Reliability of individual differences in initial sensitivity and acute tolerance to nitrous oxide hypothermia.

On average, the hypothermia exhibited by rats receiving 60% nitrous oxide (N2O) eventually abates despite the continued inhalation of the drug (i.e., acute tolerance develops). However, large individual differences occur in both the magnitude of hypothermia achieved and the degree of acute tolerance that develops. To determine whether the degree of temperature loss and subsequent recovery during N2O administration are reliable characteristics of an individual, we measured intraperitoneal temperature via telemetry in 77 Long-Evans rats that each received 60% N2O for 5 h during two sessions separated by 14 days. Good intersession reliability (Pearson's r) was observed for simple change and adjusted change scores for both initial N2O temperature sensitivity (.61 < or = r < or = .62), and acute tolerance development (.46 < or = r < or = .52). In a separate experiment, three groups of rats were selected based on their individual body temperature patterns during an initial N2O administration: (1) insensitive to N2O hypothermia (n = 8); (2) marked hypothermia followed by acute tolerance development (n = 6); and (3) marked hypothermia followed by little acute tolerance development (n = 6). When retested 10 days later, each group exhibited a body temperature profile similar to that observed during the initial N2O exposure. Thus, the temperature profile observed during a rat's initial exposure to 60% N2O reflects a reproducible response for that animal.

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 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 k1k2, 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 k1k2 (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 k1k2, 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.

Reduced beta-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding.

The ability to increase beta-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces beta-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance (K(g)), insulin sensitivity (S(I)), and the acute insulin response to glucose (AIR(g)) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, S(I) decreased by 57% (P = 0.003) but AIR(g) was unchanged. This absence of beta-cell compensation to insulin resistance contributed to a 41% reduction of K(g) (P = 0.003) and abolished the normal hyperbolic relationship between AIR(g) and S(I) observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level (P = 0.004) in association with an 8% reduction of glucose (P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.

Model for the regulation of energy balance and adiposity by the central nervous system.

In 1995, we described a new model for adiposity regulation. Since then, data regarding the biology of body weight regulation has accumulated at a remarkable rate and has both modified and strengthened our understanding of this homeostatic system. In this review we integrate new information into a revised model for further understanding this important regulatory process. Our model of energy homeostasis proposes that long-term adiposity-related signals such as insulin and leptin influence the neuronal activity of central effector pathways that serve as controllers of energy balance.

New model for the regulation of energy balance and adiposity by the central nervous system.

We describe a new model for adiposity regulation in which two distinct classes of peripheral afferent signals modulate neuronal pathways in the brain that control meal initiation, meal termination, and the autonomic outflow influencing the fate of ingested energy. These brain pathways, termed central-effector pathways for the control of energy balance, respond to 1) short-term, situational-, and meal-related signals that are crucial to the size and timing of individual meals, but that are not components of the system serving to regulate adipose stores, and 2) long-term, adiposity-related signals that participate in the negative feedback control of fat stores. Long-term signals, such as the pancreatic hormone insulin, are secreted into the circulation in proportion to energy balance and adipose mass. These signals enter the brain where they influence central-effector pathways, in part by changing the sensitivity of these pathways to short-term signals. Through this mechanism, the central nervous system response to short-term signals is adjusted in proportion to changes in body adiposity, resulting in compensatory changes in food intake and energy expenditure that collectively favor the long-term stability of fat stores. This model provides a comprehensive framework for experimental design and data interpretation in the study of body adiposity regulation.