Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation

We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Δ = 13.5 ± 3.6 µg/dl; P < 0.05) and NE (Δ = 235 ± 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 ± 35 vs. 112 ± 13 and 106 ± 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 ± 13 (oleate) vs. 135 ± 20 (caprylate) and 96 ± 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.

Galanin in the PVN increases nutrient intake and changes peripheral honnone levels in the rat

Abstract In self-selection feeding paradigms, rats display differential patterns of nutrient (protein, carbohydrate or fat) intake. Factors known to influence this selection include brain peptides as well as circadian parameters. In this series of experiments we investigated the role of PVN galanin in nutrient intake during the early and late dark periods in the rat. Rats were allowed to select between three isocaloric diets enriched in protein, carbohydrate or fat. Following a 2-week adaptation period, the animals&apos; 24-h intake was monitored for 4 weeks. Galanin was injected into the PVN and food intake was measured 1, 2 and 24 h post-injection. Galanin significantly increased the 1 h total food intake but it failed to increase the intake of any particular nutrient. Galanin had no effect 2 or 24 h post-injection. Analysis of the data grouped by preference based on the rats 24 h baseline selection patterns over the 4-week period revealed that galanin seem to increase the preferred nutrient. That is, galanin preferentially increased the intake of the carbohydrate-or fatrich diet in animals with high (over 40% of the total food intake) 24-h baselines in this particular nutrient. Finally, analysis of the plasma hormone levels after paraventricular galanin administration revealed a significant increase in noradrenaline levels, a small reduction in plasma insulin with no effects on adrenaline, glucose or corticosterone. The data revealed that galanin in the PVN influences both food intake and metabolic functioning. PVN galanin significantly increases sympathetic outflow and seems to stimulate the intake of the individual rat&apos;s preferred macronutrient

Overfeeding, Autonomic Regulation and Metabolic Consequences

The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperinsulinemia. There might be a causal relationship between autonomic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate homeostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

Circadian Control of Insulin Secretion Is Independent of the Temporal Distribution of Feeding

To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood glucose responses were fairly similar during the six different meals, but glucose increments were clearly delayed during the last two meals consumed during the light period. Insulin increments were highest during the dark phase and clearly diminished during the second half of the light phase. This situation was reversed when the scheduled meals were replaced by i.v. glucose infusions, i.e., no significant differences were detected between insulin responses, whereas glucose increments were reduced during the dark period. These results show that there is a circadian regulation of basal blood glucose and feeding-induced insulin responses, which is independent of the temporal distribution of feeding activity.

Time-dependent effects of neuropeptide Y infusion in the paraventricular hypothalamus on ingestive and associated behaviors in rats

In this study the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the daily regulation of feeding, drinking, locomotor activity, and nestbox occupation was investigated. These behaviors were recorded during and after bilateral infusion of NPY into the PVN of rats during the early (E) or late (L) part of the light phase. Administration of NPY caused a significant increase in feeding behavior at E, but not at L. In contrast to the feeding at E, L feeding was associated with increased water intake following NPY infusion. While locomotor activity was similar in sCSF- and NPY-infused rats at all times of the daily cycle, administration of NPY at L, but not at E increased nestbox occupation during the first few hours of the dark phase. This increased nestbox occupation was not associated with altered food intake or drinking behavior, implying that NPY-treated rats made frequent excursions between nestbox and food hopper/water bottle. Thus, feeding-associated drinking and explorative behavior are time-dependently modulated by NPY in the PVN, independent of locomotor activity.

The psychobiology of meals

Meals are considered as bouts of behavior that, although necessary for supplying nutrients to the body, result in undesirable perturbations of homeostatically controlled parameters. If the environment dictates that an animal mainly eat very large meals, these meal-associated perturbations become potentially dangerous. When the opportunity to eat a very large meal is regular and predictable, animals adopt strategies that maximize the efficiency of the process while minimizing the threatening homeostatic disturbances. Hence, prior to the onset of meals, animals elevate their body temperatures, presumably to facilitate critical processes involved in ingestion and/or digestion. Temperature continues to rise during the meal, and as it approaches potentially dangerous levels, the meal is terminated and temperature falls to "safer" levels. Animals also undergo a slow decline of blood glucose prior to the initiation of meals, thus minimizing the postprandial elevation of blood glucose caused by the absorption of ingested carbohydrates. Analogously, prior to meals, animals undergo a decrease of metabolic rate, thus precluding the necessity for postprandial increases of metabolic rate to reach even higher absolute levels. These premeal changes of regulated parameters have been interpreted by others as indicating depletion of one or more energy supplies so that the animal is compelled to eat. Contrary to this, we interpret the changes as ones that enable the animal to prepare adequately to consume a large meal when the environment is predictable.