Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice

Pierre, Karin; Parent, Annabelle; Jayet, Pierre‐Yves; Halestrap, Andrew P.; Scherrer, Urs; Pellerin, Luc

doi:10.1113/jphysiol.2007.138594

Cited by 75 publications

(58 citation statements)

References 47 publications

(65 reference statements)

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“…Thus even very small concentrations (100 pmol/l) produced an almost maximal effect in many cases. This suggests that neuronal uptake of ketone bodies via MCT2 transporters (3,10,34,35) is not a key regulatory step and that production of ATP and/or ROS from these ketone bodies in neurons is likely to be the main factor overriding both glucose and FA sensing (5,24). On the other hand, 3 days of prior HE diet intake significantly altered VMN neuronal glucosensing in GI neurons of DIO rats, while it had less to no impact in DR rats.…”

Section: Discussionmentioning

confidence: 77%

Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

Foll

Dunn-Meynell

Miziorko

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Le Foll C, Dunn-Meynell AA, Miziorko HM, Levin BE. Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats. Am J Physiol Regul Integr Comp Physiol 308: R872-R878, 2015. First published March 18, 2015; doi:10.1152/ajpregu.00015.2015.-The objective of this study was to determine the potential role of astrocyte-derived ketone bodies in regulating the early changes in caloric intake of diet induced-obese (DIO) versus diet-resistant (DR) rats fed a 31.5% fat high-energy (HE) diet. After 3 days on chow or HE diet, DR and DIO rats were assessed for their ventromedial hypothalamic (VMH) ketone bodies levels and neuronal ventromedial hypothalamic nucleus (VMN) sensing using microdialysis coupled to continuous food intake monitoring and calcium imaging in dissociated neurons, respectively. DIO rats ate more than DR rats over 3 days of HE diet intake. On day 3 of HE diet intake, DR rats reduced their caloric intake while DIO rats remained hyperphagic. Local VMH astrocyte ketone bodies production was similar between DR and DIO rats during the first 6 h after dark onset feeding but inhibiting VMH ketone body production in DR rats on day 3 transiently returned their intake of HE diet to the level of DIO rats consuming HE diet. In addition, dissociated VMN neurons from DIO and DR rats were equally sensitive to the largely excitatory effects of ␤-hydroxybutyrate. Thus while DR rats respond to increased VMH ketone levels by decreasing their intake after 3 days of HE diet, this is not the case of DIO rats. These data suggest that DIO inherent leptin resistance prevents ketone bodies inhibitory action on food intake. food intake; ketones; hypothalamus; neurons; obesity OBESITY AND TYPE 2 DIABETES MELLITUS are major worldwide public health issues (1,2,4,12,16, 19,37,38). Both obesity and Type 2 diabetes have important comorbidities that make it imperative to understand the underlying mechanisms that regulate food intake. Increased consumption of highly palatable, energy-dense foods, especially those rich in fats, represents a major cause of excess caloric intake (13). Indeed, a direct relationship exists between total fat intake and obesity (8). However, the effects and the mechanisms of chronic and excessive high-fat diet (HFD) consumption in the development of obesity are still poorly understood. Toward this end, we have used selectively bred diet-induced obese (DIO) rats as a model of human obesity (26,27,32) to assess the underlying factors that regulate their responses to high-energy (HE; 31.5% fat) diet intake. These rats are selectively bred to produce polygenically inherited diet-induced obesity or to remain diet resistant (DR) when fed an HE diet. DIO rats are larger but not fatter than DR rats when fed a low-fat chow diet but rapidly become hyperphagic, obese, and insulin resistant when fed an HE diet (27,30). Most importantly, when chow-fed DIO and DR rats are fed an HE diet, both overeat for 3 days. Whereas DR rats then reduce their intake to chow-fed levels on day 3, ...

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Section: Discussionmentioning

confidence: 77%

Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

Foll

Dunn-Meynell

Miziorko

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The excitatory effect of lactate on the firing frequency was concentration dependent, suggesting that orexin neurons are lactate sensors capable of detecting differences in extracellular lactate levels. Almost exclusive dependence on lactate indicates that orexin neurons can be influenced by not only the absolute levels of brain glucose but also the efficiency of glucose conversion to lactate, lactate release by astrocytes, and uptake by neurons, for example, during excitatory transmission (Pellerin and Magistretti, 1994), oxidative stress (Liddell et al, 2009), high-fat diet (Pierre et al, 2007), and hypoxia (Véga et al, 2006). Nonetheless, we cannot overlook the possibility that energy substrates additional to lactate may act as a significant fuel source for orexin neurons in vivo, which deserves future investigation.…”

Section: Orexin Neurons Prefer Lactate Over Glucose As An Energy Subsmentioning

confidence: 99%

ATP-Sensitive Potassium Channel-Mediated Lactate Effect on Orexin Neurons: Implications for Brain Energetics during Arousal

Parsons¹,

Hirasawa²

2010

Journal of Neuroscience

106

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Active neurons have a high demand for energy substrate, which is thought to be mainly supplied as lactate by astrocytes. Heavy lactate dependence of neuronal activity suggests that there may be a mechanism that detects and controls lactate levels and/or gates brain activation accordingly. Here, we demonstrate that orexin neurons can behave as such lactate sensors. Using acute brain slice preparations and patch-clamp techniques, we show that the monocarboxylate transporter blocker ␣-cyano-4-hydroxycinnamate (4-CIN) inhibits the spontaneous activity of orexin neurons despite the presence of extracellular glucose. Furthermore, fluoroacetate, a glial toxin, inhibits orexin neurons in the presence of glucose but not lactate. Thus, orexin neurons specifically use astrocyte-derived lactate. The effect of lactate on firing activity is concentration dependent, an essential characteristic of lactate sensors. Furthermore, lactate disinhibits and sensitizes these neurons for subsequent excitation. 4-CIN has no effect on the activity of some arcuate neurons, indicating that lactate dependency is not universal. Orexin neurons show an indirect concentration-dependent sensitivity to glucose below 1 mM, responding by hyperpolarization, which is mediated by ATP-sensitive potassium channels composed of Kir6.1 and SUR1 subunits. In conclusion, our study suggests that lactate is a critical energy substrate and a regulator of the orexin system. Together with the known effects of orexins in inducing arousal, food intake, and hepatic glucose production, as well as lactate release from astrocytes in response to neuronal activity, our study suggests that orexin neurons play an integral part in balancing brain activity and energy supply.

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“…However, evidence showing that the brain can use alternative energy substrates has been provided. For instance, fatty acids and ketone bodies contribute significantly to fulfill brain energy needs under specific conditions (6,13,36). Despite the fact that it has been known for decades that cerebral ketone body utilization increases under particular metabolic conditions (13), central ketone body detection has been poorly studied.…”

Section: Dysfunction In Both Cerebral Detection Of Nutrients Andmentioning

confidence: 99%

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

Carneiro

Geller

Fioramonti

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis. energy homeostasis; monocarboxylate transporters; ␤-hydroxybutyrate; obesity; glucose homeostasis DYSFUNCTION IN BOTH CEREBRAL DETECTION OF NUTRIENTS and integration of circulating signals has been implicated in the pathogenesis of obesity and associated disorders (11). For this reason, numerous studies have explored the possible role of nutrient and endocrine sensing of hypothalamic brain areas and their involvement in energy homeostasis regulation (34). The most studied circulating energy substrate is glucose, which represents a critical nutrient monitored by the brain. As the main energy source for brain cells, glucose also plays an important role in brain energy homeostasis (33). However, evidence showing that the brain can use alternative energy substrates has been provided. For instance, fatty acids and ketone bodies contribute significantly to fulfill brain energy needs under specific conditions (6,13,36). Despite the fact that it has been known for decades that cerebral ketone body utilization increases under particular metabolic conditions (13), central ketone body detection has been poorly studied.Under basal conditions, blood ketone body concentrations are low (Ͻ0.3 mmol/l), and their cerebral utilization is considered to be of little significance. However, ketone body levels are increased under conditions such as fasting, type 1 diabetes, or obesity (13). The brain can use ketone bodies when their blood concentrations reach Ϸ4 mmol/l, a value close to the K m of the monocarboxylate transporter 1 (MCT1) expressed on endothelial cells of cerebral blood vessels for ketone bodies (24,31,44). The brain's ability to use ketone bodies varies from...

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Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice

Cited by 75 publications

References 47 publications

Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

ATP-Sensitive Potassium Channel-Mediated Lactate Effect on Orexin Neurons: Implications for Brain Energetics during Arousal

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

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