Chronic insulinopenia/hyperglycemia decreases cannabinoid CB1 receptor density and impairs glucose uptake in the mouse forebrain
Brain Research Bulletin. 2019-04-01; 147: 101-109
DOI: 10.1016/j.brainresbull.2019.01.024
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Both endocannabinoids and insulin regulate peripheral and cerebral glucose
homeostasis via convergent signaling pathways that are impacted by diabetes. Here
we asked how glucose metabolism and important facets of insulin signaling are
affected in the forebrain of cannabinoid CB1 receptor knockout mice (CB1R-KO) and
their wild-type (WT) littermates, seven weeks after the induction of
insulinopenia/hyperglycemia (diabetes) with intraperitoneal streptozotocin
injection. Sham-injected animals served as control. Diabetes caused milder weight
loss in the WT mice compared to the phenotypically ˜11% leaner CB1R-KO, while
hyperglycemia was similar. Resting [3H]deoxyglucose uptake was significantly
reduced by ˜20% in acute ex vivo frontocortical and hippocampal slices obtained
from both the sham-injected CB1R-KO and the diabetic WT mice. Surprisingly, the
third cohort, the diabetic CB1R-KO showed no further impairment in glucose
uptake, as compared to the sham-injected CB1R-KO. Depolarization-induced
[3H]deoxyglucose uptake was proportional to the respective resting values only in
the cortex in all four cohorts. The dissipative metabolism of [14C]-U-glucose
remained largely unaffected in all cohorts of animals. However, diabetes reduced
cortical CB1R density by ˜20%, as assessed by Western blotting. Albeit the
changes in insulin signaling did not reflect the glucose uptake profile in each
cohort, there were significant interactions between diabetes and genotype. In
conclusion, a chronic decrease or lack of CB1R expression reduces glucose uptake
in the mouse brain. Additionally, diabetes failed to cause further impairment in
cerebral glucose uptake in the CB1R-KO. These suggest that diabetic
encephalopathy may be in part associated with lower CB1R expression.