Importantly, acss1 and acss2 mutant mice develop normally without any overt phenotypes suggesting that acss1 and acss2mediated acetate metabolism is dispensable for normal cell functions in mice 20, 49. Oxidation of both glucose and acetate in nt brain is demonstrated by the presence of s and d34 from glucose and 1604 cell 159, 16031614, december 18, 2014. This increase in brain acetylcoa metabolism increases brain phosphocreatine levels and reduces amp levels, suggesting a potential role in altering brain purine metabolism. Cerebral metabolism of acetate and glucose studied by cn. Acetate, a glialspecific substrate, is an attractive alternative to glucose for the study of neuronalglial interactions. Alcohol decreases baseline brain glucose metabolism more. Enhanced brain acetate metabolism may reward heavy drinkers.
The rate and site of acetate metabolism in the body. Preferential utilization of acetate by astrocytes is. We observed that rat cortical astrocytes produce 14 co 2 from 0. Acute etoh intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic etoh exposure may lead to the adaptation of the rat brain to etoh in acetate utilization. In the t1dm unaware subjects, acetate accounted for approximately 50% of glial metabolism, which based on previous studies is 10%12% of total brain metabolism 28. To carry out metabolic processes, thousands of chemical reactions occur every moment in cells throughout your body. Introduction numerous studies performed after brief postabsorptive periods have shown that the only sig. Evaluation of cerebral acetate transport and metabolic. Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo. No effect of tetrodotoxin on brain respiration takes place when stimulation is brought about. Acetate metabolism does not reflect astrocytic activity, contributes. Human brain glycogen metabolism during and after hypoglycemia human brain glycogen metabolism during and. Whereas some metabolic reactions break down molecules to extract energy, others synthesize building blocks to produce new molecules.
Jci increased brain uptake and oxidation of acetate in. It also inhibits increase in the rate of the respiration that occurs when calcium ions are omitted from the incubation medium. The main products of the acetate malonate pathway are the fatty acids, both those primary metabolites which occur universally and the more unusual compounds with a restricted distribution. Oxidation of ethanol in the brain and its consequences. The time courses of incorporation of c from clabelled glucose or acetate into cerebral amino acids glutamate, glutamine and 4aminobutyrate and lactate were monitored by using cn. Cerebral metabolism of acetate and glucose studied by c. Metabolism of clabelled pyruvate and acetate during f acetate treatment. Acetate in plasma is supplied by both exogenous and endogenous sources. All results are expressed as means sd with significance set at p 0.
During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Although acetate metabolism has been characterized in situations other than drinking, links between acetate metabolism and alcohol consumption are not clear. Pdf metabolism, compartmentation, transport and production of. Brain uptake of 14cacetate has been reported to be a useful marker of astrocytic energy metabolism. Here, using a guinea pig brain cortical tissue slice model metabolizing 1cd glucose and 1,2cac etate, we investigated control of acetate metabolism. This 10%12% is in the range of the reduction in glucose metabolism reported at moderate levels of hypoglycemia in control subjects 30. We observed that rat cortical astrocytes produce14co2 from 0. Recent data show that alcohol decreases brain glucose utilization 2931 and increases acetate uptake 30. Acute alcohol intoxication decreases glucose metabolism but. Exogenous acetate delivered to tumors via the blood may derive from the diet, with a substantial portion generated by gut microbiome metabolism of intestinal contents.
Alcohol produced opposite changes in regional brain metabolism than acetate uptake. Acetylcoa synthetases that catalyse the conversion of acetate to. Labeled acetate as a marker of astrocytic metabolism institute of. Jan 01, 20 acute alcohol intoxication decreases glucose metabolism, increases acetate uptake in the human brain. Evaluating acetate metabolism for imaging and targeting in. It is available both alone and in combination with an estrogen. When 1cglucose was used as precursor the c2 of 4aminobutyrate was more highly labelled than the analogous c4 of glutamate, whereas no label was observed in glutamine. Since the first applications of labeled acetate for brain studies about 50 years ago, numerous methodologies have been developed and employed in compartmentspecific investigations of brain metabolism. The metabolism of brain pyruvate and acetate in the. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. Increased brain uptake and oxidation of acetate in heavy drinkers jci. Alcohol decreases baseline brain glucose metabolism more in. Figure 1 twocompartment metabolic model of brain acetate transport and utilization, with pools and rates defined in table 1. In the brain, ketone bodies are also used to make acetylcoa into longchain fatty acids.
Effects of the acute and chronic ethanol intoxication on. Pet imaging reveals acetate as an alternative energy source during alcohol intoxication. Exogenous acetate is preferentially metabolized by astrocytes in the cns, but the biochemical basis for this selectivity is unknown. When blood acetate levels exceed 7 mmoll, blood concentrations of maleate and citrate increase, 49 with a higher risk of a continuing metabolic acidosis. Acetate metabolism in physiology, cancer, and beyond. Acetate derived from alcohol metabolism directly influences. Aug 26, 2016 recent highprofile reports have reignited an interest in acetate metabolism in cancer. Acetate can also be oxidized in mitochondria for the derivation of metabolic energy. Fatty acids are a family of molecules classified within the lipid macronutrient class. Here, we studied acetate metabolism and targeting in mmc in vitro and tested the efficacy of 11 cacetatepositron emission tomography pet to detect and quantitatively image myeloma treatment response in vivo. Fasting induces the liver to generate ketones for metabolism by other tissues. Evaluation of cerebral acetate transport and metabolic rates.
Thus ethanol directly alters metabolism in the liver, and causes the production of large amounts of acetate which may serve as a substrate for brain, possibly contributing to intoxication and dependence. During alcohol intoxication, the human brain increases metabolism of acetate and. Metabolic acetate therapy for the treatment of traumatic. Feb 20, 2019 pyruvate dehydrogenase deficiency pdhd is a rare disorder caused by altered glucose metabolism. Here, using a guinea pig brain cortical tissue slice model metabolizing 1cdglucose and 1,2cac etate, we investigated control of acetate metabolism. One role of fatty acids in animal metabolism is energy production, captured in. A 3micromolar concentration of tetrodotoxin completely inhibits the stimulation of respiration of rat brain cortex that takes place upon application of electrical impulses. Acetate could potentially promote continued heavy drinking with a reward in the form of caloric benefit or adenosinergic adaptation. Subsequent studies examined whether this was attributable to cellular differences in. When 1cglucose was used as precursor the c2 of 4aminobutyrate was more highly labelled than the analogous c4 of glutamate, whereas no.
Moreover, the relative contribution of acetate to brain metabolism has been shown to increase following brain injury, which limits glucose oxidation bartnikolson et al. Patients suffering from traumatic brain injury tbi have decreased markers of energy metabolism, including nacetylaspartate naa and atp. Metabolic acetate therapy for the treatment of traumatic brain injury article pdf available in journal of neurotrauma 271. All of these effects were blocked when the researchers severed the vagus nerve, suggesting that acetate affects metabolism indirectly via the brain and parasympathetic nervous system. Mortensen 93 the intracisternal injection of pyruvate204, acetate1c14, and acetate2cl4 into rats. Pyruvate dehydrogenase deficiency pdhd is a rare disorder caused by altered glucose metabolism. Because singledose glyceryl triacetate gta treatment increases brain phosphocreatine and reduces brain amp levels, we postulate that gta modulates adenosine metabolizing enzymes and receptors, which may be a possible mechanism to reduce. At such high plasma acetate concentration, the ratelimiting step for glial acetate metabolism is not the bloodbrain barrier, but occurs after entry of acetate into. Here, we investigated these anomalies by examining transport, production and metabolism of acetate. Acetate supplementation elevates plasma acetate approximately 19 mm, brain acetate approximately 11 mm, and acetyl coa approximately 9. Enhanced brain acetate uptake with alcohol was highest in heavy alcohol users.
These considerations would be irrele vant if the brain could produce its own acetaldehyde from ethanol. Alcohol metabolism contributes to brain histone acetylation nature. In the nervous system, naaderived acetate provides acetylcoa required for myelin lipid synthesis. This finding may be analogous to brain tumor regions with a paucity of active neurons and. The metabolism of brain pyruvate and acetate was studied by determining the labeling patterns in free brain glutamate after. Highlights acute alcohol reduces glucose metabolism and increases acetate uptake in human brain. In this method, the metabolism of inhaled ethanol is slowed, providing for more prolonged and consistent blood levels of ethanol, producing physical dependence in mice. We hypothesized that in multiple myeloma cells mmc, high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Pdf metabolism, compartmentation, transport and production. Metabolism, compartmentation, transport and production of. Fatty acid metabolism consists of catabolic processes that generate energy, and anabolic processes that create biologically important molecules triglycerides, phospholipids, second messengers, local hormones and ketone bodies. Research article role of gut microbiota, gutbrain and gut liver axes in physiological regulation of inflammation, energy balance, and metabolism microbiome potentiates endurance exercise through intestinal acetate production.
Acetate metabolism in brain the labeling patterns found in glutamate after the administration of acetate lc4 and acetate 2cyare shown in table ii. Alcohol is eliminated from the body by various metabolic mechanisms. Enhanced brain acetate metabolism may reward heavy drinkers 8 march 20 in addition to its wellknown effects on the cns, alcohol consumption has a significant impact on. Results to test the hypothesis that acetate supplementation modulates brain adenosine metabolizing enzymes cd73 and ak and adenosine a2a receptor levels, we measured the levels of these proteins and the activity of.
We compared cerebral acetate to see whether the increased acetate metabolism in the unaware t1dm group was driven by higher brain acetate levels as a consequence of higher transport activity or alternatively whether the enzymes involved in converting acetate to acetylcoa were also upregulated. It is an accepted marker of astrocytic metabolism, and a substrate for production of metabolites such as glutamine, glutamate and gaba. These arenot greatly different from the patterns that have been reported for liver and carcass 1, 2. Increased brain uptake and oxidation of acetate in heavy drinkers graeme mason of yale university discusses how heavy drinking influences metabolism and leads to alternate fuel use in the brain.
Ketone bodies are produced by the liver under the circumstances listed above, resultant of intense gluconeogenesis, which is the production of glucose from noncarbohydrate sources including fatty acids. Acetate is a major nutrient that supports acetylcoenzyme a accoa metabolism and thus lipogenesis and protein acetylation. In its metabolism, acetate leads to the production of adenosine, a powerful physiological mediator. Acetate and the related metabolism of acetylcoenzyme a acetylcoa confer numerous metabolic functions, including energy production, lipid synthesis, and protein acetylation. Effect of astrocytic energy metabolism depressant on 14cacetate uptake in intact rat brain. This pathway also makes an important contribution to plant aliphatic and aromatic compounds, which are biosynthesised through the formation of polyketides. We have investigated the effect of acetate on central nervous system cns function in rodents.
Results consistent with the use of acetate as brain energy source during intoxication. Acetate is a bioenergetic substrate for human glioblastoma. Glucoseindependent acetate metabolism promotes melanoma. The mechanism of alcoholinduced changes in the brain is multifaceted. Brain metabolism modulates neuronal excitability in a mouse. Low doses of alcohol substantially decrease glucose metabolism in.
Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. The symptoms of pdhd are predominantly neurological, and patients develop intractable epilepsy early in infancy. Acetate is a two carbon intermediate in metabolism. However, the mechanisms responsible for the increased brain excitability are mostly unknown. Recent highprofile reports have reignited an interest in acetate metabolism in cancer.
Acetate metabolism in normal human subjects appears to be first order. This dissertation describes two separate approaches to study the metabolic effects of ethanol. Acetate, resulting from ethanol metabolism in the liver, is released into the circulation and is utilized in a number of tissues, including the brain. Acute alcohol intoxication decreases glucose metabolism. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of 2 cacetate using nmr spectroscopy. Despite its importance as a nutrient for cellular metabolism, its source has been unclear.
Increased acetate production by an altered gut microbiota in rats fed a highfat diet activates the parasympathetic nervous system, which in turn promotes increased insulin secretion, increased. Acetate, the product of hepatic alcohol metabolism, might contribute to addictive behaviour by regulating gene expression. For studying brain energy metabolism, the use of the astrocytespecific energy substrate acetate has proven to be of great value. Brain acetate consumption is inducible by conditions that can occur with heavy alcohol use. Acute alcohol intoxication decreases glucose metabolism, increases acetate uptake in the human brain. Effects of fat mobilization on liver acetate metabolism. Alcoholderived acetate modulates brain function nature. Acetate supplementation reduces neuroglia activation and proinflammatory cytokine expression in rat models of neuroinflammation and lyme neuroborreliosis. However, higher blood acetate concentrations may be achieved during hemodialysis and further studies are indicated to investigate the kinetics of acetate metabolism during hemodialysis. Pdf effect of astrocytic energy metabolism depressant on. When plasma acetate concentration was increased, the rate of brain acetate utilization cmr ace increased.
Acetate has a potential role in obesity and metabolic syndrome. Increased brain transport and metabolism of acetate in. To understand more fully the role of acetate in the energetics of the whole ani mal, we have examined the metabolism of both the methyl and the carboxyl carbons, and also the metabolism of acetate infused into a rumen vein as opposed to a jugular vein. To test this hypothesis, we compared the effects of alcohol intoxication 0.
By increasing plasma acetate, a ketonic diet may help prevent some of the adverse effects associated with alcohol withdrawal. We compared cerebral acetate to see whether the increased acetate metabolism in the unaware t1dm group was driven by higher brain acetate levels as a consequence of higher transport activity or alternatively whether the enzymes involved in converting acetate to. Metabolism, compartmentation, transport and production of acetate in the cortical brain tissue slice. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of 2 c acetate using nmr spectroscopy. Here, we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals. Mar 16, 2020 acetate also doubled the rats calorie intake and weight gain during the 10day study period, an effect largely explained by the rise in ghrelin. Acetylcoa synthetases that catalyse the conversion of acetate to acetylcoa have now been implicated in the. However, anomalies exist in the current explanations of compartmentation and metabolism of acetate. The most active metabolic sites include your liver, muscle, and. In the presence of similar levels of plasma acetate, heavy drinkers were able to use more acetate as an alternative energy fuel to support brain metabolism. We propose that acetate metabolism in melanoma presents a potential targetable vulnerability.
Labeled acetate as a marker of astrocytic metabolism. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of 2. The maximal rate of acetate metabolism in normal subjects is estimated to be 5 mmolmin and seems to be lower in patients undergoing dialysis 34 mmolmin. Although acetate metabolism has been characterized in situations other than drinking, links between acetate metabolism and alcohol. The in vitro results suggest that kidney is the most active tissue in acetate metabolism. In insulin deficiency, release of ffa from adipose tissue and increased mobilization of lipids to the liver are followed by excessive ketone body production and a reduction in the incorporation of c14 from labeled acetate into fatty acids.
1298 1198 1000 24 741 844 37 240 911 1479 302 389 764 1095 1177 1490 1293 1541 370 1042 182 596 1220 1218 361 247 1102 38