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Biomedical subjects

Stephen C Cunnane

Publications and source records attributed to Stephen C Cunnane.

At least 19 recordsLinked to original sources
PubMed2006

Omega-3 fatty acids, energy substrates, and brain function during aging.

The maintenance of optimal cognitive function is a central feature of healthy aging. Impairment in brain glucose uptake is common in aging associated cognitive deterioration, but little is known of how this problem arises or whether it can be corrected or bypassed. Several aspects of the challenge to providing the brain with an adequate supply of fuel during aging seem to relate to omega-3 fatty acids. For instance, low intake of omega-3 fatty acids, especially docosahexaenoic acid (DHA), is becoming increasingly associated with several forms of cognitive decline in the elderly, particularly Alzheimer's disease. Brain DHA level seems to be an important regulator of brain glucose uptake, possibly by affecting the activity of some but not all the glucose transporters. DHA synthesis from either alpha-linolenic acid (ALA) or eicosapentaenoic acid (EPA) is very low in humans begging the question of whether these DHA precursors are likely to be helpful in maintaining cognition during aging. We speculate that ALA and EPA may well have useful supporting roles in maintaining brain function during aging but not by their conversion to DHA. ALA is an efficient ketogenic fatty acid, while EPA promotes fatty acid oxidation. By helping to produce ketone bodies, the effects of ALA and EPA could well be useful in strategies intended to use ketones to bypass problems of impaired glucose access to the brain during aging. Hence, it may be time to consider whether the main omega-3 fatty acids have distinct but complementary roles in brain function.

Aging↗
PubMed2006

Markedly raised intake of saturated and monounsaturated fatty acids in rats on a high-fat ketogenic diet does not inhibit carbon recycling of 13C-alpha-linolenate.

Under various dietary and physiological conditions, carbon from alpha-linolenic acid (ALA) is extensively recycled into saturated and monounsaturated fatty acids. In this study we investigated whether carbon is still recycled from ALA when a dietary source of saturated and monounsaturated fatty acids is provided in excess. 13C-labeled ALA was given to rats consuming a high-fat ketogenic diet and to rats consuming a low-fat control diet. In rats on the ketogenic diet, 13C recycling from alpha-linolenate into several, but not all, saturated and monounsaturated fatty acids matched or exceeded that in the controls (P < 0.05). We conclude that carbon recycling into saturated and monounsaturated fatty acids persists when the main end products of ALA recycling are provided in excess, using a ketogenic diet.

Animals↗
PubMed2005

Suckling rats actively recycle carbon from alpha-linolenate into newly synthesized lipids even during extreme dietary deficiency of n-3 polyunsaturates.

Docosahexaenoate is usually considered to be the principal endpoint of alpha-linolenate metabolism in mammals. Nevertheless, several studies over the past 30 y have shown that more carbon from alpha-linolenate is recycled into newly synthesized lipids than is used to make docosahexaenoate. Our objective in this study was to assess carbon recycling from alpha-linolenate in suckling rats made deficient in n-3 polyunsaturated fatty acids (PUFA). Female Long-Evans rats were given a diet deficient in n-3 PUFA at weaning and then bred 8 wk later. Pups from the second generation were nursed by their respective dams and gavaged with 1 mg [U-13C]-alpha-linolenate at 10 d old. Brain and liver were obtained 24 h later, and the fatty acid profiles and 13C enrichment analyzed. Docosahexaenoate was markedly depleted in brain (-82%) and liver (-97%) of the n-3 PUFA-deficient rats. In the controls, 13C enrichment in products of carbon recycling (cholesterol and fatty acids other than n-3 PUFA) exceeded that in docosahexaenoate by 2.4-fold (liver) and 7.5-fold (brain). n-3 PUFA deficiency reduced the ratio of 13C enrichment in products of carbon recycling compared with 13C incorporated into docosahexaenoate by 63% in the brain but not in the liver. Despite severe n-3 PUFA deficiency, carbon recycling still consumed 50% more 13C from alpha-linolenate than went into docosahexaenoate in the liver and 2.8-fold more in the brain. We conclude that carbon recycling is an integral part of neonatal metabolism of alpha-linolenate and is not simply an overflow pathway arising from excess availability of preformed docosahexaenoate.

Animals↗
PubMed2005

Breath acetone predicts plasma ketone bodies in children with epilepsy on a ketogenic diet.

OBJECTIVE: The high-fat ketogenic diet has long been used to treat refractory childhood seizures, but whether there is a relation between the degree of ketosis and effectiveness of seizure control remains unclear. Frequent measurements of plasma ketones are difficult in children so the goal was to determine the utility of breath acetone as a marker of systemic ketosis and seizure control in children given the ketogenic diet because of seizures refractory to medication. METHODS: In experiment I, breath acetone and plasma ketones were assessed every 2 h during an 8-h test day in seven children. In experiment II, a preliminary assessment of the possible relation between breath acetone and seizure frequency was made over 14 d in five children and one adolescent on the ketogenic diet. RESULTS: Breath acetone was positively and curvilinearly related to plasma acetone (r2 = 0.99, P < 0.0001), plasma acetoacetate (r2 = 0.89, P < 0.0001), and plasma beta-hydroxybutyrate (r2 = 0.94, P < 0.0001). No significant relation was found between breath acetone and seizure frequency or change in seizure frequency. CONCLUSIONS: Breath acetone is indicative of systemic ketosis while on the ketogenic diet. However, owing to the wide range of seizure types and plasma acetone, more subjects will be needed to determine whether there is a clear link between breath acetone and seizure frequency or decreased seizure frequency while on the high-fat ketogenic diet.

Adolescent↗
PubMed2005

Effects of a diet high in plant sterols, vegetable proteins, and viscous fibers (dietary portfolio) on circulating sterol levels and red cell fragility in hypercholesterolemic subjects.

Plant sterols, soy proteins, viscous fibers, and nuts are advised for cholesterol reduction, but their combined effect on plant sterol absorption has never been tested. We assessed their combined action on serum sterols in hyperlipidemic subjects who were following low-saturated fat diets before starting the study and who returned to these diets post-test. The 1-mon test (combination) diet was high in plant sterols (1 g/1,000 kcal), soy protein (23 g/1,000 kcal), viscous fiber (9 g/1,000 kcal), and almonds (14 g/1000 kcal). Fasting blood was obtained for serum lipids and sterols, and erythrocytes were obtained for fragility prior to and at 2-wk intervals during the study. The combination diet raised serum campesterol concentrations by 50% and beta-sitosterol by 27%, although these changes were not significant after Bonferroni correction; near-maximal rises were found by the end of the first week, but no change was found in red cell fragility despite a 29% reduction in the LDL cholesterol level. No significant associations were observed between changes in red cell fragility and blood lipids or sterols. We conclude that plant sterols had a minimal impact on serum sterol concentrations or red cell fragility in hyperlipidemic subjects on diets that greatly reduced their serum lipids.

Adult↗
PubMed2005

Despite transient ketosis, the classic high-fat ketogenic diet induces marked changes in fatty acid metabolism in rats.

In contrast to humans, rats on a high-fat ketogenic diet seem incapable of maintaining plasma beta-hydroxybutyrate above 1 mmol/L for more than a week. Our goal was to determine whether fatty acid metabolism in rats changes despite the absence of sustained ketosis induced by the ketogenic diet. Fatty acid metabolism was assessed as changes in tissue fatty acid profiles and change in 13C-alpha-linolenic acid incorporation into plasma, liver, adipose tissue, and brain lipids. Despite loss of ketosis, the ketogenic diet reduced some polyunsaturated fatty acids in adipose tissue (up to 44%) and plasma (up to 90%) but raised polyunsaturates in liver triglycerides by up to 25-fold and raised arachidonic and docosahexaenoic acids in the brain by 15%. Lower tissue incorporation of 13C-alpha-linolenic acid but higher unlabeled and 13C-labeled docosahexaenoic acid in brain supports the view that the principal changes in fatty acid composition resulted from enhanced mobilization of polyunsaturates from adipose tissue to liver and brain. In the absence of sustained ketosis, changes in fatty acid metabolism resulting in an increase in brain polyunsaturates, particularly docosahexaenoic acid may, nevertheless, contribute to the seizure protection by the ketogenic diet.

Adipose Tissue↗
PubMed2004

Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols.

AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by <10% and did not significantly change brain 7-dehydrocholesterol. Either lovastatin has a different mechanism of action than these late-stage cholesterol inhibitors or the brain sterol changes are not directly responsible for seizures in this model.

Animals↗
PubMed2004

Dietary 18:3omega3 influences immune function and the tissue fatty acid response to antigens and adjuvant.

Alpha-linolenic acid (18:3omega3) has many important physiological functions including being beta-oxidized, serving a precursor to the synthesis of other lipids and it has immunomodulation properties. The objective of the present study was to test the effects of immunization and dietary 18:3omega3 on immune function and the fatty acid profile of immunized pig tissues. Piglets suckled from sows consuming either a control or high 18:3omega3 diet until 14 days old when they were weaned onto a similar diet as the sow and were moved to a segregated nursery for the remainder of the study. At 35 days of age, pigs on both diets (2 x 2 factorial design) received either an injection containing hen eggwhite lysozyme (HEWL), killed Mycobacterium tuberculosis and Freund's complete adjuvant (immunized) or phosphate buffered saline (PBS) (non-immunized) into the neck followed by a booster injection 2 weeks later and induction of delayed-type hypersensitivity (DTH) one week later. Immunization increased (compared to non-immunized) while the high 18:3omega3 diet decreased haptoglobin by 30% compared to pigs consuming the control diet. Immunized pigs had a seven-fold increase in antibodies to HEWL and pigs consuming the high 18:3omega3 diet also had transiently higher levels of serum antibodies. There was a diet by immunization interaction on the DTH reaction such that immunized pigs consuming the high 18:3omega3 had the largest DTH reaction. The neck muscle proximal to the site of injection of immunized pigs had 10-30% lower levels of triglyceride and phospholipid linoleic (18:2omega6) and 18:3omega3 compared to non-immunized pigs. Thus, a high 18:3omega3 intake in pigs modulates immune function and tissue fatty acids in response to immunization.

Adjuvants, Immunologic↗
PubMed2004

Metabolism of polyunsaturated fatty acids and ketogenesis: an emerging connection.

This paper summarizes the emerging literature indicating that at least two polyunsaturated fatty acids (PUFA; linoleate, alpha-linolenate) are moderately ketogenic and that via ketone bodies significant amounts of carbon are recycled from these fatty acids into de novo synthesis of lipids including cholesterol, palmitate, stearate and oleate. This pathway (PUFA carbon recycling) is particularly active in several tissues during the suckling period when, depending on the tissue, >200 fold more carbon from alpha-linolenate can be recycled into newly synthesized lipids than is used to make docosahexaenoate. At least in rats, PUFA carbon recycling also occurs in adults and even during extreme linoleate deficiency. Hence, this pathway should be considered an obligatory component of PUFA metabolism. It is still speculative but part of the clinical benefit of the very high fat ketogenic diet in intractable seizures may be achieved by raising plasma levels of PUFA that have anti-seizure effects, especially arachidonate and docosahexaenoate. Hence, in addition to some PUFA being ketogenic substrates, the state of ketosis involves potentially beneficial changes in PUFA homeostasis. Both the molecular controls on these pathways and their clinical significance still need elucidation.

Animals↗
PubMed2003

Whole-body utilization of n-3 PUFA in n-6 PUFA-deficient rats.

We evaluated the utilization of a-linolenic acid (18:3n-3) in growing rats consuming a diet deficient in n-6 PUFA. After 90 d, whole-body 18:3n-3 accumulation was 55% lower, total n-3 PUFA accumulation was 21% lower, and 18:3n-3 disappearance was 14% higher in n-6 PUFA-deficient rats. Part of the reduction of whole-body 18:3n-3 in n-6 PUFA-deficient rats was due to the 25% increase in net conversion of 18:3n-3 to long-chain n-3 PUFA. Despite adequate 18:3n-3 intake, n-6 PUFA deficiency decreased the accumulation of 18:3n-3 and total n-3 PUFA.

Animals↗
PubMed2003

Why is carbon from some polyunsaturates extensively recycled into lipid synthesis?

We summarize here the evidence indicating that carbon from alpha-linolenate and linoleate is readily recycled into newly synthesized lipids. This pathway consumes the majority of these fatty acids that is not beta-oxidized as a fuel. Docosahexaenoate undergoes less beta-oxidation and carbon recycling than do alpha-linolenate or linoleate, but is it still actively metabolized by this pathway? Among polyunsaturates, arachidonate appears to undergo the least beta-oxidation and carbon recycling, an observation that may help account for the resistance of brain membranes to loss of arachidonate during dietary deficiency of n-6 polyunsaturates. Preliminary evidence suggests that de novo lipid synthesis consumes carbon from alpha-linolenate and linoleate in preference to palmitate, but this merits systematic study. Active beta-oxidation and carbon recycling of 18-carbon polyunsaturates does not diminish the importance of being able to convert alpha-linolenate and linoleate to long-chain polyunsaturates but suggests that a broad perspective is required in studying the metabolism of polyunsaturates in general and alpha-linolenate and linoleate in particular.

Animals↗
PubMed2003

Intramuscular injection of antigens and adjuvant preferentially decreases 18:2n-6 and 18:3n-3 in pig neck muscle.

Linoleic (18:2n-6) and alpha-linolenic acids (18:3n-3) have many important physiological functions including immunomodulation. We tested how immunization influences the metabolism of 18:2n-6 and 18:3n-3 in the neck muscle of pigs. At 35 d old, pigs received either an intramuscular neck injection containing hen egg white lysozyme (HEWL), killed Mycobacterium tuberculosis, and Freund's complete adjuvant (immunized) or PBS (control). At 49 d old, immunized pigs received a booster injection of HEWL and Freund's incomplete adjuvant, and the control pigs received PBS into the neck. At 56 d old, all pigs received an intradermal injection of Mycobacterium bovis into the hind leg to induce a delayed-type hypersensitivity (DTH) reaction. At 57 d old, immunized pigs had a twofold increase in serum haptoglobin, a 10-fold increase in antibodies to HEWL, and the skinfold at the DTH reaction site was 10 times thicker than the controls. Both 18:2n-6 and 18:3n-3 (% composition) were approximately 25% lower in muscle TG, 40% lower in FFA, 50% lower in phospholipids, but not different in cholesteryl esters of the neck muscle of immunized pigs. The antigens in this model induce an increased response in the innate (haptoglobin), humoral (antibodies), and cellular (DTH) immune systems as well as a preferential decrease of 18:2n-6 and 18:3n-3 in the inflamed neck muscle. It appears that 18:2n-6 and 18:3n-3 are preferentially metabolized (possibly beta-oxidized) in response to antigens.

Animals↗
PubMed2003

Dietary alpha-linolenic acid increases the n-3 PUFA content of sow's milk and the tissues of the suckling piglet.

alpha-Linolenic acid (18:3n-3) is a precursor to DHA (22:6n-3), which is essential for normal growth and development in the infant. This study was undertaken to assess how a raised 18:3n-3 intake in sows affects the n-3 PUFA content of the suckling piglet. Sows consumed a high-18:3n-3 or control diet (n-3 PUFA/n-6 PUFA, 0.5 vs. 0.05, respectively) for 10 d prior to parturition and for 14 d postpartum. Piglets suckled from their mothers until 14 d of age, when they were sacrificed. Sows consuming the high-18:3n-3 diet had 141% more 18:3n-3 and 86% more 22:6n-3 in their milk compared to control sows. There was no difference in the proximate composition of the piglets. The n-3/n-6 PUFA ratio was 82% higher in the milk of sows consuming the high-18:3n-3 diet compared to controls. Piglets suckling from sows consuming the high-18:3n-3 diet had 423% more 18:3n-3 in the carcass as well as a 460% higher n-3/n-6 PUFA ratio than controls. The piglets suckling from sows consuming the high-18:3n-3 diet had 333% more 18:3n-3 and 54% more 22:6n-3 in the liver, as well as a 114% higher n-3/n-6 ratio than control piglets. Piglets suckling from sows consuming a high-18:3n-3 diet also had 24% more 22:6n-3 and a 33% higher n-3/n-6 ratio in the brain compared to control piglets. A high 18:3n-3 intake in the sow increases not only the 18:3n-3 but also the 22:6n-3 content of sow's milk and the tissues of the suckling piglet.

Animals↗
PubMed2003

Problems with essential fatty acids: time for a new paradigm?

The term 'essential fatty acid' is ambiguous and inappropriately inclusive or exclusive of many polyunsaturated fatty acids. When applied most rigidly to linoleate and alpha-linolenate, this term excludes the now well accepted but conditional dietary need for two long chain polyunsaturates (arachidonate and docosahexaenoate) during infancy. In addition, because of the concomitant absence of dietary alpha-linolenate, essential fatty acid deficiency is a seriously flawed model that has probably led to significantly overestimating linoleate requirements. Linoleate and alpha-linolenate are more rapidly beta-oxidized and less easily replaced in tissue lipids than the common 'non-essential' fatty acids (palmitate, stearate, oleate). Carbon from linoleate and alpha-linolenate is recycled into palmitate and cholesterol in amounts frequently exceeding that used to make long chain polyunsaturates. These observations represent several problems with the concept of 'essential fatty acid', a term that connotes a more protected and important fatty acid than those which can be made endogenously. The metabolism of essential and non-essential fatty acids is clearly much more interconnected than previously understood. Replacing the term 'essential fatty acid' by existing but less biased terminology, i.e. polyunsaturates, omega3 or omega6 polyunsaturates, or naming the individual fatty acid(s) in question, would improve clarity and would potentially promote broader exploration of the functional and health attributes of polyunsaturated fatty acids.

Animals↗
PubMed2003

Survival of the fattest: fat babies were the key to evolution of the large human brain.

In the past 2 million years, the hominid lineage leading to modern humans evolved significantly larger and more sophisticated brains than other primates. We propose that the modern human brain was a product of having first evolved fat babies. Hence, the fattest (infants) became, mentally, the fittest adults. Human babies have brains and body fat each contributing to 11-14% of body weight, a situation which appears to be unique amongst terrestrial animals. Body fat in human babies provides three forms of insurance for brain development that are not available to other land-based species: (1) a large fuel store in the form of fatty acids in triglycerides; (2) the fatty acid precursors to ketone bodies which are key substrates for brain lipid synthesis; and (3) a store of long chain polyunsaturated fatty acids, particularly docosahexaenoic acid, needed for normal brain development. The triple combination of high fuel demands, inability to import cholesterol or saturated fatty acids, and dependence on docosahexaenoic acid puts the mammalian brain in a uniquely difficult situation compared with other organs and makes its expansion in early humans all the more remarkable. We believe that fresh- and salt-water shorelines provided a uniquely rich, abundant and accessible food supply, and the only viable environment for evolving both body fat and larger brains in human infants.

Adipose Tissue↗