Editors' ChoiceObesity

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Science Translational Medicine  31 Aug 2016:
Vol. 8, Issue 354, pp. 354ec140
DOI: 10.1126/scitranslmed.aah6076

Glucose is a critical energy source for the brain and regulates the activity of specialized neural populations in the central nervous system (CNS) to modulate peripheral energy metabolism. Insulin regulates metabolism through CNS actions. For example, CNS administration of insulin modulates hepatic glucose production and adipose tissue lipolysis; therefore, insulin resistance seen in obesity might contribute to Alzheimer’s disease. However, the sites and targets of insulin’s actions in the CNS are incompletely understood. In recent work, García-Cáceres et al. have uncovered an effect of insulin on astrocytes, cells that are abundant in the brain and important for regulation of neural functions.

First, the authors selectively ablated insulin receptors from astrocytes, which resulted in reduced astrocyte glucose uptake and altered astrocyte morphology. Neighboring hypothalamic neurons also showed altered mitochondrial networks, changes in synaptic density, and blunted neural response to peripheral glucose. Next, the researchers examined whether astrocyte insulin signaling is required for physiological responses to altered blood glucose. In response to elevated glucose levels, CNS circuits suppress feeding and regulate hormone release to reduce blood glucose. In mice lacking astrocyte insulin receptors, the responses to glucose given directly into the CNS were normal but those to peripheral glucose administration were diminished; the mice continued to eat, and blood glucose levels were higher than in control mice. Last, the authors examined glucose and insulin levels in the cerebrospinal fluid with changes in blood glucose. When circulating glucose was increased in mice without astrocyte insulin receptors, the expected rise in insulin and glucose in the cerebrospinal fluid was significantly blunted. Positron emission tomography showed reduced glucose accumulation in the brain of these mice.

These studies suggest that astrocyte insulin signaling regulates CNS glucose uptake and therefore, the homeostatic responses that regulate glucose. Insulin resistance at the level of the astrocyte might contribute to impaired glucose tolerance or even reduced cognition associated with obesity. If these pathways are present in humans, then modulating astrocyte insulin sensitivity may provide an alternative approach to treat diabetes and to determine if astrocyte insulin resistance contributes to neural pathologies seen in Alzheimer's disease.

C. García-Cáceres et al., Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166, 867–880 (2016). [Abstract]

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