Biomedical subjects

Randy J Seeley

Publications and source records attributed to Randy J Seeley.

62 records · Page 4Linked to original sources

PubMed2002

The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness.

Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 microg of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 microg of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited.

Amygdala↗

PubMed2002

The catabolic action of insulin in the brain is mediated by melanocortins.

Like leptin, the pancreatic hormone insulin is an important adiposity signal to the brain. We report that the hypothalamic melanocortin system is an important target of the actions of insulin to regulate food intake and body weight. Hypothalamic neurons expressing insulin receptors were found to coexpress the melanocortin precursor molecule pro-opiomelanocortin (POMC), and administration of insulin into the third cerebral ventricle of fasted rats increased expression of POMC mRNA. Finally, a subthreshold dose of the melanocortin antagonist SHU-9119 prevented the reduction in food intake caused by third-ventricular insulin administration. These data suggest that the hypothalamic melanocortin system mediates the anorexic effects of central insulin, as well as of leptin.

Animals↗

PubMed2002

Acute 3rd-ventricular amylin infusion potently reduces food intake but does not produce aversive consequences.

In this study, a conditioned taste aversion (CTA) paradigm was used to assess the possibility that 3rd-ventricular (i3vt) administration of the pancreatic hormone amylin produces aversive consequences that secondarily reduce food intake independently of the normal regulation of energy balance. After 1-h daily access to water for 7 days, rats were given 1-h access to a 0.15% saccharin solution, followed immediately by i3vt amylin (100 pmol) in one group (n=7) and i3vt CSF vehicle in another (n=7). As positive control for the formation of a CTA, a third group of seven rats received intraperitonial (i.p.) lithium chloride (LiCl). Saline was given i.p. to a fourth group (n=7) as control for i.p. LiCl. As expected, the LiCl rats exhibited a marked aversion to the saccharin in a subsequent two-bottle intake test. In contrast, although the 100 pmol i3vt amylin dose is substantially higher than that required to reduce food intake, no evidence of a CTA was observed in the rats that had received i3vt amylin. In summary, these data are consistent with the conclusion that acute i3vt amylin infusion does not reduce food intake by producing aversive consequences.

Amyloid↗

PubMed2002

Cloned mice have an obese phenotype not transmitted to their offspring.

Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.

Adipose Tissue↗

PubMed2002

Principles for interpreting interactions among the multiple systems that influence food intake.

The widespread use of molecular biological tools has led to a pronounced increase in the number of signals that are now implicated in the controls of food intake and body weight. However, a complete understanding of the roles of these multiple signals requires that we assess how they interact with one another to alter ingestive behavior. Although many such experiments are being conducted, the methods employed to delineate these interactions are often fraught with interpretive difficulties. The purpose of this article is to explore these difficulties and offer practical advice for minimizing these issues in experiments that seek to explore the important interactions among these signals. In particular, the issues of additive vs. nonadditive results, the use of sub- or suprathreshold dose combinations, and the choosing of multiple-dose analyses are all addressed. Furthermore, the possibilities of using intake measures other than cumulative intake and complementary nonbehavioral endpoints are encouraged.

Animals↗

PubMed2002

Insulin and leptin combine additively to reduce food intake and body weight in rats.

Leptin and insulin are distinct adiposity signals that regulate food intake and body weight. Because recent evidence suggests that the central catabolic action of each is mediated by the hypothalamic melanocortin system, we tested the hypothesis that leptin and insulin interact within the brain, either additively or synergistically, to suppress food intake and reduce body weight. Using a within-subjects design, we co-administered leptin and insulin into the 3rd cerebral ventricle (i.c.v.) over a wide range of doses, and compared the combined effects to what occurred following the administration of each peptide alone. The data suggest that leptin and insulin interact sub-additively to regulate food intake and body weight over the first few hours. That is, the ability of combinations of leptin and insulin to reduce food intake and body weight was less than what would be predicted by the sum of their independent actions. Over 24 hours, however, the combined doses fit a strictly additive model. These data therefore imply a redundancy in the functional intracellular pathways or neuronal circuits that leptin and insulin utilize in the acute regulation of food intake and body weight, and they further imply that over time, the redundancy dissipates.

Animals↗

PubMed2002

Eating elicited by orexin-a, but not melanin-concentrating hormone, is opioid mediated.

Melanin-concentrating hormone (MCH) and orexin-A are orexigenic peptidergic neurotransmitters produced primarily in the lateral hypothalamus. Because two other hypothalamic peptides, neuropeptide Y and agouti-related peptide, increase food intake by a mechanism that depends on activation of opioid receptors, we assessed whether MCH or orexin-A also elicits food intake via opioid receptor activation. A dose of naloxone (0.3 mg/kg, ip) that had no effect on its own reduced the acute orexigenic effect of third ventricular (i3vt) orexin-A (3 ng/rat). However, this same dose of naloxone had no effect on i3vt MCH (5 microg/rat)-induced hyperphagia. Because the opioid system has also been linked to food selection, we investigated whether MCH or orexin-A alters food choice when rats have simultaneous access to two diets differing in the relative amounts of fat and carbohydrate. Whereas i3vt MCH stimulated intake of both diets and did not alter food choice, i3vt orexin-A stimulated intake of only the high fat diet. These data indicate that despite several similarities between MCH and orexin-A, these two lateral hypothalamic area peptides stimulate food intake by recruiting different neural circuits and exert different effects on food choice.

Animals↗

PubMed2002

Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion.

Mice respond to fatty acid synthase (FAS) inhibitors by profoundly reducing their food intake and body weight. Evidence indicates that the central nervous system (CNS) may be the critical site of action; however, a peripheral contribution cannot be ruled out. We compared doses of the FAS inhibitor C75 in the CNS (third ventricle [i3vt]) and periphery (intraperitoneal [IP]) to reduce food intake and body weight in rats. Centrally, the threshold dose was 3 micro g, whereas a dose of 10 mg/kg was required peripherally. Such data argue for FAS activity in the CNS as a potent target for the actions of C75. To control for nonspecific effects of FAS inhibition, we compared C75 administration in two models of illness, conditioned taste aversion and need-induced sodium appetite. Our results suggest the anorexia produced by IP C75 is accompanied by visceral illness, whereas the anorexia produced by i3vt is not. In addition, we placed animals in an indirect calorimeter after an IP injection of C75. We found that consistent with behavioral measures of visceral illness, peripheral C75 reduced heat expenditure and resulted in animals losing less weight than fasted control animals, suggesting that peripherally administered C75 has aversive properties. Understanding the mechanisms by which FAS inhibition in the CNS reduces food intake could lead to specific targets for the manipulation of energy balance and the treatment of obesity.

4-Butyrolactone↗