Physiological functions of glucose‐inhibited neurones

Abstract

Glucose-inhibited neurones are an integral part of neurocircuits regulating cognitive arousal, body weight and vital adaptive behaviours. Their firing is directly suppressed by extracellular glucose through poorly understood signalling cascades culminating in opening of post-synaptic K + or possibly Cl − channels. In mammalian brains, two groups of glucose-inhibited neurones are best understood at present: neurones of the hypothalamic arcuate nucleus (ARC) that express peptide transmitters NPY and agouti-related peptide (AgRP) and neurones of the lateral hypothalamus (LH) that express peptide transmitters orexins/hypocretins. The activity of ARC NPY/AgRP neurones promotes food intake and suppresses energy expenditure, and their destruction causes a severe reduction in food intake and body weight. The physiological actions of ARC NPY/AgRP cells are mediated by projections to numerous hypothalamic areas, as well as extrahypothalamic sites such as the thalamus and ventral tegmental area. Orexin/hypocretin neurones of the LH are critical for normal wakefulness, energy expenditure and reward-seeking, and their destruction causes narcolepsy. Orexin actions are mediated by highly widespread central projections to virtually all brain areas except the cerebellum, including monosynaptic innervation of the cerebral cortex and autonomic pre-ganglionic neurones. There, orexins act on two specific G-proteincoupled receptors generally linked to neuronal excitation. In addition to sensing physiological changes in sugar levels, the firing of both NPY/AgRP and orexin neurones is inhibited by the 'satiety' hormone leptin and stimulated by the 'hunger' hormone ghrelin. Glucose-inhibited neurones are thus well placed to coordinate diverse brain states and behaviours based on energy levels. Keywordsappetite; glucose; hypocretin; hypothalamus; orexin; sleep Discovery of hypothalamic glucose-inhibited neuronesAnimal survival depends on constantly adjusting behaviour to body energy resources. In mammals, the hypothalamus is central for this process. Hypothalamic neurones sense diverse information relevant to body energy status and translate it into coordinated changes in brain state, energy expenditure and behaviour. One of the earliest clues for how the

Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons

“…Phl reduces glucose entry only into cells that express the SGLT receptor. Blockade of SGLT has been shown to inhibit activity of GE neurons and to activate SGLT-expressing GI neurons in the hypothalamus (6,12). The response of these neurons to antimetabolic glucose analogues mimics the effect of glucose.…”

“…Phl reduces glucose entry only into cells that express the SGLT receptor. The latter include some hypothalamic neurons of both the GE and GI type (6,12,31). These neurons respond to changes in extracellular glucose but are not responsive to GcA, alloxan, or N-acetyl-D-glucosamine and do not express GK.…”

“…These neurons respond to changes in extracellular glucose but are not responsive to GcA, alloxan, or N-acetyl-D-glucosamine and do not express GK. Because the response of SGLT-expressing neurons to antimetabolic glucose analogues mimics the effect of glucose, this transporter has been described as a nonmetabolic glucose sensor, possibly serving to inform the brain about ambient extracellular glucose levels (6,12).…”

Role of orexin in the central regulation of glucose and energy homeostasis [Review]

“…Sugar-sensing neurons exist in restricted brain regions, such as hypothalamus and brain stem, and they are classified into two groups, namely glucose-excited (GE) neurons and glucose-inhibited (GI) neurons, in terms of the mode of response to extracellular glucose changes within physiological cerebrospinal fluid (CSF) range [20,21]. For example, orexin neurons in the LHA and neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the ARC are glucose-inhibited, whereas melanin-concentrating hormone (MCH) neurons in LHA and proopiomelanocortin (POMC)…”

“…Emerging evidence indicates that orexin not only senses peripheral metabolic signals but also controls glucose production and utilization in the peripheral tissues via the autonomic nervous system [18,19]. These findings open up the possibility that orexin functions as a master regulator to coordi-neurons in the ARC are glucose-excited [20,22].…”