Chronic intrahypothalamic insulin infusion in the rat: Behavioral specificity

McGowan, Malcolm K.; Andrews, Karolyn M.; Fenner, Deborah; Grossman, Sebastian P.

doi:10.1016/0031-9384(93)90320-f

Cited by 36 publications

(19 citation statements)

References 15 publications

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“…In contrast, chronic infusion of low doses of insulin inhibits feeding (VanderWeele et al 1982). Infusion of insulin into the ventricular system decreases food intake and body weight of baboons (Woods et al 1979) and rodents (Brief & Davis, 1984;Arase et al 1988;McGaowan et al 1993;Schwartz et al 1994;Porte et al 1998). A similar finding was reported for animals eating a highcarbohydrate diet but not in those eating a high-fat diet (Arase et al 1988).…”

Section: Insulinmentioning

confidence: 67%

Afferent signals regulating food intake

2000

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Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. β-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

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Section: Insulinmentioning

confidence: 67%

Afferent signals regulating food intake

2000

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“…In mammals, delivery of insulin to the brain causes anorexigenic (appetite-suppressing) effects, resulting in a reduction in body weight (20)(21)(22). Inhibition of insulin signaling in the brain produces opposite (orexigenic) effects (12,23,24).…”

Section: Regulation Of Neuropeptide Expressionmentioning

confidence: 99%

Central insulin action in energy and glucose homeostasis

Plum

Belgardt²,

Brüning³

2006

Journal of Clinical Investigation

368

271

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Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level. History and backgroundMore than 150 years ago, the French physiologist Claude Bernard identified the liver as a reservoir for glucose. Remarkably, he also showed in rabbits that "piqûre" (pricking) of the floor of the fourth ventricle of the brain resulted in glucosuria (1) and concluded that the CNS plays an essential role in the control of peripheral blood glucose levels. More recently, insulin signaling in neuronal cells has been shown to regulate life span, growth, reproduction, and energy homeostasis in primitive organisms such as Caenorhabditis elegans and Drosophila melanogaster (2, 3). The insulin/IGF-1 signal transduction pathway shows similar characteristics in C. elegans, D. melanogaster, rodents, and humans, pointing to an evolutionarily conserved mechanism (4). Signaling of the insulin/IGF-1 receptor homolog dauer formation-2 (DAF-2) via the class IA PI3K (AGE-1) pathway in C. elegans has been shown to control development, reproductive function, and longevity in response to environmental stimuli such as energy supply, a mechanism involving the forkhead-O transcription factor (FOXO) homolog 6). Likewise, the insulin receptor substrate (IRS) protein homolog CHICO in D. melanogaster regulates somatic growth, reproduction, and lipid metabolism (7).It has been shown that overexpression of D. melanogaster insulinlike peptides (dILPs) in the nervous system of fasted larvae suppresses the hunger-driven ingestion of food and that upregulation of D. melanogaster p70/S6 kinase (dS6K) activity in dILP neurosecretory cells leads to a diminished hunger response in fasted larvae (8). Furthermore, ablation of dILP neurons in the Drosophila brain was found to result in prolonged lifespan, reduced fertility, increased fasting glucose levels, increased storage of lipids and carbohydrates, and reduced tolerance to heat and cold (2, 9), clearly assigning neurosecretory cells a pivotal importance in the regulation of lifespan and fuel metabolism in D. melanogaster.The finding that insulin, like the adipocyte-derived hormone leptin, affects both neuropeptide expression in the hypothalamus and food intake has recently led to the appreciation of the brain as an insulin target tissue with regard t...

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“…Insulin is transported across the BBB via a saturable process , and insulin receptors are widely expressed in the brain, expressed in relatively high content in areas implicated in the regulation of energy homeostasis such as the ARC, and localize to both NPY/ AgRP and POMC/CART neurons (Havrankova et al, 1978;Benoit et al, 2002). Indeed, previous reports demonstrate the ability of exogenously administered insulin to decrease appetite and food intake in rodents, nonhuman primates, and humans (Woods et al, 1979(Woods et al, , 1984Ikeda et al, 1986;McGowan et al, 1993;Hallschmid et al, 2004). The anorexigenic effects of insulin are consistent with its abilities to decrease the expression of NPY in the ARC (Schwartz et al, 1991(Schwartz et al, , 1992 and the expression of AgRP (Könner et al, 2007); the latter effect, however, seems not to alter food intake but instead decreases hepatic glucose production.…”

Section: Pancreas-derived Hormones Regulating Appetite and Energy Hommentioning

confidence: 99%