Brain lipid sensing and nervous control of energy balance

doi:10.1016/j.diabet.2010.11.001

Diabetes & Metabolism

Volume 37, Issue 2, April 2011, Pages 83-88

https://doi.org/10.1016/j.diabet.2010.11.001 Get rights and content

Abstract

Nutrient sensitive neurons (glucose and fatty acids (FA)) are present in many sites throughout the brain, including the hypothalamus and brainstem, and play a key role in the neural control of energy and glucose homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as both insulin secretion and action. For example, central administration of oleate inhibits food intake and glucose production in rats. This suggests that daily variations in plasma FA concentrations might be detected by the central nervous system as a signal which contributes to the regulation of energy balance. At the cellular level, subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Possible molecular effectors of these FA effects likely include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K⁺ channel appear to be necessary for some of the signaling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, a FA transporter/receptor that does not require intracellular metabolism to activate downstream signaling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Besides these physiological effects, FA overload or metabolic dysfunction might impair neural control of energy homeostasis and contribute to obesity and/or type 2 diabetes in predisposed subjects.

Résumé

Des neurones sensible aux nutriments (glucose, acides gras libres [AGL]) ont été localisés dans différentes structures du système nerveux central (SNC), notamment l’hypothalamus et le tronc cérébral, régions clés impliquées dans le contrôle nerveux de la balance énergétique. Sur la base de modèles précliniques, il a été ainsi montré que les AGL participent au contrôle nerveux de la prise alimentaire, ainsi qu’à la sécrétion et à l’action de l’insuline, à la suite de leur effet sur certains neurones hypothalamiques et un relais efférent via le système nerveux autonome. Cela suggère que les variations circadiennes des concentrations circulantes des AGL pourraient être détectées dans des conditions physiologiques par le SNC et contribuer ainsi à la régulation de l’homéostasie énergétique. À l’échelon cellulaire, des sous-populations de neurones « excités » ou « inhibés » par les AGL ont donc été identifiées dans différents noyaux hypothalamiques (arqué ou ventromédian). L’effet activateur ou inhibiteur des AGL implique notamment des canaux chlorures ou potassiques. Le métabolisme intracellulaire des AGL semble être aussi important pour relayer leurs effets mais des données récentes indiquent que dans la moitié au moins des neurones sensibles au AGL, ce soit un mécanisme dépendant du transporteur membranaire des acides gras, FAT/CD36, qui soit impliqué. En conclusion, les AGL ou leurs métabolites ont donc un effet important de régulation de l’homéostasie énergétique via un effet sur les neurones hypothalamiques spécialisés dans la détection des variations quotidiennes des concentrations circulantes des nutriments. À côté de ces aspects physiologiques, une surcharge en lipides ou une dérégulation du métabolisme lipidique pourrait affecter ce système central de détection et consécutivement être un évènement précoce pouvant conduire à une détérioration du contrôle nerveux de la balance énergétique. Cela pourrait participer, au moins en partie, au développement des maladies métaboliques (obésité/diabète de type 2) chez des sujets prédisposés.

Section snippets

Transport of FA uptake into the brain and neurons

Cerebral lipids are an essential component of both membranes and intracellular signaling pathways. They represent 50% of brain dry weight; the highest organ lipid content after adipose tissue [3], [4]. However, the mechanism by which FA are transported into the brain remains poorly understood. A growing body of evidence suggests that cerebral lipids are derived both from local synthesis and uptake from the blood [5]. Several studies show that some poly-unsaturated FA (PUFA) have the ability to

Some hypothalamic neurons are lipid responsive

The presence of neurons sensitive to variations in extracellular glucose levels is clearly demonstrated in the brain and, in particular, in the hypothalamus [1], [9], [10]. Thirty-five years ago, Oomura et al. first showed that FA activated lateral hypothalamic neurons which suggested a role for FA as neuronal signaling molecules [11]. As shown in Fig. 1, FA also modify neuronal firing rate in hypothalamic arcuate nucleus (ARC) [12]. Such data suggest that physiological variations of plasma FA

Molecular mechanisms involved in neuronal FA sensing

In FA sensitive neurons, exposure to long chain FA can alter the activity of a wide variety of ion channels including Cl⁻, GABA_A [23], potassium, K⁺-Ca²⁺ [24] or calcium channels [25]. Additionally, FA inhibit the Na⁺-K⁺ ATPase pump [25]. For example, OA activates ARC POMC neurons by inhibiting ATP-sensitive K⁺ (K_ATP) channel activity [26] and the effect of OA on HGP is abolished by icv administration of a K_ATP channel inhibitor [26]. However, K_ATP channels are ubiquitously expressed on neurons

Metabolic-dependent FA sensing effects

The effects of FA on activity of some neurons are dependent upon intracellular metabolism of FA. Enzymes involved in FA metabolism such as FA synthase (FAS), CPT1 and acetyl-CoA carboxylase (ACC) are expressed in some hypothalamic neurons as well as in glial cells [1], [7]. Malonyl-CoA may be an important sensor of energy levels in the hypothalamus. It is derived from either glucose or FA metabolism via the glycolysis or β-oxidation, respectively. The steady-state level of malonyl-CoA is

Non metabolic-dependent neuronal FA sensing

While intracellular FA metabolism may be responsible for altering neuronal activity in some FA sensitive neurons such as ARC POMC neurons [26], it accounts for a relatively small percent of the effects of OA on dissociated VMN neurons [7]. In those neurons, inhibition of CPT1, reactive oxygen species formation, long-chain acyl CoA synthetase and K_ATP channel activity or activation of uncoupling protein 2 (UCP2) accounts for no more than 20% of the excitatory or approximately 40% of the

Which neurotransmitters or neuropeptides?

The ultimate consequence of the activation or inactivation of a neuron is the release of neurotransmitters and neuropeptides. Since FA decrease food intake, they might be expected to alter activity neurons specifically involved in the regulation of feeding. In fact, OA activates catabolic POMC neurons directly, apparently via ß-oxidation and inactivation of the K_ATP channel in hypothalamic slice preparations [26]. In vivo, Obici et al. [17] reported that icv administration of OA markedly

Pathological implications of excess FA

Besides physiological regulation of energy balance by hypothalamic neuronal FA sensing, impaired regulation of such sensing might contribute to the development of metabolic diseases such as obesity and type 2 diabetes in predisposed subjects exposed to a chronic lipid overload [1], [9]. Excessive brain lipid levels may indeed alter control of glucose and lipid homeostasis through changes of autonomic nervous system activity. Increasing brain FA levels reduces sympathetic activity and increases

Conclusion

In conclusion, there is now increasing evidence that specialized neurons within hypothalamus and other areas such as the brainstem or hippocampus can detect changes in plasma FA levels by having FA directly or indirectly alter the FA sensitive neurons involved in the regulation of energy and glucose homeostasis. The neuronal networks of these FA sensitive neurons that sense and respond to FA are likely very complex given the fact that FA can either inhibit or excite specific neurons. In

Conflict of interest statement

None.

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ReviewBrain lipid sensing and nervous control of energy balanceDétection centrale des acides gras et contrôle de la balance énergétique

Abstract

Résumé

Section snippets

Transport of FA uptake into the brain and neurons

Some hypothalamic neurons are lipid responsive

Molecular mechanisms involved in neuronal FA sensing

Metabolic-dependent FA sensing effects

Non metabolic-dependent neuronal FA sensing

Which neurotransmitters or neuropeptides?

Pathological implications of excess FA

Conclusion

Conflict of interest statement

J Lipid Res

Physiol Behav

J Biol Chem

Brain Res

Psychiatr Clin North Am

Physiol Behav

Biochim Biophys Acta

Brain Res

J Nutr

Metabolism

Fatty acid signaling in the hypothalamus and the neural control of insulin secretion

Diabetes

Brain uptake and utilization of fatty acids: applications to peroxisomal biogenesis diseases

J Mol Neurosci

Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport

J Mol Neurosci

Fatty acid uptake and incorporation in brain: studies with the perfusion model

J Mol Neurosci

Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing

Am J Physiol Regul Integr Comp Physiol

Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults

J Neurosci

The central nervous system at the core of the regulation of energy homeostasis. Front Biosci (Schol Ed)

Brain glucose sensing mechanism and glucose homeostasis

Curr Opin Clin Nutr Metab Care

Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels

J Neurophysiol

Intracerebroventricular infusion of a triglyceride emulsion leads to both altered insulin secretion and hepatic glucose production in rats

Pflugers Arch

Review
Brain lipid sensing and nervous control of energy balanceDétection centrale des acides gras et contrôle de la balance énergétique