There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white ...matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.
The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific ...knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.
Display omitted
•Hepatic fatty acid oxidation (FAO) is critical for liver physiology during starvation•Hepatic FAO suppresses adipose lipolysis and systemic catabolism•Upon fasting, loss of hepatic FAO induces Pparα target genes in the liver•A ketogenic diet induces severe lipolysis and lethality in hepatic FAO-deficient mice
Lee et al. have generated mice that lack mitochondrial long-chain fatty acid β-oxidation specifically in the liver. They report that these mice can survive a 24-hr fast but not a low-carbohydrate ketogenic diet. Surprisingly, whole-body energy expenditure is largely maintained due to increased peripheral catabolism.
While the brain's high energy demands are largely met by glucose, brain is also equipped with the ability to oxidize fatty acids for energy and metabolism. The brain expresses the carnitine ...palmitoyltransferases (CPTs) that mediate carnitine‐dependent entry of long‐chain acyl‐CoAs into the mitochondrial matrix for β‐oxidation – CPT1a and CPT2 located on the outer and inner mitochondrial membranes, respectively. Their developmental profile, regional distribution and activity as well as cell type expression remain unknown. We determined that brain CPT1a RNA and total protein expression were unchanged throughout post‐natal development (PND0, PND7, PND14, PND21 and PND50); however, CPT2 RNA peaked at PND 21 and remained unchanged through PND50 in all regions studied (cortex, hippocampus, midbrain, and cerebellum). Both long‐chain acyl CoA dehydrogenase and medium acyl‐CoA dehydrogenase showed a similar developmental profile to CPT2. Acylcarnitines, generated as a result of CPT1a activity, significantly increased with age and peaked at PND21 in all brain regions, concurrent with the increased expression of enzymes involved in mitochondrial β‐oxidation. The CPT system is highly enriched in vivo in hippocampus and cerebellum, relative to cortex and midbrain, and is exclusively present in astrocytes and neural progenitor cells, while absent in neurons, microglia, and oligodendrocytes. Using radiolabeled oleate, we demonstrate regional differences in brain fatty acid oxidation that may be blocked by the irreversible CPT1a inhibitor etomoxir. This study contributes to the field of knowledge in brain cell‐specific metabolic pathways, which are important for understanding normal brain development and aging, as well as pathophysiology of neurological diseases.
Read the Editorial Comment for this article on page 347.
The high metabolic demands of mammalian brain are largely met by glucose, but brain can also oxidize fatty acids. Here we describe the expression profiles of the enzymes required for mitochondrial β‐oxidation of fatty acids across early postnatal development in rat brain. We observed increased expression of the β‐oxidation enzymatic machinery through postnatal day 21, and these enzymes are enriched in astrocytes and neural progenitor cells. This work contributes to a better understanding of cell‐type‐specific brain metabolism during normal development.
Read the Editorial Comment for this article on page 347.
Brain development is a highly orchestrated complex process. The developing brain utilizes many substrates including glucose, ketone bodies, lactate, fatty acids and amino acids for energy, cell ...division and the biosynthesis of nucleotides, proteins and lipids. Metabolism is crucial to provide energy for all cellular processes required for brain development and function including ATP formation, synaptogenesis, synthesis, release and uptake of neurotransmitters, maintaining ionic gradients and redox status, and myelination. The rapidly growing population of infants and children with neurodevelopmental and cognitive impairments and life-long disability resulting from developmental brain injury is a significant public health concern. Brain injury in infants and children can have devastating effects because the injury is superimposed on the high metabolic demands of the developing brain. Acute injury in the pediatric brain can derail, halt or lead to dysregulation of the complex and highly regulated normal developmental processes. This paper provides a brief review of metabolism in developing brain and alterations found clinically and in animal models of developmental brain injury. The metabolic changes observed in three major categories of injury that can result in life-long cognitive and neurological disabilities, including neonatal hypoxia–ischemia, pediatric traumatic brain injury, and brain injury secondary to prematurity are reviewed.
Rats are frequently used for studying water content of normal and injured brain, as well as changes in response to various osmotherapeutic regimens. Magnetic resonance imaging in humans has shown ...that brain water content declines with age as a result of progressive myelination and other processes. The purpose of this study was to quantify changes in brain water content during rat development and aging. Brain water content was measured by standard techniques in 129 normal male Sprague-Dawley rats that ranged in age (weight) from 13 to 149 days (18 to 759 g). Overall, the results demonstrated a decrease in water content from 85.59% to 76.56% with increasing age (weight). Nonlinear allometric functions relating brain water to age and weight were determined. These findings provide age-related context for prior rat studies of brain water, emphasize the importance of using similarly aged controls in studies of brain water, and indicate that age-related changes in brain water content are not specific to humans.
There are several forms of acute pediatric brain injury, including neonatal asphyxia, pediatric cardiac arrest with global ischemia, and head trauma, that result in devastating, lifelong neurologic ...impairment. The only clinical intervention that appears neuroprotective is hypothermia initiated soon after the initial injury. Evidence indicates that oxidative stress, mitochondrial dysfunction, and impaired cerebral energy metabolism contribute to the brain cell death that is responsible for much of the poor neurologic outcome from these events. Recent results obtained from both
in vitro and animal models of neuronal death in the immature brain point toward several molecular mechanisms that are either induced or promoted by oxidative modification of macromolecules, including consumption of cytosolic and mitochondrial NAD
+ by poly-ADP ribose polymerase, opening of the mitochondrial inner membrane permeability transition pore, and inactivation of key, rate-limiting metabolic enzymes, e.g., the pyruvate dehydrogenase complex. In addition, the relative abundance of pro-apoptotic proteins in immature brains and neurons, and particularly within their mitochondria, predisposes these cells to the intrinsic, mitochondrial pathway of apoptosis, mediated by Bax- or Bak-triggered release of proteins into the cytosol through the mitochondrial outer membrane. Based on these pathways of cell dysfunction and death, several approaches toward neuroprotection are being investigated that show promise toward clinical translation. These strategies include minimizing oxidative stress by avoiding unnecessary hyperoxia, promoting aerobic energy metabolism by repletion of NAD
+ and by providing alternative oxidative fuels, e.g., ketone bodies, directly interfering with apoptotic pathways at the mitochondrial level, and pharmacologic induction of antioxidant and anti-inflammatory gene expression.
The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of ...hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2L−/− mice). Paradoxically, Cpt2L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.
Display omitted
•Loss of hepatic fatty acid oxidation (FAO) confers resistance to obesity•Loss of hepatic FAO results in beneficial hormesis•The suppression of FAO is sufficient to improve diet-induced glucose intolerance•Resistance to obesity results from increased energy expenditure
Lee et al. show that, contrary to expectations, the loss of hepatic fatty acid oxidation (FAO) confers resistance to weight gain and adiposity in response to a high-fat diet. Additionally, they show that loss of hepatic FAO—and, consequently, hepatic gluconeogenesis—protects mice from high-fat-diet-induced glucose intolerance.
Ambient temperature affects energy intake and expenditure to maintain homeostasis in a continuously fluctuating environment. Here, mice with an adipose-specific defect in fatty acid oxidation ...(Cpt2A−/−) were subjected to varying temperatures to determine the role of adipose bioenergetics in environmental adaptation and body weight regulation. Microarray analysis of mice acclimatized to thermoneutrality revealed that Cpt2A−/− interscapular brown adipose tissue (BAT) failed to induce the expression of thermogenic genes such as Ucp1 and Pgc1α in response to adrenergic stimulation, and increasing ambient temperature exacerbated these defects. Furthermore, thermoneutral housing induced mtDNA stress in Cpt2A−/− BAT and ultimately resulted in a loss of interscapular BAT. Although the loss of adipose fatty acid oxidation resulted in clear molecular, cellular, and physiologic deficits in BAT, body weight gain and glucose tolerance were similar in control and Cpt2A−/− mice in response to a high-fat diet, even when mice were housed at thermoneutrality.
Display omitted
•Fatty acid oxidation (FAO) is required for the induction of Ucp1 and Pgc1α in BAT•Increasing ambient temperature potentiates defects in FAO-deficient BAT•Loss of adipose FAO induces mtDNA stress in BAT•Loss of adipose FAO does not alter body weight or adiposity at thermoneutrality
Lee et al. show that a loss of adipose fatty acid oxidation (FAO) at thermoneutrality results in defective induction of thermogenic genes and mtDNA stress in BAT. Long-term housing of FAO-deficient mice results in a loss of interscapular BAT; however, body weight gain and glucose tolerance were unaffected.
J. Neurochem. (2010) 114, 820-831. Acetyl- l-carnitine (ALCAR) is an endogenous metabolic intermediate that facilitates the influx and efflux of acetyl groups across the mitochondrial inner membrane. ...Exogenously administered ALCAR has been used as a nutritional supplement and also as an experimental drug with reported neuroprotective properties and effects on brain metabolism. The aim of this study was to determine oxidative metabolism of ALCAR in the immature rat forebrain. Metabolism was studied in 21-22 day-old rat brain at 15, 60 and 120 min after an intraperitoneal injection of 2-¹³Cacetyl- l-carnitine. The amount, pattern, and fractional enrichment of ¹³C-labeled metabolites were determined by ex vivo¹³C-NMR spectroscopy. Metabolism of the acetyl moiety from 2-¹³CALCAR via the tricarboxylic acid cycle led to incorporation of label into the C4, C3 and C2 positions of glutamate (GLU), glutamine (GLN) and GABA. Labeling patterns indicated that 2-¹³CALCAR was metabolized by both neurons and glia; however, the percent enrichment was higher in GLN and GABA than in GLU, demonstrating high metabolism in astrocytes and GABAergic neurons. Incorporation of label into the C3 position of alanine, both C3 and C2 positions of lactate, and the C1 and C5 positions of glutamate and glutamine demonstrated that 2-¹³CALCAR was actively metabolized via the pyruvate recycling pathway. The enrichment of metabolites with ¹³C from metabolism of ALCAR was highest in alanine C3 (11%) and lactate C3 (10%), with considerable enrichment in GABA C4 (8%), GLN C3 (~ 4%) and GLN C5 (5%). Overall, our ¹³C-NMR studies reveal that the acetyl moiety of ALCAR is metabolized for energy in both astrocytes and neurons and the label incorporated into the neurotransmitters glutamate and GABA. Cycling ratios showed prolonged cycling of carbon from the acetyl moiety of ALCAR in the tricarboxylic acid cycle. Labeling of compounds formed from metabolism of 2-¹³CALCAR via the pyruvate recycling pathway was higher than values reported for other precursors and may reflect high activity of this pathway in the developing brain. This is, to our knowledge, the first study to determine the extent and pathways of ALCAR metabolism for energy and neurotransmitter biosynthesis in the brain.
Microglia play an integral role in brain development but are also crucial for repair and recovery after traumatic brain injury (TBI). TBI induces an intense innate immune response in the immature, ...developing brain that is associated with acute and chronic changes in microglial function. These changes contribute to long-lasting consequences on development, neurologic function, and behavior. Although alterations in glucose metabolism are well-described after TBI, the bulk of the data is focused on metabolic alterations in astrocytes and neurons. To date, the interplay between alterations in intracellular metabolic pathways in microglia and the innate immune response in the brain following an injury is not well-studied. In this review, we broadly discuss the microglial responses after TBI. In addition, we highlight reported metabolic alterations in microglia and macrophages, and provide perspective on how changes in glucose, fatty acid, and amino acid metabolism can influence and modulate the microglial phenotype and response to injury.
PDF
