Biomedical subjects

Stephen C Benoit

Publications and source records attributed to Stephen C Benoit.

36 records · Page 2Linked to original sources

PubMed2004

Clinical endocrinology and metabolism. Regulation of energy homeostasis by peripheral signals.

The increased incidence of obesity makes it imperative to understand the regulation of food intake and body weight. We review the signals that interact with the brain to control energy homeostasis, i.e. energy intake and expenditure. Three broad categories can be distinguished. Signals generated in the gastrointestinal tract during meals ('satiety' signals, e.g. cholecystokinin) elicit satiation and contribute to stopping the meal. The potency of these acutely acting signals must be increased if they are to be used therapeutically. Hormonal signals whose secretion is proportional to body fat (adiposity signals, leptin and insulin) robustly reduce food intake and body weight by directly stimulating receptors locally in the brain. Therapeutic applications will have to find ways to circumvent the systemic actions of these hormones, targeting only the brain. Satiety and adiposity signals interact with neuronal circuits in the brain that utilize myriad neurotransmitters to cause net catabolic or anabolic responses. Considerable effort is being directed towards finding ways to intervene in specific circuits to help accomplish weight loss.

Animals↗

PubMed2004

Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats.

The authors hypothesized that insulin and leptin, hormones that convey metabolic and energy balance status to the central nervous system (CNS), decrease the reward value of food, as assessed by conditioned place preference (CPP). CPP to high-fat diet was blocked in ad-lib fed rats given intraventricular insulin or leptin throughout training and test or acutely before the test. Insulin or leptin given only during the training period did not block CPP. Thus, elevated insulin and leptin do not prevent learning a food's reward value, but instead block its retrieval. Food-restricted rats receiving cerebrospinal fluid, insulin, or leptin had comparable CPPs. Results indicate that the CNS roles of insulin and leptin may include processes involving memory and reward.

Animals↗

PubMed2004

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity.

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3-null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3-null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3-null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets.

Animals↗

PubMed2004

Insulin and leptin as adiposity signals.

There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simultaneously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropeptide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits.

Adipose Tissue↗

PubMed2003

7-OH-DPAT selectively reduces intake of both chow and high fat diets in different food intake regimens.

Mesolimbic dopaminergic system activation correlates with ingestive behavior in numerous feeding regimens. DA release is enhanced by food intake following deprivation, amount of food consumed, and the palatability of the food consumed. The dopamine-3 receptor (D3-R) has a limited expression pattern that is restricted largely to the mesolimbic dopaminergic system. The D3-R has been hypothesized to inhibit DA-mediated reward, locomotion and motivation. To test the potential for an inhibitory role of the D3-R on food intake, we administered the D3-R agonist 7-OH-DPAT (5, 10 and 50 microg/kg ip) to rats that had ad libitum access to standard rodent chow (3.41 kcal/gm, 0.51 kcal/gm from fat) or a preferable, high fat (HF) (4.4 kcal/gm, 1.71 kcal/gm from fat). In the second set of experiments we administered 7-OH-DPAT (10, 50 and 100 microg/kg) to rats that had access to chow or HF diet for only 3 h per day (meal fed). In the third set of experiments we administered 7-OH-DPAT (10 and 50 microg/kg) to rats that had access to chow or HF diet after a 21-h food restriction. The 10 and 50 microg/kg doses significantly, but equally reduced intake of chow and HF diet in animals that were ad libitum fed. In animals that were meal-fed the dose response was effectively shifted to the right and the 10 microg/kg dose was ineffective at reducing intake. The 50 and 100 microg/kg doses significantly but equally reduced intake of both diets. In animals that were 21-h restricted and had access to chow both the 10 and 50 microg/kg doses were ineffective at reducing intake. However, in animals that had access to HF diet, 7-OH-DPAT dose-dependently reduced intake. These results support a potential role for the D3-R in ingestive behavior particularly in situations that involve a significant learned component.

Animals↗

PubMed2003

Two novel paradigms for the simultaneous assessment of conditioned taste aversion and food intake effects of anorexic agents.

The conditioned taste aversion (CTA) is routinely used to assess the aversive consequences of anorexic agents, including potential pharmacological therapies for obesity. In a typical CTA paradigm, rats briefly sampling a novel tastant (e.g., saccharin) are acutely administered with toxin (e.g., lithium chloride, LiCl). After as few as one taste-toxin pairing, rats will reliably avoid the novel tastant. This paradigm is frequently used for the assessment of possible aversive consequences of drugs that are candidates for pharmacological therapies. The degree to which the drug supports development of a CTA is interpreted as an index of its aversive properties. Difficulties with previous work include the inability to assess affects on food intake and CTA simultaneously, particularly during chronic drug administration. We report here two novel CTA paradigms for the assessment of appetitive and aversive consequences of anorexic agents, simultaneously. In the first experiment, animals receive an intraoral infusion of a novel and highly palatable tastant immediately prior to administration of increasing doses of LiCl. In the second experiment, rats were implanted intraperitoneally with osmotic minipumps that chronically delivered a low dose of LiCl for 7 days. LiCl did not affect short or long term food intake in either experiment. However, LiCl did support the development of a CTA in both paradigms. These results suggest that both the appetitive and aversive consequences of anorexic agents can be assessed simultaneously during either acute or chronic drug administration.

Animals↗

PubMed2003

Altered feeding responses in mice with targeted disruption of the dopamine-3 receptor gene.

Dopamine signaling has been implicated in the control of food intake and body weight. In particular, dopamine is important in the control of meal size and number and is thought to mediate the response to metabolic deprivation states. In the present experiments, the authors assessed the role of the dopamine-3 receptor (D3R) in the feeding responses to 2-deoxy-D-glucose, mercaptoacetate, and peripheral insulin. All 3 compounds increased food intake in wild-type mice, but the hyperphagic responses were blunted in D3R-/- mice. In other experiments, D3R-/- mice were hyperresponsive to the administration of amylin and leptin relative to wild-type mice. These results support the hypothesis that D3Rs chronically inhibit the effects of adiposity hormones, thereby contributing to a net anabolic state.

Animals↗

PubMed2003

Ethanol consumption in mice with a targeted disruption of the dopamine-3 receptor gene.

Considerable evidence suggests that the mesolimbic dopaminergic system is an important substrate for the rewarding effects of ethanol consumption. Previous data have demonstrated that pharmacological agents that alter dopamine signaling also influence the self-administration of ethanol. The present experiments were designed to assess the role of the dopamine-3 receptor (D3-R) on voluntary ethanol consumption in C57BL/6 mice. Mice with targeted disruption of the D3-R gene (D3-R - /-) were compared to wild-type controls in an ethanol intake paradigm. In Experiment 1, mice had 24-hour access to ethanol each day in a two-bottle choice paradigm for a period of 7 days per concentration. The concentrations tested were 3, 6, 10 and 15%. In Experiment 2, mice had I hour of access to ethanol each day in a two-bottle paradigm for a period of 7 days per concentration. The same concentrations in Experiment I were compared in Experiment 2. In Experiment 3 we sought to test the development of a conditioned taste aversion (CTA) after receiving an intraperitoneal (ip.) injection of 2.0 g/kg ethanol. In Experiment 4, blood ethanol levels where assessed following a 2.0 g/kg ip.injection of ethanol. Experiment 5 assessed taste preference for saccharine and quinine in wild-type and D3-R -/- mice. Contrary to our predictions, both D3-R -/- and wild-types on a CS57BL/6 background had similar intakes of ethanol, at all concentrations tested, in the 24-hour and 1-hour intake paradigms. Wild-type and D3-R -/- mice respond to injected ethanol similarly by developing a conditioned taste aversion. Metabolic analysis revealed mutant mice are slower in metabolizing a bolus injection of ethanol. Lastly, wild-type and D3-R -/- mice showed similar consumption to increasing concentration of both sweet and bitter tastes. These data suggest that deletion of the D3-R gene does not increase ethanol consumption above that found on the C57BL/6 genetic background. Furthermore, the D3-R -/- mice adequately learn a CTA to ethanol and do not ham differing taste reactivity to saccharin or quinine. However, D3-R -/- mice do appear to have a slower rate of ethanol metabolism.

Alcohol Drinking↗

PubMed2003

Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway.

Syndecan-3, expressed in the developing nervous system and adult brain, alters feeding behavior through its interaction with the CNS melanocortin system, which provides critical tonic inhibition of both food intake and body adipose stores. A variety of both in vitro and transgenic data supports the hypothesis that syndecan-3 modulates melanocortin activity via syndecan-3 facilitation of agouti-related protein (AgRP), a competitive antagonist of alpha-melanocyte-stimulating hormone (alpha-MSH) at the melanocortin-3 and -4 receptors. Consistent with this hypothesis, mice lacking syndecan-3, which therefore would be predicted to have less effective AgRP, are more sensitive to inhibition of food intake by the melanocortin agonist MTII. Additionally, we took advantage of the fact that syndecan-3 facilitation of AgRP is limited to when it is bound to the cell membrane. Pharmacologic inhibition of the enzyme that cleaves syndecan-3 from the cell membrane leads to increased food intake in fasted rats, which have elevated levels of AgRP. Furthermore, the shedding process appears to be regulated under physiologic conditions, because a putative inhibitor of the shedding process, tissue inhibitor of metalloprotease-3 (TIMP-3), is increased by food deprivation. These observations contribute to the hypothesis that syndecan-3 regulation of melanocortin signaling contributes to the normal control of energy balance. Collectively, the data suggest that the modulation of melanocortin regulation of energy balance by syndecan-3 is modulated by the action of a TIMP-3-sensitive metalloprotease.

Agouti-Related Protein↗

PubMed2003

Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake.

The lateral hypothalamus (LH) has a critical role in the control of feeding and drinking. Melanin-concentrating hormone (MCH) is an orexigenic peptidergic neurotransmitter produced primarily in the LH, and agouti-related protein (AgRP) is an orexigenic peptidergic neurotransmitter produced exclusively in the arcuate (ARC), an area that innervates the LH. We assessed drinking and eating after third ventricular (i3vt) administration of MCH and AgRP. MCH (2.5, 5, and 10 micro g i3vt) significantly increased food as well as water intake over 4 h when administered during either the light or the dark portion of the day-night cycle. When MCH (5 micro g) was administered to rats with access to water but no food, they drank significantly more water than when given the vehicle. AgRP (7 micro g i3vt), on the other hand, increased water intake but only in proportion to food intake during the dark and the light, and water intake was not increased after i3vt AgRP in the absence of food. Hence, in contrast to AgRP, MCH elicits increased water intake independent of food intake. These results are consistent with historical data linking activity of the LH with water as well as food intake.

Agouti-Related Protein↗

PubMed2003

Increased dietary fat attenuates the anorexic effects of intracerebroventricular injections of MTII.

The hypothalamic melanocortin (MC) system provides a critical inhibitory control on food intake and body weight. Because access to high-fat (HF) diets is associated with the development of obesity, we hypothesized that increased dietary fat attenuates signaling through the MC system. To evaluate this hypothesis, we compared the efficacy of the MC3/4 receptor agonist, MTII, to reduce food intake in rats fed carefully matched HF or low-fat (LF) diets for 12 wk. Rats given the HF diet ad libitum were significantly more obese than rats given the LF diet, and had significantly higher plasma insulin and leptin levels. MTII given into the third cerebral ventricle in doses of 0.1, 0.3, and 1.0 nmol was less effective at reducing food intake in HF rats than in LF rats. Whole-hypothalamic expression of the MC agonist precursor gene, proopiomelanocortin, the MC antagonist agouti-related protein, and the MC4 receptor, were not different between the HF and LF groups. These results indicate that consumption of a HF diet decreases signaling through the melanocortin system, an abnormality that could contribute to diet-induced obesity.

Agouti-Related Protein↗

PubMed2003

Learned meal initiation attenuates the anorexic effects of the melanocortin agonist MTII.

The central melanocortin system is critically involved in the control of food intake and body weight. Administration of melanocortin agonists reduces food intake and adiposity, and the central melanocortin system is demonstrated to mediate the anorexic effects of both leptin and insulin. An important unanswered question has been whether melanocortin agonists would also reduce food intake that is driven by factors other than homeostatic mechanisms (e.g., conditioned eating). In the first experiment, we identified that long-term maintenance on a meal-feeding schedule attenuated rats' sensitivity to central administration of the melanocortin agonist MTII. The results from a second experiment demonstrate that the attenuation of the MTII-induced anorexia was due to learned schedules of food intake rather than food deprivation per se. Results from the final experiment suggest that this attenuation of MTII-induced anorexia may be independent of the decreased sensitivity caused by a high-fat diet. These results support the hypothesis that meal-feeding schedules can lead to anticipatory physiological responses that attenuate the anorexic effects of exogenous melanocortin agonists.

Animals↗

PubMed2003

Differential sensitivity to central leptin and insulin in male and female rats.

The distribution of fat in the body differs between the male and female sexes and is associated with the relative secretion of the two "adiposity" hormones leptin and insulin. We now report that the brains of male and female rats are differentially sensitive to the catabolic actions of small doses of these two hormones. Leptin (1 or 3.5 microg/2 microl) or saline (2 microl) was administered into the third cerebral ventricle of age- and weight-matched male and female rats. Leptin significantly reduced food intake in female and male rats over 4 h; however, leptin reduced 24-h intake in female but not in male rats. When the same rats were administered insulin (1 or 4 mU/2 microl) or saline (2 microl), male but not female rats had a robust reduction in food intake over 24 h. Previous research demonstrates the melanocortins are a central mediator of the effects of both leptin and insulin. However, we found no sex differences in sensitivity to the melanocortin agonist MTII (0.01, 0.1, 0.3, and 1.0 nmol/2 microl). These results suggest that the sex differences in sensitivity to leptin and insulin at the doses that we injected occur upstream of the melanocortin receptors. Because insulin and leptin reflect different fat beds and are differentially distributed in the male and female sexes, the implication is that the male and female sexes regulate adiposity-relevant parameters differently.

Animals↗

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 third ventricular administration of insulin decreases food intake in two paradigms.

The pancreatic hormone, insulin, has been hypothesized to be an important regulator of food intake. Consistent with this hypothesis is the finding that exogenous insulin, in doses that do not affect blood glucose, reliably suppresses food intake and body weight. However, previous experiments have utilized a long-term delivery paradigm, in which insulin is administered via osmotic minipump and changes in body weight and food intake are measured across days. In separate experiments, we report that acute central injections of insulin can reduce food intake. In Experiment 1, injection of insulin (8 mU) into the third cerebral ventricle reliably suppressed intake of pelleted rat chow beginning at onset of the rats' dark phase. In Experiment 2, central insulin reliably and dose dependently suppressed intake of a 1-h 15% sucrose meal in the middle of the light phase. These data suggest that insulin can reduce food intake in acute delivery paradigms and provide another means by which to assess the roles of other central systems in the mediation of insulin's effects on energy homeostasis.

Animals↗

PubMed2002

Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity.

Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.

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

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↗