Fatty Acid Signaling in the Hypothalamus and the Neural Control of Insulin Secretion

Migrenne, Stéphanie; Cruciani-Guglielmacci, Céline; Lee, Kang; Wang, Ruokun; Rouch, Claude; Lefèvre, Anne-Laure; Ktorza, Alain; Routh, Vanessa H.; Levin, Barry E.; Magnan, Christophe

doi:10.2337/db06-s017

Cited by 56 publications

(46 citation statements)

References 45 publications

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“…Transmitters such as norepinephrine (5, 41), GABA (5,11), and glutamate (55) and neuropeptides such as neuropeptide Y (59), corticotrophinreleasing factor, and urocortin (35) act as important modulators of neuronal activity in the VMH, the counterregulatory responses to hypoglycemia, and the dampening of these responses that follow even a single bout of hypoglycemia. In addition, glucosensing neurons respond directly to a variety of hormones such as insulin (22,51,59) and leptin (28,50) and the availability of alternate fuels such as lactate (49) and fatty acids (36,58). Thus, although we demonstrate here that antecedent hypoglycemia directly alters the glucose responsiveness of VMH glucosensing neurons, it also affects many of these other critical inputs to these neurons.…”

Section: Perspectives and Significancementioning

confidence: 41%

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Lee¹,

Sanders²,

Dunn-Meynell³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Kang L, Sanders NM, Dunn-Meynell AA, Gaspers LD, Routh VH, Thomas AP, Levin BE. Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. Am J Physiol Regul Integr Comp Physiol 294: R784-R792, 2008. First published December 19, 2007 doi:10.1152/ajpregu.00645.2007.-Antecedent insulin-induced hypoglycemia (IIH) reduces adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia. The ventromedial hypothalamus [VMH: arcuate (ARC) ϩ ventromedial nuclei] contains glucosensing neurons, which are thought to be mediators of these AMR. Since type 1 diabetes mellitus often begins in childhood, we used juvenile (4-to 5-wk-old) rats to demonstrate that a single bout of IIH (5 U/kg sc) reduced plasma glucose by 24% and peak epinephrine by 59% 1 day later. This dampened AMR was associated with 46% higher mRNA for VMH glucokinase, a key mediator of neuronal glucosensing. Compared with neurons from saline-injected rats, ventromedial nucleus glucose-excited neurons from insulin-injected rats demonstrated a leftward shift in their glucose responsiveness (EC50 ϭ 0.45 and 0.10 mmol/l for saline and insulin, respectively, P ϭ 0.05) and a 31% higher maximal activation by glucose (P ϭ 0.05), although this maximum occurred at a higher glucose concentration (saline, 0.7 vs. insulin, 1.5 mmol/l). Although EC50 values did not differ, ARC glucose-excited neurons had 19% higher maximal activation, which occurred at a lower glucose concentration in insulin-than salineinjected rats (saline, 2.5 vs. insulin, 1.5 mmol/l). In addition, ARC glucose-inhibited neurons from insulin-injected rats were maximally inhibited at a fivefold lower glucose concentration (saline, 2.5 vs. insulin, 0.5 mmol/l), although this inhibition declined at Ͼ0.5 mmol/l glucose. These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR. glucokinase; counterregulatory response; hypoglycemia-associated autonomic failure; calcium imaging; arcuate nucleus; ventromedial nucleus; ventromedial hypothalamus RECURRENT BOUTS of insulin-induced hypoglycemia (IIH) are common in patients with type 1 diabetes mellitus, especially children (3,4,23,43). Such recurrent bouts lead to severe dampening of the hormonal counterregulatory and adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia, a component of the clinical syndrome known as hypoglycemiaassociated autonomic failure (2, 13, 53). In nondiabetic adult rats, we showed that a single bout of hypoglycemia results in impairment of AMR, in association with upregulation of glucokinase (GK) mRNA expression in the ventromedial hypothalamus (VMH) (15, 53). This hypothalamic area, which includes the arcuate (ARC) and ventromedial nuclei (VMN), contains glucosensing neurons, which we postulate to be critical elements in the detection of and response to hypoglycemia (8,22,25,38,48,60). In contrast to most neurons in the brain, which utilize glu...

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Section: Perspectives and Significancementioning

confidence: 41%

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Lee¹,

Sanders²,

Dunn-Meynell³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Although there is not an absolute parallel between changes in glucose-and fatty acidinduced [Ca 2ϩ ] i fluctuations and neuronal action potential frequency, we have shown that they do correlate well with changes in membrane potential in dissociated VMN neurons (16,19) and with changes in action potential frequency using patch-clamp technique in hypothalamic slices (32,42). Thus, because the use of calcium imaging in dissociated neurons provides a relatively high-throughput means of screening large numbers of neurons simultaneously, this method has proved to be very useful and is a reasonable surrogate for assessing glucose-and OA-induced changes in neuronal activity.…”

Section: Resultsmentioning

confidence: 87%

“…Some of these same glucosensing neurons also respond to long-chain fatty acids such as oleic acid (OA), as signaling molecules in a glucosedependent fashion (19). Such "metabolic sensing" neurons enable the brain to regulate glucose and energy homeostasis in the body because of their ability to sense and respond to phasic changes in peripheral metabolic substrates (2,16,18,32,34,35,39,41,46).…”

mentioning

confidence: 99%

Effects of maternal genotype and diet on offspring glucose and fatty acid-sensing ventromedial hypothalamic nucleus neurons

Foll

Irani

Magnan

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Le Foll C, Irani BG, Magnan C, Dunn-Meynell A, Levin BE. Effects of maternal genotype and diet on offspring glucose and fatty acid sensing ventromedial hypothalamic nucleus neurons. Am J Physiol Regul Integr Comp Physiol 297: R1351-R1357, 2009. First published August 26, 2009 doi:10.1152/ajpregu.00370.2009.-Maternal obesity accentuates offspring obesity in dams bred to develop diet-induced obesity (DIO) on a 31% fat, high-sucrose, high-energy (HE) diet but has no effect on offspring of diet-resistant (DR) dams. Also, only DIO dams become obese when they and DR dams are fed HE diet throughout gestation and lactation. We assessed glucose and oleic acid (OA) sensitivity of dissociated ventromedial hypothalamic nucleus (VMN) neurons from 3-to 4-wk old offspring of DIO and DR dams fed chow or HE diet using fura-2 calcium imaging to monitor intracellular calcium fluctuations as an index of neuronal activity. Offspring of DIO dams fed chow had ϳ2-fold more glucose-inhibited (GI) neurons than did DR offspring. This difference was eliminated in offspring of DIO dams fed HE diet. At 2.5 mM glucose, offspring of chow-fed DIO dams had more GI neurons that were either excited or inhibited by OA than did DR offspring. Maternal HE diet intake generally increased the percentage of neurons that were excited and decreased the percentage that were inhibited by OA in both DIO and DR offspring. However, this effect was more pronounced in DIO offspring. These data, as well as concentration-dependent differences in OA sensitivity, suggest that genotype, maternal obesity, and dietary content can all affect the sensitivity of offspring VMN neurons to glucose and long-chain fatty acids. Such altered sensitivities may underlie the propensity of DIO offspring to become obese when fed high-fat, high-sucrose diets.long-chain fatty acids; glucosensing; development; metabolic sensing; epigenetic THE MAJORITY OF NEURONS IN the brain require glucose to fuel the metabolic demands imposed upon them by changes in their activity (19). However, in brain areas, such as the ventromedial hypothalamic nucleus (VMN), populations of specialized glucosensing neurons also utilize glucose as a signaling molecule to alter their activity in response to changes in ambient glucose concentrations. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons decrease their activity as glucose levels rise (2,11,16,18,33,42). Some of these same glucosensing neurons also respond to long-chain fatty acids such as oleic acid (OA), as signaling molecules in a glucosedependent fashion (19). Such "metabolic sensing" neurons enable the brain to regulate glucose and energy homeostasis in the body because of their ability to sense and respond to phasic changes in peripheral metabolic substrates (2,16,18,32,34,35,39,41,46). These regulatory processes are also affected by long-term changes in metabolic state in a manner that is often dependent upon the genotype of the individual. For example, the offspring of dams selectively bred to develop diet-induced obesity (...

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“…Many of these same VMH glucosensing neurons are also fatty acid sensors which respond to long-chain fatty acids by altering their activity (230,278,280,281,337,374). While early work suggested that this fatty acid sensing was mediated by intracellular metabolism of long-chain fatty acids (230), it now appears that much of this sensing is mediated by fatty acid translocator/CD36 (which appears to act as a receptor and may also be a transporter of fatty acids) in many VMH neurons and that this regulatory step is independent of neuronal fatty acid oxidation (278,280,281).…”

Section: B Metabolic Sensing Neurons: the Basic Integrators And Regumentioning

confidence: 99%

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

Bouret

Levin

Ozanne

2015

Physiological Reviews

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103

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LBouret S, Levin BE, Ozanne SE. Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity. Physiol Rev 95: 47-82, 2015; doi:10.1152/physrev.00007.2014.-Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre-and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease.

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Fatty Acid Signaling in the Hypothalamus and the Neural Control of Insulin Secretion

Cited by 56 publications

References 45 publications

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Effects of maternal genotype and diet on offspring glucose and fatty acid-sensing ventromedial hypothalamic nucleus neurons

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

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