A dietary fat excess alters metabolic and neuroendocrine responses before the onset of metabolic diseases

Abstract

Early changes in neuroendocrine pathways are essential in the development of metabolic pathologies. Thus, it is important to have a better understanding of the signals involved in their initiation. Long-term consumption of high-fat diets induces insulin resistance, obesity, diabetes. Here, we have investigated early neural and endocrine events in the hypothalamus and hippocampus induced by a short-term high fat, low carbohydrate diet in adult male Wistar rats. The release of serotonin, which is closely associated with the actions of insulin and leptin, was measured, by electrochemical detection following reverse-phase liquid chromatography (HPLC), in the extracellular space of the medial hypothalamus and the dorsal hippocampus in samples obtained from non-anesthetized animals, by microdialysis. The high-fat diet had a specific effect on the hypothalamus. Serotonin release induced by food intake was reduced after 1 week, and effectively ceased after 6 weeks of the diet. After 1 week, there was an increased gene expression of the insulin receptor and the insulin receptor substrates IRS1 and IRS2, as measured by real-time PCR. After 6 weeks of diet, insulin gene expression increased. Leptinemia increased in all cases. This new data support the concept that high-fat diets, in addition to have peripheral effects, cause a rapid alteration in specific central mechanisms involved in energy and glucose homeostasis. The changes in the gene expression of insulin and signaling elements represent possible adaptations aimed at counterbalancing the reduced responsiveness of the serotonergic system to nutritional signals and maintaining homeostasis.

Fig. 1

Food intake increases the serotonin release in the hippocampus of chow-fed and high-fat-fed rats. (a) Serotonin (5-HT) or (b) 5-hydroxyindoleacetic acid (5-HIAA) levels in 15 min microdialysate samples from dorsal hippocampus during and after a chow meal ingested by chow-fed (solid line) or 1 week high-fat-fed (dashed line) rats. Results are expressed as percentage of baseline samples preceding the meal. Error bars indicate SEM. Significant differences are designed as within-group, * P < 0.05, ** P < 0.01, from time 0 min, corresponding to basal levels

Fig. 2

The high-fat diet given for 1 week attenuates the serotonin release induced by food intake in the hypothalamus. (a) Serotonin (5-HT) or (b) 5-hydroxyindoleacetic acid (5-HIAA) levels in 15 min microdialysate samples from medial (VMH and PVN) hypothalamus during and after a chow meal ingested by chow-fed (solid line) or 1 week high-fat-fed (dashed line) rats. Results are expressed as mean of the percentage of variation relative to the mean of the baseline samples preceding the meal. Error bars indicate SEM. Significant differences are designed as within-group * P < 0.05, from time 0 min corresponding to basal levels, or between-groups ^# P < 0.05

Fig. 3

The high-fat diet given for 6 weeks blocks the serotonin release induced by food intake in the hypothalamus. (a) Serotonin (5-HT) or (b) 5-hydroxyindoleacetic acid (5-HIAA) levels in 15 min microdialysate samples from medial (VMH and PVN) hypothalamus during and after a 1 week chow meal ingested by chow-fed (solid line) or 6 weeks high fat-fed (dashed line) rats. Results are expressed as mean of the percentage of variation relative to the mean of the baseline samples preceding the meal. Error bars indicate SEM. Significant differences are designed as within-group * P < 0.05, from time 0 min corresponding to basal levels, or between-groups ^### P < 0.001

Fig. 4

Gene expression in the hippocampus is similar in chow or high fat-fed rats. (a) One week high-fat-fed rats or (b) 6 weeks high-fat-fed rats (white bars), toward chow-fed controls (black bars). Results are expressed in arbitrary units (AU), as percentage variations of samples obtained from the corresponding chow diet-fed rats. Error bars indicate SEM. The expression of the following genes is reported: insulin, insulin receptor, IRS1, IRS2, and of leptin receptor

Fig. 5

The high-fat diet modifies hypothalamic gene expression. (a) One week high-fat diet-fed rats or (b) 6 weeks high-fat diet fed rats (white bars), compared with chow-fed controls (black bars). Results are expressed in AU, as percentage variations of samples obtained from the corresponding chow diet-fed rats. Error bars indicate SEM. Significant differences toward respective chow-fed controls *P < 0.05, **P < 0.01. The expression of the following genes is reported: insulin, insulin receptor, IRS1, IRS2, or leptin receptor. (c) As a control of insulin gene expression, PCR was carried out on messenger RNA isolated from various tissues: for positive controls, pancreas, and beta cells were tested, for negative controls liver, muscle, and adipose tissues. Using the same primer as shown in (a, b), insulin messenger RNA was detected in the brain, the hippocampus, and the hypothalamus