Cesarean Delivery Impacts Infant Brain Development.

BACKGROUND AND PURPOSE: The cesarean delivery rate has increased globally in the past few decades. Neurodevelopmental outcomes associated with cesarean delivery are still unclear. This study investigated whether cesarean delivery has any effect on the brain development of offspring. MATERIALS AND METHODS: A total of 306 healthy children were studied retrospectively. We included 3 cohorts: 2-week-old neonates (cohort 1, n = 32/11 for vaginal delivery/cesarean delivery) and 8-year-old children (cohort 2, n = 37/23 for vaginal delivery/cesarean delivery) studied at Arkansas Children's Hospital, and a longitudinal cohort of 3-month to 5-year-old children (cohort 3, n = 164/39 for vaginal delivery/cesarean delivery) studied independently at Brown University. Diffusion tensor imaging, myelin water fraction imaging, voxel-based morphometry, and/or resting-state fMRI data were analyzed to evaluate white matter integrity, myelination, gray matter volume, and/or functional connectivity, respectively. RESULTS: While not all MR imaging techniques were shared across the institutions/cohorts, post hoc analyses showed similar results of potential effects of cesarean delivery. The cesarean delivery group in cohort 1 showed significantly lower white matter development in widespread brain regions and significantly lower functional connectivity in the brain default mode network, controlled for a number of potential confounders. No group differences were found in cohort 2 in white matter integrity or gray matter volume. Cohort 3 had significantly different trajectories of white matter myelination between groups, with those born by cesarean delivery having reduced myelin in infancy but normalizing with age. CONCLUSIONS: Cesarean delivery may influence infant brain development. The impact may be transient because similar effects were not observed in older children. Further prospective and longitudinal studies may be needed to confirm these novel findings.

Brain functional magnetic resonance imaging response to glucose and fructose infusions in humans.

AIMS: In animals, intracerebroventricular glucose and fructose have opposing effects on appetite and weight regulation. In humans, functional brain magnetic resonance imaging (fMRI) studies during glucose ingestion or infusion have demonstrated suppression of hypothalamic signalling, but no studies have compared the effects of glucose and fructose. We therefore sought to determine if the brain response differed to glucose vs. fructose in humans independently of the ingestive process. METHODS: Nine healthy, normal weight subjects underwent blood oxygenation level dependent (BOLD) fMRI measurements during either intravenous (IV) glucose (0.3 mg/kg), fructose (0.3 mg/kg) or saline, administered over 2 min in a randomized, double-blind, crossover study. Blood was sampled every 5 min during a baseline period and following infusion for 60 min in total for glucose, fructose, lactate and insulin levels. RESULTS: No significant brain BOLD signal changes were detected in response to IV saline. BOLD signal in the cortical control areas increased during glucose infusion (p = 0.002), corresponding with increased plasma glucose and insulin levels. In contrast, BOLD signal decreased in the cortical control areas during fructose infusion (p = 0.006), corresponding with increases of plasma fructose and lactate. Neither glucose nor fructose infusions significantly altered BOLD signal in the hypothalamus. CONCLUSION: In normal weight humans, cortical responses as assessed by BOLD fMRI to infused glucose are opposite to those of fructose. Differential brain responses to these sugars and their metabolites may provide insight into the neurologic basis for dysregulation of food intake during high dietary fructose intake.

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.

OBJECTIVE: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. RESEARCH DESIGN AND METHODS: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. RESULTS: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). CONCLUSION: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity.

We hypothesized that certain proteins encoded by temperature-responsive genes in brown adipose tissue (BAT) contribute to the remarkable metabolic shifts observed in this tissue, thus prompting a differential mRNA expression analysis to identify candidates involved in this process in mouse BAT. An mRNA species corresponding to a novel partial-length gene was found to be induced 2-3-fold above the control following cold exposure (4 degrees C), and repressed approximately 70% by warm acclimation (33 degrees C, 3 weeks) compared with controls (22 degrees C). The gene displayed robust BAT expression (i.e. approximately 7-100-fold higher than other tissues in controls). The full-length murine gene encodes a 594 amino acid ( approximately 67 kDa) open reading frame with significant homology to the human hypothetical acyl-CoA thioesterase KIAA0707. Based on cold-inducibility of the gene and the presence of two acyl-CoA thioesterase domains, we termed the protein brown-fat-inducible thioesterase (BFIT). Subsequent analyses and cloning efforts revealed the presence of a novel splice variant in humans (termed hBFIT2), encoding the orthologue to the murine BAT gene. BFIT was mapped to syntenic regions of chromosomes 1 (human) and 4 (mouse) associated with body fatness and diet-induced obesity, potentially linking a deficit of BFIT activity with exacerbation of these traits. Consistent with this notion, BFIT mRNA was significantly higher ( approximately 1.6-2-fold) in the BAT of obesity-resistant compared with obesity-prone mice fed a high-fat diet, and was 2.5-fold higher in controls compared with ob/ob mice. Its strong, cold-inducible BAT expression in mice suggests that BFIT supports the transition of this tissue towards increased metabolic activity, probably through alteration of intracellular fatty acyl-CoA concentration.

Perspectives on the biology of uncoupling protein (UCP) homologues.

In mammals, it is believed that a portion of tissue metabolic rate is driven by counteraction of uncoupling, in which the energetically inefficient process of proton leak acts to diminish the mitochondrial electrochemical membrane potential. It is proposed that specific proteins associated with the mitochondrion catalyse uncoupling, and the biology of such putative uncoupling proteins (UCPs) is the subject of active research efforts. UCP4 and UCP5 are interesting in light of their abundant expression in the brain, which may signal an important metabolic function in thermogenesis or regulation of reactive oxygen species in that tissue. While each is expressed to various degrees outside of the brain, their impact on whole-animal metabolism remains to be clarified further. Transgenic mice expressing murine UCP5(L), the long isoform of UCP5, using an inducible metallothionine promoter (to drive expression of the transgene in liver, testis, heart, lung, spleen, intestine, kidney and brain) did not display any overt metabolic phenotype, despite liver UCP5(L) mRNA expression equivalent to that of normal mouse brain. This highlights the need for further studies to examine the nature of UCP5 physiology. Evidence for uncoupling behaviour has recently emerged from studies of the human 2-oxoglutarate carrier (OGC), indicating that the possibility of physiological proton leak elicited by the OGC and other mitochondrial carriers warrants further experimental evaluation.

Improving the delivery of adolescent clinical preventive services through skills-based training.

OBJECTIVE: To examine the efficacy of skills-based training workshops on primary care providers' screening and counseling practices with adolescents during routine outpatient well visits. DESIGN: Sixty-three primary care providers in outpatient pediatric departments within a managed health care organization participated in two 4-hour workshops on clinical preventive services for adolescents. The workshops focused on adolescent health, confidentiality, screening, and anticipatory guidance/brief counseling for 5 risk behaviors including: helmet and seatbelt use, tobacco use, alcohol use, and sexual behavior. A pre/posttest design was used to assess clinicians' screening and counseling practices during the pretraining and posttraining periods. Independent adolescent reports of clinicians' practices were obtained from 2 samples of 14- to 16-year-old adolescents immediately after their routine well visit in the outpatient clinics. One sample of adolescents reported during a pretraining period and a separate sample reported during a period after the training. RESULTS: Adolescent reports indicated that after the training workshops, the average percentage of adolescents screened by their primary care providers increased significantly for seatbelt use (from mean 38% to 56%), helmet use (from mean 27% to 45%), tobacco use (from mean 64% to 76%), alcohol use (from mean 59% to 76%), and sexual behavior (from mean 61% to 75%). Additionally, the average percentage of adolescents offered brief counseling by their clinicians increased significantly after training in the areas of seatbelt use (from mean 36% to 51%), helmet use (from mean 25% to 43%), and sexual behavior (from mean 42% to 58%). Improvement after the training in brief counseling for tobacco use was marginally significant (from mean 60% to 69%) and for alcohol use was not significant, although there was an increase. Clinicians also significantly increased their discussion of the limits of confidentiality with their adolescent patients after the training workshops (from mean 32% to 45%). CONCLUSIONS: This study offers strong support for the efficacy of skills-based training for primary care providers as a method for increasing screening and counseling practices with adolescents. The present findings suggest that with appropriate skills-based training, practicing clinicians can implement several of the national guidelines that direct them to provide preventive services for multiple behaviors in a routine outpatient visit. Screening and counseling in these visits are important in the early identification, detection, and prevention of behaviors associated with the primary adolescent morbidities and mortalities. Thus, enhancing the delivery of clinical preventive services is an important step in the prevention of untoward health outcomes for youth.

Overexpression of the human 2-oxoglutarate carrier lowers mitochondrial membrane potential in HEK-293 cells: contrast with the unique cold-induced mitochondrial carrier CGI-69.

Using differential mRNA expression analysis, a previously uncharacterized gene was found to be up-regulated 2-fold in brown adipose tissue (BAT) of mice exposed to cold (4 degrees C) for 48 h. Contig and homology analysis revealed that the gene represents the murine orthologue to a sequence from a public database encoding a putative human protein (CGI-69). The presence of mitochondrial carrier domains in the human protein, its transmembrane topology and cold-induction of the mouse CGI-69 gene in BAT prompted an analysis of the idea that CGI-69 may represent a new uncoupling protein (UCP) functional homologue. However, transfection of human CGI-69 isoforms in HEK-293 cells yielded no change in mitochondrial membrane potential (Deltapsi(m)), despite localization of FLAG-tagged CGI-69 to mitochondria of MCF7 cells. Surprisingly, overexpression of the human 2-oxoglutarate carrier (OGC) protein (originally designed as a negative control) sparked a significant drop in Deltapsi(m), possibly signalling a previously unappreciated uncoupling activity for the OGC.

Can it be done? Implementing adolescent clinical preventive services.

OBJECTIVE: To evaluate the implementation of an intervention to increase the delivery of adolescent preventive services within a large managed care organization. Target health areas were tobacco, alcohol, sexual behavior, and safety (seat belt and helmet use). DATA SOURCE/STUDY DESIGN: Adolescent reports of clinician screening and counseling were obtained from adolescents who attended well visits with their primary care providers. A prepost study design was used to evaluate the preventive services intervention. The intervention had three components: (1) 89 clinicians from three outpatient pediatric clinics attended a training to increase the delivery of preventive services; (2) customized adolescent screening and provider charting forms were integrated into the clinics; and (3) the resources of a health educator were provided to the clinics. DATA COLLECTION: Following a visit, adolescents completed surveys reporting on clinician screening and counseling for each of the target risk areas. Preimplementation (three months), 104 adolescents completed surveys. Postimplementation of the training, tools, and health educator intervention, 211 adolescents completed surveys (five months). For 18 months postimplementation clinicians delivered services and 998 adolescents completed surveys. PRINCIPAL FINDINGS: Chi-square analyses of changes in screening from preimplementation to postimplementation showed that screening increased in all areas (p < .000), with an average increase in screening rates from 47 percent to 94 percent. Postimplementation counseling in all areas also increased significantly, with an average increase in counseling rates from 39 percent to 91 percent. There were slight decreases in screening from postimplementation to follow-up. CONCLUSIONS: This study offers support for the efficacy of providing training, tools, and resources as a method for increasing preventive screening and counseling of adolescents across multiple risky health behaviors during a routine office visit.

Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation.

Mitochondrial uncoupling proteins have been implicated in the maintenance of metabolic rate and adaptational thermoregulation. We recently reported the identification of a brain-specific mitochondrial uncoupling protein homologue, UCP4. Here we characterized another newly described member of the uncoupling protein family, termed UCP5 (also called BMCP1). UCP5 transcripts are present in multiple human and mouse tissues, with an especially high abundance in the brain and testis. Expression of UCP5 in mammalian cells reduces the mitochondrial membrane potential. Multiple isoforms of UCP5 were identified and exhibited tissue-specific distribution and different potency in reduction of membrane potential. Furthermore, the mRNA abundance of both UCP4 and UCP5 is modulated by nutritional status or temperature in a tissue-specific manner in mice. Brain UCP4 and UCP5 mRNA transcripts rose by 1.5- and 1.7-fold, respectively, and liver UCP5 expression increased by 1.8-fold in response to acute cold exposure. A high-fat diet increased UCP5 mRNA in liver by 1.6-fold selectively in the obesity-resistant A/J but not in the obesity-prone C57BL/6J mouse strain. Liver UCP5 expression decreased significantly with a 24 h fast and was restored to the normal level after refeeding. In contrast, brain transcripts for both genes were not significantly altered by fasting or high-fat diet. These findings are consistent with the notion that UCP4 and UCP5 may be involved in tissue-specific thermoregulation and metabolic changes associated with nutritional status.

Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics.

Linking tissue uncoupling protein (UCP) homolog abundance with functional metabolic outcomes and with expression of putative genetic regulators promises to better clarify UCP homolog physiological function. A murine endotoxemia model characterized by marked alterations in thermoregulation was employed to examine the association between heat production, UCP homolog expression, and mitochondrial proton leak ("uncoupling"). After intraperitoneal lipopolysaccharide (LPS, approximately 6 mg/kg) injection, colonic temperature (T(c)) in adult female C57BL6/J mice dropped to a nadir of approximately 30 degrees C by 8 h, preceded by a four- to fivefold drop in liver UCP2 and UCP5/brain mitochondrial carrier protein 1 mRNA levels, with no change in their hindlimb skeletal muscle (SKM) expression. SKM UCP3 mRNA rose fivefold during development of hypothermia and was correlated with an LPS-induced increase in plasma free fatty acid concentration. UCP2 and UCP5 transcripts recovered about three- to sixfold in both tissues starting at 6-8 h, preceding a recovery of T(c) between 16 and 24 h. SKM UCP3 followed an opposite pattern. Such results are not consistent with an important influence of UCP3 in driving heat production but do not preclude a role for UCP2 or UCP5 in this process. The transcription coactivator PGC-1 displayed a transient LPS-evoked rise (threefold) or drop (two- to fivefold) in SKM and liver expression, respectively. No differences between control and LPS-treated mouse liver or SKM in vitro mitochondrial proton leak were evident at time points corresponding to large differences in UCP homolog expression.

Uncoupling protein homologs: emerging views of physiological function.

The widespread occurrence of excess weight and related diseases demands that efforts be made to understand energy expenditure from the gene to the whole animal. For some time, it has been understood that mitochondrial oxidation of fuels generates an electrochemical gradient via outward pumping of protons by the electron transport chain. ATP production via F(1)F(0) ATP synthase is then facilitated by the inward flux of protons down the gradient. There is a growing appreciation that a significant portion of the metabolic rate of endotherms is attributable to counteracting "proton leak" (uncoupling), wherein a flux of protons down the electrochemical gradient generates heat independently of ATP production. Proton leak is especially apparent in thermogenic brown adipose tissue, which expresses a tissue-specific uncoupling protein (UCP1). The recent discovery of widely expressed putative UCP1 homologs [UCP2, UCP3, UCP4, UCP5/brain mitochondrial carrier protein-1 (BMCP1)] raised the possibility that innate proton leak and metabolic rate are regulated by UCP1-like proteins. On the basis of current published data, one may not exclude the possibility that UCP homologs influence metabolic rate.

UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells.

Uncoupling proteins (UCPs) are a family of mitochondrial transporter proteins that have been implicated in thermoregulatory heat production and maintenance of the basal metabolic rate. We have identified and partially characterized a novel member of the human uncoupling protein family, termed uncoupling protein-4 (UCP4). Protein sequence analyses showed that UCP4 is most related to UCP3 and possesses features characteristic of mitochondrial transporter proteins. Unlike other known UCPs, UCP4 transcripts are exclusively expressed in both fetal and adult brain tissues. UCP4 maps to human chromosome 6p11.2-q12. Consistent with its potential role as an uncoupling protein, UCP4 is localized to the mitochondria and its ectopic expression in mammalian cells reduces mitochondrial membrane potential. These findings suggest that UCP4 may be involved in thermoregulatory heat production and metabolism in the brain.

Expression and possible role of muscle-type carnitine palmitoyltransferase I during sperm development in the rat.

Because we had found whole testis from adult rats to be much richer in the messenger RNA for the muscle (M) than for the liver (L) form of mitochondrial carnitine palmitoyltransferase I (CPT I), we sought to determine which cell type(s) accounts for this expression pattern and how it might relate to reproductive function. Studies with immature (14-day-old) and adult animals included 1) Northern blot analysis of testis mRNA; 2) in situ hybridization with slices of testis; 3) enzyme assays for CPT I, CPT II, and carnitine acetyltransferase (CAT) in testicular germ cells and nongerm cells, together with measurement of the malonyl-coenzyme A (CoA) sensitivity and affinity for carnitine of CPT I; 4) labeling of testicular CPT I with [3H]etomoxir, a covalent inhibitor of the enzyme; and 5) the response of testicular and nontesticular CPT I to dietary etomoxir. The data established the following: 1) L-CPT I was the sole isoform detected in immature testis. 2) Expression of the M-CPT I gene was associated only with meiotic and postmeiotic germ cells. 3) Adult testis contains a mixture of the L- and M-CPT I enzymes, the L and M form dominating in extratubular cells and spermatids, respectively. Mature epididymal spermatozoa appear to be devoid of CPT I activity while possessing abundant levels of CPT II and CAT. 4) Five days of dietary etomoxir treatment at a dose that resulted in essentially complete inhibition of CPT I in liver, heart, skeletal muscle, and kidney was totally without effect on either the L- or M-type enzyme in the testis of mature rats. The data point to an important role for transient expression of M-CPT I, coupled with sustained activity of CAT, in the maturation and/or function of rat sperm. They also suggest that, at least in the case of one CPT I inhibitor (etomoxir), the testis is unusually resistant to the agent when given orally.

Psychological predictors of good health in three longitudinal samples of educated midlife women.

Concurrent and longitudinal associations between cognitive and affective personality variables--intellectual efficiency (IE), anxiety, and hostility--and observer ratings of physical health were examined in 3 longitudinal samples of women: Mills Longitudinal Study (n = 101); Radcliffe Study (RS, n = 118); and University of California, San Francisco Study (n = 44). Observer ratings of health were based on participants' reports of health problems. The California Psychological Inventory (H. G. Gough, 1996) IE, Hostility, and Anxiety Scales were used in all studies at Times 1 and 2, except in RS, when at Time 1 the Zung Anxiety (W. K. Zung, 1971) and the Profile of Mood States (D. M. McNair, M. Lorr, & L. F. Droppleman, 1971) Hostility Scales were used. In the majority of analyses, IE was positively associated with good health, and Anxiety and Hostility were negatively associated with health. IE was the strongest independent predictor of health, indicating that cognitive characteristics may have an important role in health and should be examined further.

Acetogenesis does not replace ketogenesis in fasting piglets infused with hexanoate.

The current studies were performed to better understand the physiological relevance of acetate in the poorly ketogenic piglet and to determine if endogenous acetogenesis rises with increased mitochondrial fatty acid beta-oxidation, analogous to ketogenesis. Plasma acetate concentration values in newborn, fasted, or suckled piglets (230-343 microM) were at least 10-fold higher than the ketone bodies, a pattern opposite to that in 24- to 48-h suckled rats (77-175 microM). Employing continuous infusion techniques with sodium [3H]acetate tracer in fasting approximately 40-h-old piglets, acetate rate of appearance (Ra) was found to be 34 +/- 4 micromol . min-1 . kg body wt-1. This basal Ra was double that observed in animals coinfused with sodium [1-14C]hexanoate (P < 0.001), despite active oxidation of the latter as determined by 14CO2 production. Active acetogenesis in vivo and relatively abundant acetate in piglet blood are consistent with the hypothesis that acetate plays an important physiological role in piglets. However, the negative impact of hexanoate oxidation upon acetate Ra and the lack of significant changes in circulating acetate in newborn, suckled, and fasted piglets draws into question the extent of analogy between acetogenesis and ketogenesis in vivo.

A hostility scale for the California Psychological Inventory: MMPI, observer Q-sort, and big-five correlates.

Using two samples, we developed and validated a hostility scale that can be scored from the California Psychological Inventory (CPI) and serves as an alternate for the Cook-Medley Hostility Scale (Ho; Cook & Medley, 1954). The CPI Hostility (H) scale consists of 33 items that are either duplicates or close equivalents of specific Ho items, and the two scales correlate at least .90 in samples differing in sex. The H and Ho scales show a similar pattern of correlations with conceptually relevant MMPI scales and with observer-rated personality attributes tapping Barefoot, Peterson, et al.'s (1991) five hostility categories of Hostile Affect, Cynicism, Aggressive Responding, Social Avoidance, and Hostile Attributions. These findings provide evidence for the equivalence of the two hostility scales, as well as external validation for those personality characteristics that are purported to underlie the construct of hostility as tapped by both the original Ho scale and the new CPI H scale.

Gene expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in a poorly ketogenic mammal: effect of starvation during the neonatal period of the piglet.

The low ketogenic capacity of pigs correlates with a low activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase. To identify the molecular mechanism controlling such activity, we isolated the pig cDNA encoding this enzyme and analysed changes in mRNA levels and mitochondrial specific activity induced during development and starvation. Pig mitochondrial synthase showed a tissue-specific expression pattern. As with rat and human, the gene is expressed in liver and large intestine; however, the pig differs in that mRNA was not detected in testis, kidney or small intestine. During development, pig mitochondrial HMG-CoA synthase gene expression showed interesting differences from that in the rat: (1) there was a 2-3 week lag in the postnatal induction; (2) the mRNA levels remained relatively abundant through the suckling-weaning transition and at maturity, in contrast with the fall observed in rats at similar stages of development; and (3) the gene expression was highly induced by fasting during the suckling, whereas no such change in mitochondrial HMG-CoA synthase mRNA levels has been observed in rat. The enzyme activity of mitochondrial HMG-CoA synthase increased 27-fold during starvation in piglets, but remained one order of magnitude lower than rats. These results indicate that post-transcriptional mechanism(s) and/or intrinsic differences in the encoded enzyme are responsible for the low activity of pig HMG-CoA synthase observed throughout development or after fasting.

Hepatic fatty acid metabolism in pigs and rats: major differences in endproducts, O2 uptake, and beta-oxidation.

Models of mammalian hepatic lipid metabolism are based largely on observations made in adult rats, emphasizing ketogenesis as a primary adjunct to mitochondrial beta-oxidation. Studies using piglets have illustrated the divergent nature of intermediary metabolism in this model, wherein ketogenesis and beta-oxidation are small and acetogenesis is an important route of fuel carbon flux. To clarify potential species differences in hepatic lipid metabolism and its control, we compared O2 consumption and metabolic end products in fasted pig and rat liver homogenates treated with 1-[14C]C16:0. Carboxyl carbon accumulation in acid-soluble products (ASP) plus CO2 was threefold greater and O2 consumption was twofold greater in rats (P < 0.05). Unlike rats, pigs showed negligible carboxyl carbon accumulation in ketone bodies (3-7% of ASP), whereas acetate was a carboxyl carbon reservoir in both animals (17-31% of ASP in pigs). Malonate increased (approximately 2-fold) and antimycin/rotenone decreased (40-60%) radiolabel accumulation in acetate. These data concur with the hypotheses that comparatively low hepatic beta-oxidative flux in piglets is partially related to a smaller metabolic rate and that substantial acetogenesis occurs intramitochondrially in both pigs and rats.

Acetate represents a major product of heptanoate and octanoate beta-oxidation in hepatocytes isolated from neonatal piglets.

An experiment was conducted to explore the nature of the radiolabel distribution in acid-soluble products (ASPs) resulting from the oxidation of [1-14C]C7:0 or C8:0 by isolated piglet hepatocytes. The differences between odd and even chain-length and the impacts of valproate and malonate upon the rate of beta-oxidation and ASP characteristics were tested. A minor amount of fatty acid carboxyl carbon (< or = 10% of organic acids identified by radio-HPLC) accumulated in ketone bodies regardless of chain-length or inhibitor used. In all cases, acetate represented the major reservoir of carboxyl carbon, accounting for 60-70% of radiolabel in identified organic acids. Cells given [1-14C]C7:0 accumulated 85% more carboxyl carbon in Krebs cycle intermediates when compared with C8:0, while accumulation in acetate was unaffected. The results are consistent with the hypothesis that anaplerosis from odd-carbon fatty acids affects the oxidative fate of fatty acid carbon. The piglet appears unique in that non-ketogenic routes of fatty acid carbon flow (i.e. acetogenesis) predominate in the liver of this species.

Carnitine palmitoyltransferase modulation of hepatic fatty acid metabolism and radio-HPLC evidence for low ketogenesis in neonatal pigs.

A neonatal piglet model was used to study hepatic fatty acid metabolism during the early postnatal period. Hepatocytes were isolated from pigs at birth or after 24 h, in fed or unfed states (n = 4 pigs/group). Cells were incubated with 1 mmol/L [1-(14)C]-octanoate (C8) or -palmitate (C16) in the presence or absence of 1 mmol/L L-carnitine, carnitine plus tetradecylglycidic acid (TDGA; 10 mumol/L) or carnitine plus glucagon (0.5 microgram/L). Accumulation of radiolabel [nmol/(h. 10(6) cells)] in CO2 and acid-soluble products (ASP) was higher (3.5- and 4.5-fold, respectively) from C8 than from C16 (P < 0.0001). Glucagon, carnitine and TDGA had no effect on the oxidation of C8 (P > 0.1). Carnitine addition tended to increase C16 flux to ASP [from 5.3 to 7.6 nmol/(h. 10(6) cells); P < 0.1], whereas carnitine plus TDGA decreased flux (from 7.6 to 2.1; P < 0.001). Esterified products accounted for 70% of metabolized label in control C16 incubations; this was reduced to 62% by carnitine (P < 0.05) and increased to 80% by the addition of carnitine plus TDGA (P < 0.0001). The 1-(14)C flux to CO2 in cells from 24-h-old unfed piglets was 47% lower than from fed pigs (P < 0.01) but 28% higher than in pigs at birth. Radiolabel contained in ASP and total metabolized label were 48% lower from unfed pigs compared with the piglets at birth and 24-h-old fed pigs (P < 0.01) and were paralleled by changes in oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)