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

Abstract

Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by insulin receptors, physiological 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 sensitivity in peripheral tissues and favors weight gain, reduces the efficiency of insulin uptake from plasma into the CNS. To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clearance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding. These parameters, together with 24-h plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The percent changes of adiposity, body weight, and food intake after high-fat feeding 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 findings were supported by a non-model-based calculation of CNS insulin uptake: 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 these 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 this estimate was inversely associated with percent changes in body weight (r = -0.71, P = 0.03). These results demonstrate that increased food intake and weight gain during high-fat feeding are associated with and may be causally related to reduced insulin delivery into the CNS. Diabetes 49:1525-1533, 2000 I nsulin secreted by the endocrine pancreas plays a complex role in the regulation of fuel homeostasis. Even as insulin is recognized for its anabolic effects in the periphery, insulin acts in the central nervous system (CNS) as a catabolic agent by inhibiting food intake (1) and stimulating fat oxidation (2). These CNS properties, together with many convergent observations, implicate insulin as a signal that provides negative feedback to the CNS for the long-term regulation of energy balance (3-5). According to this hypothesis, interventions that chronically lower CNS insulin levels will increase the tendency for storing energy in the form of adipose tissue. Hence, interventions that chronically lower the circulating insulin levels, the efficiency of CNS insulin uptake, or both could stimulate energy intake and promote increased adiposity.In dogs, insulin enters the CNS via...

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

“…This non-linear relationship has been observed in moderate diet-induced obesity rats [37]. High-fat diet-induced obesity is also associated with reduced brain insulin transport in dogs [38], and genetically obese Zucker rats have impaired brain insulin transport [39], which can be ascribed to a decreased number of brain capillary insulin receptors [35]. Here we show that the sites of insulin-signalling impairment seem to be at the IR and post-receptor levels in the hypothalamus of obese Zucker rats.…”

Obese men respond to cognitive but not to catabolic brain insulin signaling

“…This outcome is strikingly different from the results in normal-weight men where the same treatment reduced hunger and induced a distinct loss of body fat and body weight. 16 It can be concluded that besides impaired blood-to-brain transport of insulin [11][12][13] that in our experiments was overridden by the intranasal administration of the compound, obesity is associated with central nervous resistance against the adiposity signal insulin not only in animals, but also in humans. Concordantly, intranasal insulin failed to acutely suppress food intake in obese men.…”

“…10 Animal data indicate that insulin transport to the brain is hampered in the obese state, resulting in a relative CNS deficit of the adiposity signal insulin in genetic and dietinduced models of obesity. 11,12 In humans, obesity appears to be associated with a comparable lack in CNS insulin. 13 Intranasal administration of insulin bypasses the bloodbrain barrier, increasing the concentration of the compound in cerebrospinal fluid without absorption into the blood stream.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Moreover, weight gain and insulin resistance from habitual consump-tion of palatable foods decrease insulin and leptin blood-brain barrier (BBB) penetrability (Caro et al, 1996;Kaiyala et al, 2000;Banks, 2003;Banks and Farrell, 2003;Woods et al, 2003) and their CNS effects (Couce et al, 2001;Banks and Farrell, 2003;Lindqvist et al, 2005;Porte et al, 2005), albeit some homeostatic hypothalamic areas lack BBB (Peruzzo et al, 2000;Ganong, 2000). The resultant brain insulin and leptin 'resistance' renders normal satiety signals even more ineffective (Erlanson-Albertsson, 2005;Isganaitis and Lustig, 2005) leading to further impairments in physiologic mechanisms regulating food intake (eg, overeating) and shifting the set point for energy homeostasis towards the development of overweight and obesity (Levine et al, 2003;Erlanson-Albertsson, 2005;Isganaitis and Lustig, 2005).…”