Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs

Insulin transported from plasma into the central nervous system (CNS) is hy pothesized to contribute to the negative feedback regulation of body adipos ity, Because CNS insulin uptake is likely mediated by insulin receptors, ph ysiological interventions that impair insulin action in the periphery might also reduce the efficiency of CNS insulin uptake and predispose to weight gain, We hypothesized that high-fat feeding, which both reduces insulin sen sitivity in peripheral tissues and favors weight gain, reduces the efficien cy of insulin uptake from plasma into the CNS, To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clear ance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding, These parameters, to gether with 24-h. plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The perce nt changes of adiposity, body weight, and food intake after high-fat feedin g were each inversely associated with the percent changes of the parameter k(1)k(2), which reflects the efficiency of CNS insulin uptake from plasma ( r = -0.74, -0.69, -0.63; P = 0.015, 0.03, and 0.05, respectively). These fi ndings were supported by a non-model-based calculation of CNS insulin uptak e: the CSF-to-plasma insulin ratio during the insulin infusion. This ratio changed in association with changes of k(1)k(2) (r = 0.84, P = 0.002), body weight (r = -0.66, P = 0.04), and relative adiposity (r = -0.72, P = 0.02) , By comparison, changes in insulin sensitivity according to minimal model analysis, were not associated with changes in k(1)k(2), suggesting that the se parameters are not regulated in parallel, During high-fat feeding, there was a 60% reduction of the estimated CNS insulin level (P = 0.04), and thi s estimate was inversely associated with percent: changes in body weight (r = -0.71, P = 0.03), These results demonstrate that increased food intake a nd weight gain during high-fat feeding are associated with and may be causa lly related to reduced insulin delivery into the CNS.