Brush-border membrane purification and sucrase-specific activities were unaffected by diet or by abdominal irradiation. In rats fed P, irradiation was associated with an increase in jejunal brush-border membrane total phospholipid and the ratio of phospholipid to cholesterol; these changes were not observed in animals fed S. In irradiated rats, ileal brush-border membrane phospholipid per cholesterol was high in animals fed S compared with P. In irradiated animals fed P, there was reduced jejunal and ileal uptake of several medium- and long-chain saturated and unsaturated fatty acids and cholesterol, and the ileal uptake of higher concentrations of glucose was reduced in irradiated animals fed P. In contrast, lipid uptake was similar in control and irradiated animals fed S except for cholesterol uptake, which was reduced. Ileal uptake of higher concentrations of glucose was increased in irradiated animals fed S. Quantitative autoradiography failed to demonstrate any change in the distribution of leucine or lysine transport sites along the villus 1 or 2 wk after abdominal irradiation or in response to feeding S or P. Also, these differences in transport achieved by feeding S to radiated animals were not explained by variations in the animals’ food consumption or intestinal mucosal surface area. Thus the use of short-term feeding with a saturated fatty acid diet in the prevention of acute irradiation damage to the intestine warrants further investigation in humans.”

Thomson, a B., Keelan, M., Lam, T., Cheeseman, C. I., Walker, K., & Clandinin, M. T. (1989). Saturated fatty acid diet prevents radiation-associated decline in intestinal uptake. The American Journal of Physiology, 256, G178–G187. Retrieved from http://ajpgi.physiology.org/content/ajpgi/256/1/G178.full.pdf

Pastured verses standard dairy cream

“Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepatic PPARα mRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.”

Benoit, B., Plaisancié, P., Géloën, A., Estienne, M., Debard, C., Meugnier, E., … Michalski, M.-C. (2014). Pasture v. standard dairy cream in high-fat diet-fed mice: improved metabolic outcomes and stronger intestinal barrier. The British Journal of Nutrition, 112(4), 520–35. doi:10.1017/S0007114514001172

T3 and UCPs

Lanni, a., Moreno, M., Lombardi, A., & Goglia, F. (2003). Thyroid hormone and uncoupling proteins. FEBS letters, 543(1-3), 5–10. doi:10.1016/S0014-5793(03)00320-X

Thyroid hormone (TH/T3) exerts many of its effects on energy metabolism by affecting gene transcription. However, although this is an important target for T3, only a limited number of T3-responsive genes have been identified and studied. Among these, the genes for uncoupling proteins (UCPs) have attracted the interest of scientists. Although the role of UCP1 seems quite well established, uncertainty surrounds the physiological function of the recently discovered UCP1 analogs, UCP2 and UCP3. The literature suggests that T3 affects both the expression and the activity of each of these UCPs but further studies are needed to establish whether the mechanisms activated by the hormone are the same. Recently, because of their larger range of expression, much attention has been devoted to UCP2 and UCP3. Most detailed studies on the involvement of these proteins as mediators of the effects of T3 on metabolism have focused on UCP3 because of its expression in skeletal muscle. T3 seems to be unique in having the ability to stimulate the expression and activity of UCP3 and this may be related to the capacity of T3 to activate the integrated biochemical processes linked to UCP activity, such as those related to fatty acids, coenzyme Q and free radicals.

Nicotine, BAT thermogenesis, UCPs

Nicotine uncouples the mitochondria via UCP1 (uncoupling protein 1, or thermogenin). It upregulates BAT thermogensis (brown adipose tissue) and increases in BAT thermogenesis is associated with increased longevity. I could see nicotine, aside from butter, promoting longevity. 

Mattson, M. P. (2010). Perspective: Does brown fat protect against diseases of aging? Ageing research reviews, 9(1), 69–76. doi:10.1016/j.arr.2009.11.004

The most commonly studied laboratory rodents possess a specialized form of fat called brown adipose tissue (BAT) that generates heat to help maintain body temperature in cold environments. In humans, BAT is abundant during embryonic and early postnatal development, but is absent or present in relatively small amounts in adults where it is located in paracervical and supraclavicular regions. BAT cells can “burn” fatty acid energy substrates to generate heat because they possess large numbers of mitochondria in which oxidative phosphorylation is uncoupled from ATP production as a result of a transmembrane proton leak mediated by uncoupling protein 1 (UCP1). Studies of rodents in which BAT levels are either increased or decreased have revealed a role for BAT in protection against diet-induced obesity. Data suggest that individuals with low levels of BAT are prone to obesity, insulin resistance and cardiovascular disease, whereas those with higher levels of BAT maintain lower body weights and exhibit superior health as they age. BAT levels decrease during aging, and dietary energy restriction increases BAT activity and protects multiple organ systems including the nervous system against age-related dysfunction and degeneration. Future studies in which the effects of specific manipulations of BAT levels and thermogenic activity on disease processes in animal models (diabetes, cardiovascular disease, cancers, neurodegenerative diseases) are determined will establish if and how BAT affects the development and progression of age-related diseases. Data from animal studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity and age-related diseases. Examples include: diet and lifestyle changes; specific regimens of mild intermittent stress; drugs that stimulate BAT formation and activity; induction of brown adipose cell progenitors in muscle and other tissues; and transplantation of brown adipose cells.

Yoshida, T., Yoshioka, K., Hiraoka, N., & Kondo, M. (1990). Effect of nicotine on norepinephrine turnover and thermogenesis in brown adipose tissue and metabolic rate in MSG obese mice. Journal of nutritional science and vitaminology, 36(2), 123–30. Retrieved from http://europepmc.org/abstract/MED/2388096

To clarify whether nicotine stimulates the sympathetic nervous system (SNS) and thermogenesis in brown adipose tissue (BAT) and whether it promotes the resting metabolic rate (RMR), with resulting mitigation of obesity, we measured norepinephrine (NE) turnover (an indicator of SNS activity), guanosine-5’-diphosphate (GDP) binding (a thermogenic indicator), oxygen consumption in BAT, and RMR in monosodium-L-glutamate (MSG) obese and saline control mice after 2 weeks treatment with nicotine. Nicotine significantly increased NE turnover, GDP binding, oxygen consumption in BAT, and RMR, and significantly reduced body weight in MSG obese mice as well as in control mice without affecting food intake. These results suggest that nicotine stimulates NE turnover and thermogenesis in BAT, and promotes RMR, all of which contribute to the mitigation of obesity.

Romestaing, C., Piquet, M.-A., Bedu, E., Rouleau, V., Dautresme, M., Hourmand-Ollivier, I., … Sibille, B. (2007). Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutrition & metabolism, 4, 4. doi:10.1186/1743-7075-4-4 

BACKGROUND: Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. METHODS: 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. RESULTS: MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25-28% vs standard). CONCLUSION: Long term high saturated fat feeding led to increased “peripheral” fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH.

Di Paola, M., & Lorusso, M. (2006). Interaction of free fatty acids with mitochondria: coupling, uncoupling and permeability transition. Biochimica et biophysica acta, 1757(9-10), 1330–7. doi:10.1016/j.bbabio.2006.03.024 

Long chain free fatty acids (FFA) exert, according to their actual concentration, different effects on the energy conserving system of mitochondria. Sub-micromolar concentrations of arachidonic acid (AA) rescue DeltapH-dependent depression of the proton pumping activity of the bc1 complex. This effect appears to be due to a direct interaction of AA with the proton-input mouth of the pump. At micromolar concentrations FFA increase the proton conductance of the inner membrane acting as protonophores. FFA can act as natural uncouplers, causing a mild uncoupling, which prevents reactive oxygen species production in the respiratory resting state. When Ca(2+)-loaded mitochondria are exposed to micromolar concentrations of FFA, the permeability of the inner membrane increases, resulting in matrix swelling, rupture of the outer membrane and release of intermembrane pro-apoptotic proteins. The characteristics of AA-induced swelling appear markedly different in mitochondria isolated from heart or liver. While in the latter it presents the canonical features of the classical permeability transition (PT), in heart mitochondria substantial differences are observed concerning CsA sensitivity, DeltaPsi dependence, reversibility by BSA and specificity for the activating divalent cation. In heart mitochondria, the AA-dependent increase of the inner membrane permeability is affected by ANT ligands such as adenine nucleotides and atractyloside. AA apparently causes a Ca2+-mediated conversion of ANT from a translocator to a channel system. Upon diamide treatment of heart mitochondria, the Ca2+/AA-induced CsA insensitive channel is converted into the classical PT pore. The relevance of these observations in terms of tissue-specific components of the putative PTP and heart ischemic and post-ischemic process is discussed.

ApoE4: This is your brain on ApoE4

At least until the CHO breaks you…

Dennis, N. a, Browndyke, J. N., Stokes, J., Need, A., Burke, J. R., Welsh-Bohmer, K. a, & Cabeza, R. (2010). Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 6(4), 303–11. doi:10.1016/j.jalz.2009.07.003

BACKGROUND: We sought to determine if the APOE epsilon4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults. METHODS: Twenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE epsilon4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed. RESULTS: In the absence of demographic or performance differences, APOE epsilon4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas epsilon4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices. CONCLUSIONS: These results suggest that the APOE varepsilon4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult epsilon4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer’s disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.

Evans, S., Gray, M. A., Dowell, N. G., Tabet, N., Tofts, P. S., King, S. L., & Rusted, J. M. (2013). APOE E4 Carriers show prospective memory enhancement under nicotine, and evidence for specialisation within medial BA10. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38(4), 655–63. doi:10.1038/npp.2012.230

There is evidence to suggest that the APOE ɛ4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ɛ4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ɛ4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ɛ4 from ɛ3 carriers. One BA10 subregion showed greater deactivation in ɛ4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ɛ4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ɛ4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions.

Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., … Mackay, C. E. (2009). Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proceedings of the National Academy of Sciences of the United States of America, 106(17), 7209–14. doi:10.1073/pnas.0811879106

The APOE epsilon4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE epsilon4-carriers and 18 matched noncarriers (age range: 20-35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased “default mode network” (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in epsilon4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in epsilon4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE epsilon4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.

Mondadori, C. R. A., de Quervain, D. J.-F., Buchmann, A., Mustovic, H., Wollmer, M. A., Schmidt, C. F., … Henke, K. (2007). Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cerebral cortex (New York, N.Y. : 1991), 17(8), 1934–47. doi:10.1093/cercor/bhl103

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas epsilon2 and epsilon3 carriers increased activity. This smaller neural investment of epsilon4 carriers into learning reappeared during retrieval: epsilon4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE epsilon4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

Moreau, P.-H., Bott, J.-B., Zerbinatti, C., Renger, J. J., Kelche, C., Cassel, J.-C., & Mathis, C. (2013). ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice. Behavioural brain research, 243, 1–5. doi:10.1016/j.bbr.2012.12.043

The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimer’s disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.

Rusted, J. M., Evans, S. L., King, S. L., Dowell, N., Tabet, N., & Tofts, P. S. (2013). APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. NeuroImage, 65, 364–73. doi:10.1016/j.neuroimage.2012.10.010

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis–that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

ApoE4: Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice

The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment.

Maioli, S., Puerta, E., Merino-Serrais, P., Fusari, L., Gil-Bea, F., Rimondini, R., & Cedazo-Minguez, A. (2012). Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice. Journal of Alzheimer’s disease : JAD, 32(2), 341–55. doi:10.3233/JAD-2012-120697

ApoE4: High carbohydrate diets and Alzheimer’s disease

Alzheimer’s disease (AD) is a common, progressive, neurodegenerative disease that primarily afflicts the elderly. A well-defined risk factor for late onset AD is possession of one or more alleles of the epsilon-4 variant (E4) of the apolipoprotein E gene. Meta-analysis of allele frequencies has found that E4 is rare in populations with long historical exposure to agriculture, suggesting that consumption of a high carbohydrate (HC) diet may have selected against E4 carriers. The apoE4 protein alters lipid metabolism in a manner similar to a HC diet, suggesting a common mechanism for the etiology of AD. Evolutionarily discordant HC diets are proposed to be the primary cause of AD by two general mechanisms. (1) Disturbances in lipid metabolism within the central nervous system inhibits the function of membrane proteins such as glucose transporters and the amyloid precursor protein. (2) Prolonged excessive insulin/IGF signaling accelerates cellular damage in cerebral neurons. These two factors ultimately lead to the clinical and pathological course of AD. This hypothesis also suggests several preventative and treatment strategies. A change in diet emphasizing decreasing dietary carbohydrates and increasing essential fatty acids (EFA) may effectively prevent AD. Interventions that restore lipid homeostasis may treat the disease, including drugs that increase fatty acid metabolism, EFA repletion therapy, and ketone body treatment.

Henderson, S. T. (2004). High carbohydrate diets and Alzheimer’s disease. Medical hypotheses, 62(5), 689–700. doi:10.1016/j.mehy.2003.11.028

Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes

Triiodothyronine (T3) increases mitochondrial respiration and promotes, in rodents, the uncoupling between oxygen consumption and ATP synthesis. The T3 effect is mediated partly through transcriptional control of genes encoding mitochondrial proteins. Here, we determined the effect of T3 on mRNA levels of uncoupling proteins (UCP) and proteins involved in the biogenesis of the respiratory chain in human skeletal muscle and on UCP2 mRNA expression in adipose tissue.

http://m.fasebj.org/content/15/1/13.full.pdf

“T3 is also known to stimulate fatty acid oxidation. The decrease in respiratory quotient observed in our study suggests that T3 treatment induced an increase in fatty acid oxidation.”

n-Butyrate enhances induction of thyroid hormone-responsive nuclear protein

Nishii, Y., Ichikawa, K., Miyamoto, T., Takeda, T., Kobayashi, M., Suzuki, S., … Hashizume, K. (1993). n-Butyrate enhances induction of thyroid hormone-responsive nuclear protein. Endocrine journal, 40(5), 515–21. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7951517

Effects of n-butyrate on nuclear thyroid hormone receptors and on thyroid hormone-responsive nuclear protein were investigated by means of a perfusion system in rat liver. Treatment with 5 mM n-butyrate resulted in an increase (150%) in the maximal binding capacity of 3,5,3’-L-triiodothyronine (T3) nuclear receptors without altering the affinity of receptor for T3. However, further perfusion for 4 h decreased the number of the receptors to the control level. n-Butyrate increased the amount of acetylated histone H4. The ability of nuclear T3 receptors to bind to core histones was diminished by acetylation of the core histones. Thyroid hormone-responsive nuclear protein (n protein) was increased by T3. The induction of the n protein by T3 was augmented by n-butyrate. These results suggested that n-butyrate modulates thyroid hormone-responsive gene expression in rat liver via the increased number of nuclear receptors or changes in the chromatin constitution.

Conjugated linoleic acid protects against gliadin-induced depletion of intestinal defenses

Bergamo, P., Gogliettino, M., Palmieri, G., Cocca, E., Maurano, F., Stefanile, R., … Rossi, M. (2011). Conjugated linoleic acid protects against gliadin-induced depletion of intestinal defenses. Molecular nutrition & food research, 55 Suppl 2, S248–56. doi:10.1002/mnfr.201100295

SCOPE: The involvement of oxidative stress in gluten-induced toxicity has been evidenced in vitro and in clinical studies but has never been examined in vivo. We recently demonstrated the protective activity of conjugated linoleic acid (CLA), which functions by the activation of nuclear factor erythroid 2-related factor2 (Nrf2), a key transcription factor for the synthesis of antioxidant and detoxifying enzymes (phase 2). Here, we evaluate the involvement of nuclear factor erythroid 2-related factor2 in gliadin-mediated toxicity in human Caco-2 intestinal cells and in gliadin-sensitive human leukocyte antigen-DQ8 transgenic mice (DQ8) and the protective activity of CLA.

METHODS AND RESULTS: Gliadin effects in differentiated Caco-2 cells and in DQ8 mice, fed with a gliadin-containing diet with or without CLA supplementation, were evaluated by combining enzymatic, immunochemical, immunohistochemical, and quantitative real-time PCR (qRT-PCR) assays. Gliadin toxicity was accompanied by downregulation of phase 2 and elevates proteasome-acylpeptide hydrolase activities in vitro and in vivo. Notably, gliadin was unable to generate severe oxidative stress extent or pathological consequences in DQ8 mice intestine comparable to those found in celiac patients and the alterations produced were hampered by CLA.

CONCLUSION: The beneficial effects of CLA against the depletion of crucial intestinal cytoprotective defenses indicates a novel nutritional approach for the treatment of intestinal disease associated with altered redox homeostasis.

Wistar rats allowed to self-select macronutrients from weaning to maturity choose a high-protein, high-lipid diet

Jean, C., Fromentin, G., Tomé, D., & Larue-Achagiotis, C. (2002). Wistar rats allowed to self-select macronutrients from weaning to maturity choose a high-protein, high-lipid diet. Physiology & behavior, 76(1), 65–73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12175590

The aim of this work was to study the evolution of rat food choice in relation to their age and metabolic parameters. Eighty Wistar rats were studied from birth to 13 weeks of age. At weaning, six litters were fed on a macronutrient self-selecting diet and four on a standard diet. In self-selecting males, protein intake was maximal at Week 7 of age and then plateaued (Week 13), whereas in females, protein consumption peaked at Week 7 and then steadily decreased. Females showed a strong and early preference for fat, which increased continuously with age. Males and females ingested their total energy intake during the dark period (respectively, 79% and 70%). Simple meals (composed of one item) were mainly ingested during the light phase, while mixed meals (at least two items) were ingested during the night. In males, most mixed meals began with carbohydrate bouts and finished with proteins, while in females no particular choice was observed at the beginning of meals, but most of them ended with protein bouts. Body weights of either male and female self-selecting or control fed rats were not significantly different at the end of the experiment. Differences between dietary groups in body fat mass were not observed with the exception of higher subcutaneous fat found in self-selecting rats. Moreover, insulinemia was lower in both male and female self-selecting rats. The high-protein, high-fat diet chosen by the self-selecting rats could be linked to a prevention of the age-related insulin resistance.

Features of a successful therapeutic fast of 382 days’ duration

Stewart, W. K., & Fleming, L. W. (1973). Features of a successful therapeutic fast of 382 days’ duration. Postgraduate medical journal, 49(569), 203–9. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2495396&tool=pmcentrez&rendertype=abstract

A 27-year-old male patient fasted under supervision for 382 days and has subsequently maintained his normal weight. Blood glucose concentrations around 30 mg/100 ml were recorded consistently during the last 8 months, although the patient was ambulant and attending as an out-patient. Responses to glucose and tolbutamide tolerance tests remained normal. The hyperglycaemic response to glucagon was reduced and latterly absent, but promptly returned to normal during carbohydrate refeeding. After an initial decrease was corrected, plasma potassium levels remained normal without supplementation. A temporary period of hypercalcaemia occurred towards the end of the fast. Decreased plasma magnesium concentrations were a consistent feature from the first month onwards. After 100 days of fasting there was a marked and persistent increase in the excretion of urinary cations and inorganic phosphate, which until then had been minimal. These increases may be due to dissolution of excessive soft tissue and skeletal mass. Prolonged fasting in this patient had no ill-effects.

Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species

Devasagayam, T. P., Kamat, J. P., Mohan, H., & Kesavan, P. C. (1996). Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. Biochimica et biophysica acta, 1282(1), 63–70. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8679661

Caffeine (1,3,7-trimethyl xanthine), an ingredient of coffee, has been investigated for its potential antioxidant activity against oxidative damage to rat liver microsomes. Such damage was induced by three reactive oxygen species of cardinal importance in causing membrane damage in vivo namely hydroxyl radical (.OH), peroxyl radical (ROO.) and singlet oxygen (1O2). The results obtained showed that caffeine was an effective inhibitor of lipid peroxidation, at millimolar concentrations, against all the three reactive species. The extent of inhibition was high against peroxidation induced by .OH, medium against 1O2 and low against ROO. In general, the antioxidant ability of caffeine was similar to that of the established biological antioxidant glutathione and significantly higher than ascorbic acid. Investigations into the possible mechanisms involved in the observed antioxidant effect reveal that the quenching of these reactive species by caffeine may be one of the possible factor responsible. The rate constant of caffeine with .OH was 7.3 x 10(9) M-1 s-1 and with 1O2 it was 2.9 x 10(7) M-1 s-1. Considering their potential for damage, half-life estimates and generation in biological systems, the ability of caffeine to inhibit oxidative damage induced by these reactive species in membranes suggest one more positive attribute of caffeine, whose daily intake as coffee may be considerable in most populations.

Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways

Onodera, Y., Nam, J.-M., & Bissell, M. J. (2013). Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. The Journal of clinical investigation, 124(1). doi:10.1172/JCI63146

There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between “normal” and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.

No effect of 600 grams fruit and vegetables per day on oxidative DNA damage and repair in healthy nonsmokers

Møller, P., Vogel, U., Pedersen, A., Dragsted, L. O., Sandström, B., & Loft, S. (2003). No effect of 600 grams fruit and vegetables per day on oxidative DNA damage and repair in healthy nonsmokers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 12(10), 1016–22. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14578137

In several epidemiological studies, high intakes of fruits and vegetables have been associated with a lower incidence of cancer. Theoretically, intake of antioxidants by consumption of fruits and vegetables should protect against reactive oxygen species and decrease the formation of oxidative DNA damage. We set up a parallel 24-day dietary placebo-controlled intervention study in which 43 subjects were randomized into three groups receiving an antioxidant-free basal diet and 600 g of fruits and vegetables, or a supplement containing the corresponding amounts of vitamins and minerals, or placebo. Blood and urine samples were collected before, once a week, and 4 weeks after the intervention period. The level of strand breaks, endonuclease III sites, formamidopyrimidine sites, and sensitivity to hydrogen peroxide was assessed in mononuclear blood cells by the comet assay. Excretion of 7-hydro-8-oxo-2’-deoxyguanine was measured in urine. The expressions of oxoguanine glycosylase 1 and excision repair cross complementing 1 DNA repair genes, determined by real-time reverse transcription-PCR of mRNAs, were investigated in leukocytes. Consumption of fruits and vegetables or vitamins and minerals had no effect on oxidative DNA damage measured in mononuclear cell DNA or urine. Hydrogen peroxide sensitivity, detected by the comet assay, did not differ between the groups. Expression of excision repair cross complementing 1 and oxoguanine glycosylase 1 in leukocytes was not related to the diet consumed. Our results show that after 24 days of complete depletion of fruits and vegetables, or daily ingestion of 600 g of fruit and vegetables, or the corresponding amount of vitamins and minerals, the level of oxidative DNA damage was unchanged. This suggests that the inherent antioxidant defense mechanisms are sufficient to protect circulating mononuclear blood cells from reactive oxygen species.

Effects of Coffee Consumption, Smoking, and Hormones on Risk for Primary Sclerosing Cholangitis

http://www.sciencedaily.com/releases/2013/12/131214144837.htm

Andersen, I. M., Tengesdal, G., Lie, B. A., Boberg, K. M., Karlsen, T. H., & Hov, J. R. (2013). Effects of Coffee Consumption, Smoking, and Hormones on Risk for Primary Sclerosing Cholangitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. doi:10.1016/j.cgh.2013.09.024

BACKGROUND & AIMS: Little is known about nongenetic risk factors for primary sclerosing cholangitis (PSC), except a possible protective effect of smoking. We investigated the relationship between environmental risk factors and susceptibility to PSC. METHODS: A questionnaire was distributed to patients with PSC, recruited from Oslo University Hospital Rikshospitalet in Norway through 2011, and randomly chosen individuals from the Norwegian Bone Marrow Donor Registry (control subjects). Data were analyzed from 240 patients with PSC and 245 control subjects, matched for gender and age. RESULTS: A lower proportion of patients with PSC were daily coffee drinkers than control subjects, both currently (76% vs 86%; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.32-0.82; P = .006) and at the age of 18 years (35% vs 49%; OR, 0.58; 95% CI, 0.40-0.83; P = .003). The associations were mainly attributed to differences observed in men. Twenty percent of the patients were ever (current or former) daily smokers compared with 43% of control subjects (OR, 0.33; 95% CI, 0.22-0.50; P < .001). Ever daily smoking before PSC diagnosis was associated with older age at diagnosis (42 years vs 32 years; P < .001). Ever daily smoking (P < .001) and being a coffee drinker at the age of 18 years (P = .048) were independently and negatively associated with PSC. Fewer female patients with PSC than control subjects reported ever use of hormonal contraception (51% vs 85%; P < .001). Among female patients, there was a strong correlation between increasing number of children before the diagnosis of PSC and increasing age at diagnosis (r = 0.63; P < .001). CONCLUSIONS: Coffee consumption and smoking might protect against development of PSC. In women, the disease might be influenced by hormonal factors.

Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation

Maalouf, M., Sullivan, P. G. G., Davis, L., Kim, D. Y. Y., & Rho, J. M. M. (2007). Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience, 145(1), 256–64. doi:10.1016/j.neuroscience.2006.11.065

Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones beta-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of beta-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 microM glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress.

Fatty liver induced by injection of l-tryptophan

Yukiko, H., Takashi, K., & Takashi, S. (1967). Fatty liver induced by injection of l-tryptophan. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism, 144(2), 233–241. Retrieved from http://www.sciencedirect.com/science/article/pii/0005276067901531

l-Tryptophan caused the accumulation of neutral lipids in liver within 2.5 h after its intraperitoneal injection into rats. This accumulation of neutral lipids continued for about 24 h. Peripheral fatty liver was diagnosed histologically by Sudan III staining. The minimal effective dose was 0.5 mg/g of body weight. The level of cholesterol and phospholipids in liver did not alter. 3-Hydroxyanthranilic acid and l-kynurenine were as effective as l-tryptophan in inducing the accumulation of neutral lipids, but other metabolites of tryptophan, kynurenic acid, anthranilic acid, quinolinic acid, nicotinic acid and nicotinamide did not produce the lipid accumulation. The administration of other amino acids, such as l-leucine, l-lysine, l-tyrosine, l-threonine and l-methionine, did not increase the amount of total lipids in liver. Simultaneous administration of ATP, ADP, AMP, adenosine or folic acid with l-tryptophan prevented the fatty liver. A marked decrease in the concentration of ATP in the liver was shown by the administration of l-tryptophan or l-kynurenine. These observations support the concept that l-tryptophan-induced fatty liver is due to the decreased level of ATP. A possible mechanism of ATP depression by administered l-tryptophan is discussed.

Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes

Kang, J. X., Xiao, Y. F., & Leaf, A. (1995). Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proceedings of the National Academy of Sciences, 92(9), 3997–4001. doi:10.1073/pnas.92.9.3997

Because previous studies showed that polyunsaturated fatty acids can reduce the contraction rate of spontaneously beating heart cells and have antiarrhythmic effects, we examined the effects of the fatty acids on the electrophysiology of the cardiac cycle in isolated neonatal rat cardiac myocytes. Exposure of cardiomyocytes to 10 microM eicosapentaenoic acid for 2-5 min markedly increased the strength of the depolarizing current required to elicit an action potential (from 18.0 +/- 2.4 pA to 26.8 +/- 2.7 pA, P < 0.01) and the cycle length of excitability (from 525 ms to 1225 ms, delta = 700 +/- 212, P < 0.05). These changes were due to an increase in the threshold for action potential (from -52 mV to -43 mV, delta = 9 +/- 3, P < 0.05) and a more negative resting membrane potential (from -52 mV to -57 mV, delta = 5 +/- 1, P < 0.05). There was a progressive prolongation of intervals between spontaneous action potentials and a slowed rate of phase 4 depolarization. Other polyunsaturated fatty acids–including docosahexaenoic acid, linolenic acid, linoleic acid, arachidonic acid, and its nonmetabolizable analog eicosatetraynoic acid, but neither the monounsaturated oleic acid nor the saturated stearic acid–had similar effects. The effects of the fatty acids could be reversed by washing with fatty acid-free bovine serum albumin. These results show that free polyunsaturated fatty acids can reduce membrane electrical excitability of heart cells and provide an electrophysiological basis for the antiarrhythmic effects of these fatty acids.

Targeting SOD1 reduces experimental non-small-cell lung cancer

Glasauer, A., Sena, L. A., Diebold, L. P., Mazar, A. P., & Chandel, N. S. (2013). Targeting SOD1 reduces experimental non-small-cell lung cancer. The Journal of clinical investigation, 124(1). doi:10.1172/JCI71714

Approximately 85% of lung cancers are non-small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224-dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H2O2) levels. We found that ATN-224-induced cell death was mediated through H2O2-dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers.

Nicotine primarily suppresses lung Th2 but not goblet cell and muscle cell responses to allergens

Mishra, N. C., Rir-Sima-Ah, J., Langley, R. J., Singh, S. P., Peña-Philippides, J. C., Koga, T., … Sopori, M. L. (2008). Nicotine primarily suppresses lung Th2 but not goblet cell and muscle cell responses to allergens. Journal of immunology (Baltimore, Md. : 1950), 180(11), 7655–63. Retrieved from http://www.jimmunol.org/content/180/11/7655.full

Allergic asthma, an inflammatory disease characterized by the infiltration and activation of various leukocytes, the production of Th2 cytokines and leukotrienes, and atopy, also affects the function of other cell types, causing goblet cell hyperplasia/hypertrophy, increased mucus production/secretion, and airway hyperreactivity. Eosinophilic inflammation is a characteristic feature of human asthma, and recent evidence suggests that eosinophils also play a critical role in T cell trafficking in animal models of asthma. Nicotine is an anti-inflammatory, but the association between smoking and asthma is highly contentious and some report that smoking cessation increases the risk of asthma in ex-smokers. To ascertain the effects of nicotine on allergy/asthma, Brown Norway rats were treated with nicotine and sensitized and challenged with allergens. The results unequivocally show that, even after multiple allergen sensitizations, nicotine dramatically suppresses inflammatory/allergic parameters in the lung including the following: eosinophilic/lymphocytic emigration; mRNA and/or protein expression of the Th2 cytokines/chemokines IL-4, IL-5, IL-13, IL-25, and eotaxin; leukotriene C(4); and total as well as allergen-specific IgE. Although nicotine did not significantly affect hexosaminidase release, IgG, or methacholine-induced airway resistance, it significantly decreased mucus content in bronchoalveolar lavage; interestingly, however, despite the strong suppression of IL-4/IL-13, nicotine significantly increased the intraepithelial-stored mucosubstances and Muc5ac mRNA expression. These results suggest that nicotine modulates allergy/asthma primarily by suppressing eosinophil trafficking and suppressing Th2 cytokine/chemokine responses without reducing goblet cell metaplasia or mucous production and may explain the lower risk of allergic diseases in smokers. To our knowledge this is the first direct evidence that nicotine modulates allergic responses.

Thyroid cancer was negatively associated with tobacco smoking

Guignard, R., Truong, T., Rougier, Y., Baron-Dubourdieu, D., & Guénel, P. (2007). Alcohol drinking, tobacco smoking, and anthropometric characteristics as risk factors for thyroid cancer: a countrywide case-control study in New Caledonia. American journal of epidemiology, 166(10), 1140–9. doi:10.1093/aje/kwm204

Exceptionally high incidence rates of thyroid cancer are observed in New Caledonia, particularly in Melanesian women. To investigate further the etiology of thyroid cancer and to clarify the reasons of this elevated incidence, the authors conducted a countrywide population-based case-control study in this multiethnic population. The study included 332 cases with histologically verified papillary or follicular carcinoma (293 women and 39 men) diagnosed in 1993-1999 and 412 population controls (354 women and 58 men) frequency matched by gender and 5-year age group. Thyroid cancer was negatively associated with tobacco smoking and alcohol drinking, but no inverse dose-response relation was observed. Height was positively associated with thyroid cancer, particularly in men. Strong positive associations with weight and body mass index were observed in Melanesian women aged 50 years or more, with an odds ratio of 5.5 (95% confidence interval: 1.5, 20.3) for a body mass index of 35 kg/m2 or greater compared with normal-weight women, and there was a clear dose-response trend. This study clarifies the role of overweight for thyroid cancer in postmenopausal women. Because of the high prevalence of obesity among Melanesian women of New Caledonia, this finding may explain in part the exceptionally elevated incidence of thyroid cancer in this group.

 

Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation

De Cristóbal, J., Cárdenas, A., Lizasoain, I., Leza, J. C., Fernández-Tomé, P., Lorenzo, P., & Moro, M. a. (2002). Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation. Stroke; a journal of cerebral circulation, 33(1), 261–7. doi:10.1161/hs0102.101299

BACKGROUND AND PURPOSE: Aspirin is preventive against stroke not only because of its antithrombotic properties but also by other direct effects. The aim of this study was to elucidate its direct neuroprotective effects. METHODS: Viability parameters, glutamate release and uptake, and ATP levels were measured in cultured cortical neurons exposed to oxygen-glucose deprivation (OGD). In addition, ATP levels and oxygen consumption were studied in isolated brain mitochondria or submitochondrial particles. RESULTS: Aspirin inhibited OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition of the transcription factor nuclear factor-kappaB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A pharmacological dissection of the components involved indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles. CONCLUSIONS: Taken together, our present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of ischemic events.

Neonatal ketosis

Adam, P. A., Räihä, N., Rahiala, E. L., & Kekomäki, M. (1975). Oxidation of glucose and D-B-OH-butyrate by the early human fetal brain. Acta paediatrica Scandinavica, 64(1), 17–24. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1114894

The isolated brains of 12 previable human fetuses obtained at 12 to 21 weeks’ gestation, were perfused through the interval carotid artery with glucose (3 mM) and/or DL-B-OH-butyrate (DL-BOHB), 4.5 MM, plus tracer quantities of either glucose-6-14C (G6-14C) or beta-OH-butyrate-3-14C (BOHB3-14C). Oxidative metabolism was demonstrated by serial collection of gaseous 14CO2 from the closed perfusion system, and from the recirculating medium. Glucose and BOHB were utilized at physiological rates as indicated (mean plus or minus SEM): G6-14C at 0.10 plus or minus 0.01 mumoles/min g brain (n equal 7) or 17.5 plus or minus 1.9 mumoles/min kg fetus; and BOHB3-14C at 0.16 plus or minus 0.05 mumoles/min g (n equal to 5) or 27.3 plus or minus 7.4 mumoles/min kg. Based on fetal weight, glucose metabolism by brain apparently accounted for about 1/3 of basal glucose utilization in the fetus. On a molar basis BOHB3-14C was taken up at 1.47 times the rate of G6-14C. Both BOHB3-14C and G6 14C were converted to 14CO2. The rate of BOHB3-14C conversion to 14CO2 was equal to its rate of consumption, and exceeded the conversion of glucose to CO2 because 45% of the G6-14C was incorporated into lactate-14C. Accordingly, both substrates support oxidative metabolism by brain; and BOHB is a major potential alternate fuel which can replace glucose early in human development.

Bon, C., Raudrant, D., Golfier, F., Poloce, F., Champion, F., Pichot, J., & Revol, A. (n.d.). [Feto-maternal metabolism in human normal pregnancies: study of 73 cases]. Annales de biologie clinique, 65(6), 609–19. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18039605

From 73 normal pregnancies of gestational age between 17 and 41 weeks of gestation (WG), the concentrations of glucose, pyruvate and lactate, free fatty acids, ketone bodies (aceto-acetate and beta-hydroxybutyrate) and cholesterol were assessed on maternal venous blood (MVB) and umbilical venous blood (UVB), sampled by cordocentesis. The objective of this work was to study feto-maternal metabolism, as well as nutritional exchange between maternal blood and fetal blood during the second and third trimesters of pregnancy. Maternal and fetal glycemias, as well as maternal-fetal glucose concentration gradient, were found stable during the studied gestational period; maternal glucose is always higher than fetal glucose, with a mean concentration delta of 0.69+/-0.34 mmol/L. Maternal lactate level (1.26+/-0.38 mmol/L) is lower than fetal lactate level (1.48+/-0.46 mmol/L), whereas maternal blood pyruvate concentration (0.042+/-0.020 mmol/L) is higher than fetal blood pyruvate concentration (0.025+/-0.010 mmol/L). Consequently, mean lactate / pyruvate ratio is found twice lower in maternal blood (31.77+/-9.89) than in fetal blood (64.10+/-17.12). Free fatty acids concentration is approximately three times higher in maternal blood than in fetal blood (respectively 0.435+/-0.247 mmol/L and 0.125+/-0.046 mmol/L). Maternal venous aceto-acetate (0.051+/-0.042 mmol/L) and beta-hydroxybutyrate (0.232+/-0.270 mmol/L) concentrations are significantly lower than those in UVB (respectively 0.111+/-0.058 and 0.324+/-0.246 mmol/L) and the beta-hydroxybutyrate/aceto-acetate ratio is on average 1.7 times higher in MVB (4.75+/-2.5) than in UVB (2.82+/-1.18). Cholesterol concentration is significantly higher in maternal blood (6.26+/-1.40 mmol/L) than in fetal blood (1.66+/-0.34 mmol/L). Our results show the characteristics of oxidative metabolism of the fetus compared with that of the adult. Blood concentration in energy substrates, measured with glucose and free fatty acids levels, is low in UVB and suggests increased energy needs of the growing fetus. Mean high concentrations in aceto-acetate and beta-hydroxybutyrate in UVB, indicate probably fetal ketogenesis. UVB low cholesterolemia suggests high cholesterol consumption in the fetal compartment for cellular membrane synthesis and steroid biosynthesis.

Bougneres, P. F., Lemmel, C., Ferré, P., & Bier, D. M. (1986). Ketone body transport in the human neonate and infant. The Journal of clinical investigation, 77(1), 42–8. doi:10.1172/JCI112299

Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate’s basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.

Cotter, D. G., d’Avignon, D. A., Wentz, A. E., Weber, M. L., & Crawford, P. A. (2011). Obligate role for ketone body oxidation in neonatal metabolic homeostasis. The Journal of biological chemistry, 286(9), 6902–10. doi:10.1074/jbc.M110.192369

To compensate for the energetic deficit elicited by reduced carbohydrate intake, mammals convert energy stored in ketone bodies to high energy phosphates. Ketone bodies provide fuel particularly to brain, heart, and skeletal muscle in states that include starvation, adherence to low carbohydrate diets, and the neonatal period. Here, we use novel Oxct1(-/-) mice, which lack the ketolytic enzyme succinyl-CoA:3-oxo-acid CoA-transferase (SCOT), to demonstrate that ketone body oxidation is required for postnatal survival in mice. Although Oxct1(-/-) mice exhibit normal prenatal development, all develop ketoacidosis, hypoglycemia, and reduced plasma lactate concentrations within the first 48 h of birth. In vivo oxidation of (13)C-labeled β-hydroxybutyrate in neonatal Oxct1(-/-) mice, measured using NMR, reveals intact oxidation to acetoacetate but no contribution of ketone bodies to the tricarboxylic acid cycle. Accumulation of acetoacetate yields a markedly reduced β-hydroxybutyrate:acetoacetate ratio of 1:3, compared with 3:1 in Oxct1(+) littermates. Frequent exogenous glucose administration to actively suckling Oxct1(-/-) mice delayed, but could not prevent, lethality. Brains of newborn SCOT-deficient mice demonstrate evidence of adaptive energy acquisition, with increased phosphorylation of AMP-activated protein kinase α, increased autophagy, and 2.4-fold increased in vivo oxidative metabolism of [(13)C]glucose. Furthermore, [(13)C]lactate oxidation is increased 1.7-fold in skeletal muscle of Oxct1(-/-) mice but not in brain. These results indicate the critical metabolic roles of ketone bodies in neonatal metabolism and suggest that distinct tissues exhibit specific metabolic responses to loss of ketone body oxidation.

De Boissieu, D., Rocchiccioli, F., Kalach, N., & Bougnères, P. F. (1995). Ketone body turnover at term and in premature newborns in the first 2 weeks after birth. Biology of the neonate, 67(2), 84–93. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7766735

Using the infusion of D-(-)-3-hydroxy-[1,2,3,4,-13C4]butyrate at tracer doses, we measured total ketone body turnover in 13 premature and 10 at term infants in the first 2 weeks after birth. The premature infants received parenteral and/or oral feeding. The normal newborns were either recently fed or briefly fasting. The premature and the fed at term infants had comparable concentrations of ketone body (476 +/- 86 and 406 +/- 78 mumol/l) and free fatty acids (FFA) (309 +/- 47 and 325 +/- 75 mumol/l). In the premature newborns, ketone body turnover rates (3.2 +/- 0.2 mumol kg-1 min-1) were 74% that of fed newborns at term (4.3 +/- 0.3 mumol kg-1 min-1, p < 0.05), and 18% that of normal newborns during a brief fast (17.3 +/- 1.3 mumol kg-1 min-1, p < 0.01). Ketone body production rates correlated with plasma FFA concentrations in both groups (r = 0.62 and 0.69, p < 0.05). However, for a similar plasma FFA content, ketone production was 2- to 3-fold lower in the premature, indicating an immature hepatic capacity to convert FFA into ketones. Our study therefore shows that ketogenesis is already active in infants born 10 weeks before normal term and continuously fed, but that daily ketone production is lower than at term.

Herrera, E. (2000). Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. European journal of clinical nutrition, 54 Suppl 1, S47–51. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10805038

During the first two-thirds of gestation, the mother is in an anabolic condition, increasing her fat depots thanks to both hyperphagia and enhanced lipogenesis. During the last third of gestation, the mother switches to a catabolic condition. Glucose is the most abundant nutrient crossing the placenta, which causes maternal hypoglycemia despite an increase in the gluconeogenetic activity. Adipose tissue lipolytic activity becomes enhanced, increasing plasma levels of FFA and glycerol that reach the liver; consequently there is an enhanced production of triglycerides that return to the circulation in the form of very low density lipoproteins (VLDL). Glycerol is also used as a preferential gluconeogenetic substrate, saving other more essential substrates, like amino acids, for the fetus. Under fasting conditions, fatty acids are converted into ketone bodies throughout the beta-oxidation pathway, and these compounds easily cross the placental barrier and are metabolized by the fetus. An enhanced liver production of VLDL-triglycerides together with a decrease in adipose tissue lipoprotein lipase (LPL) and an increase in plasma activity of cholesterol ester transfer protein causes both an intense increment in these lipoproteins and a proportional enrichment of triglycerides in both low and high density lipoproteins. Maternal triglycerides do not cross the placenta, but the presence of LPL and other lipases allows their hydrolysis, releasing fatty acids to the fetus. Under fasting conditions, the maternal liver uses circulating triglycerides as ketogenic substrates. Around parturition there is an induction of LPL activity in the mammary glands, driving circulating triglycerides to this organ for milk synthesis, allowing essential fatty acids derived from the mother’s diet to become available to the suckling newborn.

Herrera, E., & Amusquivar, E. (n.d.). Lipid metabolism in the fetus and the newborn. Diabetes/metabolism research and reviews, 16(3), 202–10. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10867720

During late gestation, although maternal adipose tissue lipolytic activity becomes enhanced, lipolytic products cross the placenta with difficulty. Under fasting conditions, free fatty acids (FFA) are used for ketogenesis by the mother, and ketone bodies are used as fuels and lipogenic substrates by the fetus. Maternal glycerol is preferentially used for glucose synthesis, saving other gluconeogenic substrates, like amino acids, for fetal growth. Placental transfer of triglycerides is null, but essential fatty acids derived from maternal diet, which are transported as triglycerides in lipoproteins, become available to the fetus owing to the presence of both lipoprotein receptors and lipase activities in the placenta. Diabetes in pregnancy promotes lipid transfer to the fetus by increasing the maternal-fetal gradient, which may contribute to an increase in body fat mass in newborns of diabetic women. Deposition of fat stores in the fetus is very low in the rat but high in humans, where body fat accretion occurs essentially during the last trimester of intra-uterine life. This is sustained by the intense placental transfer of glucose and by its use as a lipogenic substrate, as well as by the placental transfer of fatty acids and to their low oxidation activity. During the perinatal period an active ketonemia develops, which is maintained in the suckling newborn by several factors: (i) the high-fat and low-carbohydrate content in milk, (ii) the enhanced lipolytic activity occurring during the first few hours of life, and (iii) both the uptake of circulating triglycerides by the liver due to the induction of lipoprotein lipase (LPL) activity in this organ, and the presence of ketogenic activity in the intestinal mucose. Changes in LPL activity, lipogenesis and lipolysis contribute to the sequential steps of adipocyte hyperplasia and hypertrophia occurring during the extra-uterine white adipose tissue development in rat, and this may be used as a model to extrapolate the intra-uterine adipose tissue development in other species, including humans.

Koski, K. G., Lanoue, L., & Young, S. N. (1995). Maternal dietary carbohydrate restriction influences the developmental profile of postnatal rat brain indoleamine metabolism. Biology of the neonate, 67(2), 122–31. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7539298

Dietary glucose restriction during pregnancy can retard fetal brain development, lower term brain glycogen levels and adversely affect the serotonergic neurotransmitter system in the fetus. To study if the postnatal profile of brain indoles continues to respond to these diet-induced changes, pregnant rats were fed graded levels (0, 12, 24, 60%) of glucose from impregnation to day 15 postpartum, and neonatal brain measurements were made. A steady decrease in tryptophan levels, a steady increase in 5-hydroxytryptamine (5-HT) levels and a U-shaped change in 5-hydroxyindoleacetic acid (5-HIAA) were observed during the first 15 postpartum days. Superimposed on these development profiles was a temporary surge in the concentrations of all three indoles 24 h after birth, which was dramatic for tryptophan and more modest for 5-HT and 5-HIAA. The level of carbohydrate in the maternal diet significantly influenced the magnitude of this increase in tryptophan, 5-HT and 5-HIAA at 24 h: the values were significantly higher in the carbohydrate-restricted (12 or 24%) rat pups when compared with control or carbohydrate-free (0% glucose) offspring. No effects of dietary treatment were apparent by day 6. However, the reemergence of a significant difference in brain 5-HT content at day 15 postpartum indicates that even when energy intake is adequate the level of carbohydrate in the maternal diet may continue to play a role in modulating serotonergic neurotransmitter levels later in development.

Shambaugh, G. E. (1985). Ketone body metabolism in the mother and fetus. Federation proceedings, 44(7), 2347–51. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3884390

Pregnancy is characterized by a rapid accumulation of lipid stores during the first half of gestation and a utilization of these stores during the latter half of gestation. Lipogenesis results from dietary intake, an exaggerated insulin response, and an intensified inhibition of glucagon release. Increasing levels of placental lactogen and a heightened response of adipose tissue to additional lipolytic hormones balance lipogenesis in the fed state. Maternal starvation in late gestation lowers insulin, and lipolysis supervenes. The continued glucose drain by the conceptus aids in converting the maternal liver to a ketogenic organ, and ketone bodies produced from incoming fatty acids are not only utilized by the mother but cross the placenta where they are utilized in several ways by the fetus: as a fuel in lieu of glucose; as an inhibitor of glucose and lactate oxidation with sparing of glucose for biosynthetic disposition; and for inhibition of branched-chain ketoacid oxidation, thereby maximizing formation of their parent amino acids. Ketone bodies are widely incorporated into several classes of lipids including structural lipids as well as lipids for energy stores in fetal tissues, and may inhibit protein catabolism. Finally, it has recently been shown that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal rat brain slices. Thus during maternal starvation ketone bodies may maximize chances for survival both in utero and during neonatal life by restraining cell replication and sustaining protein and lipid stores in fetal tissues.

Yeh, Y. Y., & Sheehan, P. M. (1985). Preferential utilization of ketone bodies in the brain and lung of newborn rats. Federation proceedings, 44(7), 2352–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3884391

Persistent mild hyperketonemia is a common finding in neonatal rats and human newborns, but the physiological significance of elevated plasma ketone concentrations remains poorly understood. Recent advances in ketone metabolism clearly indicate that these compounds serve as an indispensable source of energy for extrahepatic tissues, especially the brain and lung of developing rats. Another important function of ketone bodies is to provide acetoacetyl-CoA and acetyl-CoA for synthesis of cholesterol, fatty acids, and complex lipids. During the early postnatal period, acetoacetate (AcAc) and beta-hydroxybutyrate are preferred over glucose as substrates for synthesis of phospholipids and sphingolipids in accord with requirements for brain growth and myelination. Thus, during the first 2 wk of postnatal development, when the accumulation of cholesterol and phospholipids accelerates, the proportion of ketone bodies incorporated into these lipids increases. On the other hand, an increased proportion of ketone bodies is utilized for cerebroside synthesis during the period of active myelination. In the lung, AcAc serves better than glucose as a precursor for the synthesis of lung phospholipids. The synthesized lipids, particularly dipalmityl phosphatidylcholine, are incorporated into surfactant, and thus have a potential role in supplying adequate surfactant lipids to maintain lung function during the early days of life. Our studies further demonstrate that ketone bodies and glucose could play complementary roles in the synthesis of lung lipids by providing fatty acid and glycerol moieties of phospholipids, respectively. The preferential selection of AcAc for lipid synthesis in brain, as well as lung, stems in part from the active cytoplasmic pathway for generation of acetyl-CoA and acetoacetyl-CoA from the ketone via the actions of cytoplasmic acetoacetyl-CoA synthetase and thiolase.