Studying the central control of food intake and obesity in rats

Background/Objectives:Glucose from the diet may signal metabolic status to hypothalamic sites controlling energy homeostasis. Disruption of this mechanism may contribute to obesity but its relevance has not been established. The present experiments aimed at evaluating whether obesity induced by chronic high-fat intake affects the ability of hypothalamic glucose to control feeding. We hypothesized that glucose transport to the hypothalamus as well as glucose sensing and signaling could be impaired by high-fat feeding.Subjects/methods:Female Wistar rats were studied after 8 weeks on either control or high-lard diet. Daily food intake was measured after intracerebroventricular (i.c.v.) glucose. Glycemia and glucose content of medial hypothalamus microdialysates were measured in response to interperitoneal (i.p.) glucose or meal intake after an overnight fast. The effect of refeeding on whole hypothalamus levels of glucose transporter proteins (GLUT) 1, 2 and 4, AMPK and phosphorylated AMPK levels was determined by immunoblotting.Results:High-fat rats had higher body weight and fat content and serum leptin than control rats, but normal insulin levels and glucose tolerance. I.c.v. glucose inhibited food intake in control but failed to do so in high-fat rats. Either i.p. glucose or refeeding significantly increased glucose hypothalamic microdialysate levels in the control rats. These levels showed exacerbated increases in the high-fat rats. GLUT1 and 4 levels were not affected by refeeding. GLUT2 levels decreased and phosphor-AMPK levels increased in the high-fat rats but not in the controls.Conclusions:The findings suggest that, in the high-fat rats, a defective glucose sensing by decreased GLUT2 levels contributed to an inappropriate activation of AMPK after refeeding, despite increased extracellular glucose levels. These derangements were probably involved in the abolition of hypophagia in response to i.c.v. glucose. It is proposed that ‘glucose resistance' in central sites of feeding control may be relevant in the disturbances of energy homeostasis induced by high-fat feeding.

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“… 7 , 8 , 9 In obesity, several brain energy homeostasis mechanisms are reportedly altered. 6 , 10 , 11 , 12 …”

Section: Introductionmentioning

confidence: 99%

Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis

et al. 2015

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“…These inputs modify the activity of hypothalamic anabolic and catabolic neurons, whose neuropeptide products stimulate or inhibit food intake, respectively. Disturbances of these control mechanisms have been associated with the pathogenesis of obesity [1-4]. …”

Section: Introductionmentioning

confidence: 99%

Proteomic profiling of the rat hypothalamus

et al. 2012

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BackgroundThe hypothalamus plays a pivotal role in numerous mechanisms highly relevant to the maintenance of body homeostasis, such as the control of food intake and energy expenditure. Impairment of these mechanisms has been associated with the metabolic disturbances involved in the pathogenesis of obesity. Since rodent species constitute important models for metabolism studies and the rat hypothalamus is poorly characterized by proteomic strategies, we performed experiments aimed at constructing a two-dimensional gel electrophoresis (2-DE) profile of rat hypothalamus proteins.ResultsAs a first step, we established the best conditions for tissue collection and protein extraction, quantification and separation. The extraction buffer composition selected for proteome characterization of rat hypothalamus was urea 7 M, thiourea 2 M, CHAPS 4%, Triton X-100 0.5%, followed by a precipitation step with chloroform/methanol. Two-dimensional (2-D) gels of hypothalamic extracts from four-month-old rats were analyzed; the protein spots were digested and identified by using tandem mass spectrometry and database query using the protein search engine MASCOT. Eighty-six hypothalamic proteins were identified, the majority of which were classified as participating in metabolic processes, consistent with the finding of a large number of proteins with catalytic activity. Genes encoding proteins identified in this study have been related to obesity development.ConclusionThe present results indicate that the 2-DE technique will be useful for nutritional studies focusing on hypothalamic proteins. The data presented herein will serve as a reference database for studies testing the effects of dietary manipulations on hypothalamic proteome. We trust that these experiments will lead to important knowledge on protein targets of nutritional variables potentially able to affect the complex central nervous system control of energy homeostasis.

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“…At 18:00 h, after the fourth injection, a concentric custom-constructed microdialysis probe (1.5 mm of effective membrane length) was inserted through the hypothalamic cannula and fixed to it with a small drop of dental cement. The details of probe construction have been previously described [29,30]. The animals were then connected to a swivel system, which allowed continuous probe perfusion with CSF by a microperfusion pump (Carnegie Medicin, Solna, Sweden).…”

Section: Microdialysis Experimentsmentioning

confidence: 99%

Lateral hypothalamic serotonin is not stimulated during central leptin hypophagia

Telles

Silva

Watanabe

et al. 2013

Regulatory Peptides

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Whether leptin targets the hypothalamic serotonergic system to inhibit food intake is not established. We examined the effect of a short-term i.c.v. leptin treatment on serotonin microdialysate levels in rat lateral hypothalamus. Adipose tissue gene expression was also evaluated. Male rats received four daily injections of leptin (5 μg) or vehicle (with pair-feeding to leptin-induced intake) and a fifth injection during collection of LH microdialysates. We found that serotonin and 5-HIAA levels were not affected by the leptin pre-treatment, as basal levels were similar between the leptin and the pair-fed group. These levels remained unaltered after the acute leptin injection. For gene expression studies, rats were pre-treated with five daily injections of either leptin (5 μg) or vehicle (with either pair-feeding or ad libitum intake). mRNA levels of resistin, adiponectin, lipoprotein lipase, and PPAR-gamma were unaltered by either leptin or pair-feeding. Leptin gene expression was significantly reduced by leptin but not by pair-feeding, in both the retroperitoneal (-74%) and the epididymal (-99%) depots while no differences were observed in the subcutaneous depot. The observations confirmed the absence of an acute stimulatory effect of central leptin on serotonin release in the lateral hypothalamus and showed that the pre-treatment with leptin failed to modify this pattern. This indicates that components of the serotonergic system are probably not directly affected by leptin. Additionally, the central effect of leptin was able to downregulate its own adipose tissue gene expression in a depot-specific manner while other adipokine genes were not affected.

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Studying the central control of food intake and obesity in rats

Cited by 20 publications

References 27 publications

Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis

Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis

Proteomic profiling of the rat hypothalamus

Lateral hypothalamic serotonin is not stimulated during central leptin hypophagia

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