The insulin‐like growth factor I receptor regulates glucose transport by astrocytes

Abstract

Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using 18 FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity.

Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism

“…The list of physiological duties attributed to astrocytes has grown continuously during recent decades, such that their original portrayal as a system of physical support for neurones has lead into them being recognised as vital active participants in virtually all aspects of neurological function. Indeed, astrocytes participate in neurogenesis, neuronal development, neuroprotection, synaptogenesis, synaptic plasticity and synaptic transmission . Not only do they transport nutrients and other factors into and within the brain, but also they are responsible for maintaining energy reserves in the central nervous system (CNS) in the form of glycogen .…”

“…Indeed, astrocytes participate in neurogenesis, neuronal development, neuroprotection, synaptogenesis, synaptic plasticity and synaptic transmission. [16][17][18][19][20] Not only do they transport nutrients and other factors into and within the brain, but also they are responsible for maintaining energy reserves in the central nervous system (CNS) in the form of glycogen. [16][17][18][19][20] Astrocytes can also metabolise many of the peripheral signals that they transport, such as glucose to lactate, thus controlling and modifying external messages reaching the surrounding neurones and directly influencing their responses.…”

Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

“…They are most often identified by the expression of the intermediate filament glial fibrillary acidic protein (GFAP), although not all astrocytes express this structural protein [49]. Indeed, these cells have diverse phenotypes depending on their location within the brain [50,51], exhibiting differential expression of receptors for a variety of molecules such as insulin [52], IGF-1 [53], dopamine, serotonin [54], estrogens [55,56], androgens [57], glutamate [58,59], gamma-aminobutyric acid (GABA) [60], ion channels [61], norepinephine [62], leptin and neuropeptide Y (NPY) [63]. They participate in the control of extracellular concentrations of ions and neurotransmitters [64], provide neurotrophic support [65], are involved in the formation, maintenance and functioning of synapses [66], modulate neuronal connectivity and synaptic efficacy [49], and contribute to the maintenance of the BBB [67].…”

“…When astrocytes lack leptin receptors, as a result of experimental genetic manipulation, there is a reduction in the anorexigenic response to this hormone and there is a decreased response to fasting and to the effect of ghrelin on appetite [104]. The function of astrocytic insulin signaling is essential for hypothalamic glucose sensing and systemic glucose homeostasis [52,53]. Moreover, astrocytic insulin signaling is required for efficient glucose uptake into the brain in response to changes in systemic glucose availability.…”

“…Moreover, astrocytic insulin signaling is required for efficient glucose uptake into the brain in response to changes in systemic glucose availability. If insulin signaling in astrocytes is impaired, as occurs during diet-induced systemic insulin resistance, astrocyte morphology, mitochondrial function, and circuit connectivity is affected [52,53]. In addition, there is a reduction in glucose-induced activation of hypothalamic POMC neurons with the physiological response to changes in glucose availability being impaired [52].…”