Physiological and pathophysiological implications of lipid sensing in the brain.

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects probably 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 signalling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. 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. Recently, the role of lipoprotein lipase in FA sensing has also been shown in animal models not only in hypothalamus, but also in hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Lipid sensing in the brain and regulation of energy balance.

Nutrient-sensitive neurons [to glucose and fatty acids (FAs)] are present at many sites throughout the brain, including the hypothalamus and brain stem, and play a key role in the neural control of energy and glucose homoeostasis. Through their neuronal output, FAs can modulate feeding behaviour as well as insulin secretion and activity. Central administration of oleate, for example, inhibits food intake and glucose production in rats. This suggests that daily variations in plasma FA concentrations could be detected by the central nervous system as a signal that contributes to 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 FAs. Possible molecular effectors of these FA effects most likely include the chloride and potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K(+) channels appear to be necessary for some signalling effects of FAs, at least half the FA responses in ventromedial hypothalamic neurons are mediated by interaction with fatty acid translocase (FAT)/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FAs and their metabolites can modulate neuronal activity by directly monitoring the ongoing fuel availability for brain nutrient-sensing neurons involved in the regulation of energy and glucose homoeostasis. Besides these physiological effects, FA overload or metabolic dysfunction may also impair neural control of energy homoeostasis and contribute to obesity and/or type 2 diabetes in predisposed subjects.