Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study

Schurr, Avital; Payne, Ralphiel S.; Miller, James J.; Rigor, Benjamin M.

doi:10.1016/s0006-8993(96)01106-7

Cited by 242 publications

(161 citation statements)

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“…Recent studies suggest that lactate may serve as an important source of fuel. Specifically, both in vivo and in vitro studies suggest that lactate is readily utilized as a substrate for neurons when glucose is deficient (19,20,25,26). While blood levels of lactate and its transport across the blood-brain barrier appear not to be the major source of lactate supply to the brain (24,27,28), it has been reported that lactate is produced locally in brain by astrocytic nonoxidative glucose metabolism during neuronal activation (29,30).…”

Section: Discussionmentioning

confidence: 99%

Local Lactate Perfusion of the Ventromedial Hypothalamus Suppresses Hypoglycemic Counterregulation

et al. 2003

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We have previously reported that a glucosensor integrating hormonal responses to hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH glucose perfusion blocks counterregulatory hormone responses. To determine whether the by-product of glucose metabolism, lactate, can function within the VMH as an alternative for glucose, we delivered lactate locally to the VMH, during systemic hypoglycemia. For this purpose, we combined bilateral VMH microdialysis perfusion (metabolically active L-lactate or its nonmetabolizable D-isomer) with a euglycemic-hypoglycemic clamp in conscious chronically catheterized SpragueDawley rats. Local VMH perfusion with L-lactate decreased counterregulatory hormone responses to hypoglycemia by 80 -85% as compared with the nonmetabolizable D-lactate control. Moreover, hormonal suppression with L-lactate was accompanied by an approximate fourfold increase in the amount of exogenous glucose infused to maintain a stable hypoglycemic plateau (P < 0.05). In conclusion, the glucose-sensing mechanism in the VMH responds to lactate and, thus, is not specific for glucose. This implies that the VMH may act as a fuel sensor rather than as a glucose sensor. Diabetes 52:663-666, 2003 D ata demonstrating the importance of the central nervous system in hypoglycemia detection and the activation of glucose counterregulation (1,2) have generated interest in the location of and the mechanisms used by glucose-sensing neurons to trigger hormonal responses. While it is likely that several brain regions as well as extracerebral glucose-sensing neurons are involved (3-7), there is long-standing evidence supporting a central role for the hypothalamus, particularly the ventromedial hypothalamus (VMH), which is also recognized as a regulator of food intake (8 -11). Previous studies have shown that electrical stimulation of the VMH (12) or local delivery of the nonmetabolizable glucose analog, 2-deoxyglucose, into the VMH (13) provokes the release of counterregulatory hormones. Conversely, focal lesioning of the VMH (14) or delivery of glucose by microdialysis directly into the VMH (15) suppresses counterregulatory responses to systemic hypoglycemia.The mechanisms used by neurons to detect hypoglycemia remain to be established. It has been proposed that glucose-sensing brain regions contain neurons that are capable of altering their activity in response to changes in glucose levels. More than three decades ago, Oomura et al. (4) identified glucose responsive neurons in the VMH. Subsequently, neurons that are activated or inhibited by glucose have been described in the hypothalamus, brain stem, and the portal vein (6 -9). In vitro studies have reported that the byproduct of glucose metabolism, lactate, can replace glucose as a fuel recognized by glucosesensing neurons (8). In keeping with this possibility, it has been demonstrated that isolated neurons preferentially use lactate over glucose (16 -18) and that infusion of lactate reduces the counterregulatory response to hypoglycemia (19,20).T...

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Section: Discussionmentioning

confidence: 99%

Local Lactate Perfusion of the Ventromedial Hypothalamus Suppresses Hypoglycemic Counterregulation

et al. 2003

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“…It is reasonable to assume that any rise in lactate levels after activation indicates that the rate of lactate production exceeds its rate of utilization. Additionally, when lactate levels increase significantly, as in the case of an anaerobic period (Schurr et al, 1997a(Schurr et al, , b, 1999Schurr and Rigor, 1998) or on continuous stimulation (Hu and Wilson, 1997), lactate does become the oxidative substrate of choice on reoxygenation or termination of stimulation. Moreover, in a recent paper, Kasischke et al (2004), using NADH fluorescence measurements in brain slices, have shown that, on activation of neural tissue, there is an early oxidative metabolism that is entirely neuronal, as indicated by a short-lived (B10 secs) dip in NADH fluorescence localized in neuronal dendrites, followed by an overshoot in NADH fluorescence localized in astrocytes and signaling glial glucose uptake and increased lactate-producing glycolytic activity lasting for B60 secs.…”

Section: Testing the Hypothesismentioning

confidence: 99%

Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Schurr

2006

J Cereb Blood Flow Metab

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Research over the past two decades has renewed the interest in lactate, no longer as a useless end product of anaerobic glycolysis in brain (and other tissues), but as an oxidative substrate for energy metabolism. While this topic would be considered blasphemy only three decades ago, much recent evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle, and possibly in any other tissue and organ. Nevertheless, this concept has challenged the old dogma and ignited a fierce debate, especially among neuroscientists, pitting the supporters of glucose as the major oxidative energy substrate against those who support lactate as a possible alternative to glucose under certain conditions. Meanwhile, researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, while avoiding the high decibels of an emotional debate. Employing their findings along with the existing old and new data on cerebral energy metabolism, it is postulated here that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Consequently, this postulate entails that lactate is a major, if not the only, substrate for the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis could provide better understanding of the biochemistry and physiology of (cerebral) energy metabolism, while holding important implications in the field of neuroimaging. Concomitantly, it could satisfy both 'glucoseniks' and 'lactatians' in the ongoing debate.

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“…However, experimental data have emerged over the past quarter of a century, all pointing to a major role for lactate in oxidative energy metabolism in brain, skeletal muscle, heart and probably many other mammalian tissues. These data (Brooks, 1985(Brooks, , 1998(Brooks, , 2000(Brooks, , 2002aSchurr et al, 1988bSchurr et al, , 1997aSchurr et al, , b, 1999aLarrabee, 1995Larrabee, , 1996Hu & Wilson, 1997;Brooks et al, 1999;Mangia et al, 2003;Kassischke et al, 2004;Ivanov et al, 2011) in addition to several forgotten studies from the first half of the 20 th century (Ashford & Holmes, 1929, 1931Holmes, 1930;Holmes & Ashford, 1930;Flock et al, 1938), impelled me to hypothesize that lactate is the ultimate cerebral oxidative energy substrate in the brain (Schurr, 2006) and possibly in other organs and tissues. The electrophysiological experiments described here have contributed enormously to the formulation of this hypothesis.…”

Section: Lactate As An Aerobic Energy Substrate For Excited Neuronsmentioning

confidence: 99%

“…7. The levels of lactate and glucose (nmoles/slice), as determined by using enzymatic kits (Schurr et al, 1997a), during the experimental paradigms D and F detailed in Fig. 6.…”

Section: Lactate Utilization Post-hypoxia Is Crucial and Obligatory Fmentioning

confidence: 99%

Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study

Cited by 242 publications

References 35 publications

Local Lactate Perfusion of the Ventromedial Hypothalamus Suppresses Hypoglycemic Counterregulation

Local Lactate Perfusion of the Ventromedial Hypothalamus Suppresses Hypoglycemic Counterregulation

Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Hippocampal Slices and Their Electrophysiogy in the Study of Brain Energy Metabolism

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