Reduced Neural Satiety Responses in Women Affected by Obesity.

Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity rates are on the rise worldwide with women more frequently affected than men. Hedonic responses to food seem to play a key role in obesity, but the exact mechanisms and relationships are still poorly understood. In this study, we investigate the perceived pleasantness of food rewards in relation to satiety and calories consumed during an ad libitum meal in women. Using functional magnetic resonance imaging (fMRI) and a milkshake consumption task, we studied how experienced food values are encoded in women with healthy weight, overweight or obesity. Participants rated the pleasantness and intensity of high and low caloric milkshakes in the fMRI scanner during both the fasted and fed states. We found differences in the neural responses and experienced pleasantness of high and low caloric milkshakes depending on satiety and Body Mass Index (BMI). Women with both high ad libitum consumption levels and high BMI reported greater experienced pleasantness for milkshakes. In contrast, among women with low ad libitum consumption levels, greater BMI was associated with less experienced pleasantness. At the neural level, satiety affected women with obesity to a lesser degree than women with healthy weight. Thus, having obesity was associated with altered relationships between food consumption and the hedonic responses to food rewards as well as reduced satiety effects in women.

The functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).

BACKGROUND & AIMS: Enteroendocrine cells are thought to directly sense nutrients via α-gustducin coupled taste receptors (originally identified in the oral epithelium) to modulate the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). METHODS: We measured mRNA expression of α-gustducin and T1R3 along the human gut; immunohistochemistry was used to confirm co-localization with GLP-1. Functional implication of sweet taste receptors in glucose-stimulated secretion of GLP-1 and PYY was determined by intragastric infusion of glucose with or without lactisole (a sweet taste receptor antagonist) in 16 healthy subjects. RESULTS: α-gustducin was expressed in a region-specific manner (predominantly in the proximal gut and less in ileum and colon, P < 0.05). Both, T1R3 and α-gustducin were co-localized with GLP-1. Glucose-stimulated secretions of GLP-1 (P = 0.026) and PYY (P = 0.034) were reduced by blocking sweet receptors with lactisole. CONCLUSION: Key proteins implicated in taste signaling are present in the human gut and co-localized with GLP-1 suggesting that these proteins are functionally linked to peptide secretion from enteroendocrine cells. Glucose-stimulated secretion of GLP-1 and PYY is reduced by a sweet taste antagonist, suggesting the functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of both peptides in humans.

Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats.

We recently reported that brief, remotely controlled intrameal hepatic-portal vein infusions of glucagon-like peptide-1 (GLP-1) reduced spontaneous meal size in rats. To investigate the neurobehavioural correlates of this effect, we equipped male Sprague-Dawley rats with hepatic-portal vein catheters and assessed (i) the effect on eating of remotely triggered infusions of GLP-1 (1 nmol/kg, 5 min) or vehicle during the first nocturnal meal after 3 h of food deprivation and (ii) the effect of identical infusions performed at dark onset on c-Fos expression in several brain areas involved in the control of eating. GLP-1 reduced (P < 0.05) the size of the first nocturnal meal and increased its satiety ratio. Also, GLP-1 increased (P < 0.05) the number of c-Fos-expressing cells in the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala, but not in the arcuate or paraventricular hypothalamic nuclei. These data suggest that the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala play a role in the eating-inhibitory actions of GLP-1 infused into the hepatic-portal vein; it remains to be established whether activation of these brain nuclei reflect satiation, aversion, or both.

Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice.

To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice.

Estradiol increases glucagon's satiating potency in ovariectomized rats.

Estradiol decreases meal size, food intake, and body weight in female rats. To investigate whether these effects of estradiol involve a change in the sensitivity of the signaling pathway through which pancreatic glucagon released during meals contributes to meal termination (satiation), glucagon or glucagon antibodies were infused via the hepatic portal vein in ovariectomized rats that were chronically treated with estradiol benzoate (2 microg/day sc) or vehicle alone (100 microl sesame oil). Infusions began at 1 h after dark onset, as rats were refed after 7 h of food deprivation. Glucagon (3 microg/min for 30 min) decreased feeding during the initial 45 min of food access in both groups of rats, but the inhibition was significantly greater in estradiol- than in oil-treated rats. Similarly, antagonism of endogenous glucagon by infusion of glucagon antibodies (a dose neutralizing 3 ng of glucagon in vitro during the first 3 min of refeeding) increased feeding significantly more in estradiol- than in oil-treated rats. These data indicate that an increase in the activity of the endogenous glucagon satiation-signaling pathway may be part of the mechanism for estradiol's inhibitory effect on feeding.

Prior pregastric food stimulation and gastrin-releasing peptide1-27 (GRP) synergize to inhibit sham feeding.

The hypothesis that prior pregastric food stimulation is sufficient to reveal an inhibitory effect of gastrin-releasing peptide1-27 (GRP) on sham feeding was tested in 11 male rats equipped with chronic gastric cannulas. Rats were sham fed a high-carbohydrate solution during a 45-min test session, after 17-h food deprivation. GRP (16 or 32 microg/kg) or saline was injected intraperitoneally either at the onset or 5 or 15 min after the onset of sham feeding. This allowed for a 0-, 5-, or 15-min period of pregastric food stimulation before GRP or saline injections. Sham intake was recorded every 5 min, and behavior was observed every minute. GRP inhibited sham feeding when it was administered after 5 or 15 min of prior pregastric food stimulation, but not when it was administered at test onset. A nonsignificant increase in resting behavior and decrease in feeding behavior were associated with the decrease in sham feeding. No anomalous behaviors were noted. We conclude that a synergy between GRP and prior pregastric, presumably oral, food stimulation is sufficient to inhibit sham feeding.

Cyclic estradiol treatment normalizes body weight and test meal size in ovariectomized rats.

We tested whether cyclic estradiol treatment, like continuous estradiol treatment, is sufficient to normalize meal size and body weight in ovariectomized rats. In Experiment 1, adult Long-Evans rats were ovariectomized and subcutaneously injected with 0, 0.2, or 2.0 microg estradiol benzoate (EB) in sesame oil each Tuesday and Wednesday. Oil-treated ovariectomized rats gained more weight during 4 weeks of ad lib feeding (48 +/- 5 g) than intact rats (16 +/- 1 g, p < 0.01). Cyclic treatment with 2.0 microg EB normalized weight gain (11 +/- 2 g). During the next week, plasma samples were assayed for estradiol. Cyclic treatment with 2.0 microg EB produced excursions of plasma estradiol that appeared similar to those of intact, cycling rats: estradiol level reached 190 +/- 60 pmol/L after the second EB injection before decreasing to undetectable levels (<30 pmol/L) by cycle end. In Experiment 2, test meal sizes after overnight food deprivation were measured. Cyclic treatment with 2.0 microg EB produced both tonic (i.e., at cycle onset, meal size was smaller in estradiol-treated than oil-treated rats) and phasic (i.e., meal size was smaller late in the EB-treatment cycle than early in it) decreases in meal size. Thus, a weekly cyclic regimen of estradiol treatment that produces changes in plasma estradiol concentration similar to those in intact cycling rats is sufficient to produce the body weight and meal size patterns that characterize normal hypothalamic-pituitary-gonadal function.

Cyclic estradiol treatment phasically potentiates endogenous cholecystokinin's satiating action in ovariectomized rats.

The influence of ovarian cycling and of exogenous estradiol on the cholecystokinin (CCK) satiety-signalling system was investigated in intact and ovariectomized Long-Evans rats, respectively. Intraperitoneal injection of 1 mg/kg devazepide, the most potent and selective CCK(A) receptor antagonist, increased test meal size during estrus, but not during diestrus, confirming the influence of hypothalamic-pituitary-gonadal function on CCK satiety in intact rats. Devazepide was then tested in ovariectomized rats that received chronic cyclic estradiol (2 microg estradiol benzoate on Tuesday and Wednesday each week) or oil treatment. Devazepide did not increase meal size in estradiol-treated rats on Tuesday, prior to estradiol treatment, compared to oil-treated rats, but did selectively increase meal size on Friday, late in the estradiol replacement cycle, compared to Tuesday, early in the cycle. These results suggest that a phasic potentiation of the endogenous CCK satiety-signalling system is part of the mechanism for the decrease in meal size in female rats during estrus.

Intracerebroventricular glucagon-like peptide-1 (7-36) amide inhibits sham feeding in rats without eliciting satiety.

Glucagonlike peptide-1 (7-36) amide (GLP-1) and its receptors are present in several brain regions and may play a role in the physiological control of feeding. To investigate the effect of GLP-1 on eating in the absence of postingestive food stimuli, rats were implanted with gastric cannulas for sham feeding and lateral ventricular cannulas for infusion of GLP-1. Rats (n = 10) sham fed 0.8 mol/L sucrose for 45 min, beginning 5 min after intracerebroventricular (icv) infusion of 2.5 microL of artificial cerebrospinal fluid with 0-30 microg of GLP-1 . Behaviors were observed each minute using a time-sampling technique. Additionally, lick-by-lick records of the microstructural pattern of sucrose intake were made during the first 15 min of each test for five rats receiving 3 and 10 microg of GLP-1. GLP-1 decreased sham-fed intake by as much as 50%, but GLP-1 did not terminate sham feeding. The frequency of observations of feeding was decreased, but the frequency of resting, the terminal item in the behavioral sequence of postprandial satiety in real feeding rats, did not reliably increase. No abnormal behaviors were observed. Although GLP-I did not affect the latency to begin sham feeding, it significantly reduced the initial rate of licking. GLP-I did not affect the motor aspects of licking, because the interlick intervals within individual bursts of licking or overall lick efficiency were normal. These data suggest that intracerebroventricular infusions of GLP-1 inhibit sham feeding by decreasing the orosensory positive feedback that drives licking, rather than by activating physiological satiating mechanisms or nonspecific mechanisms such as aversion or motor incapacity.

Behaviorally specific inhibition of sham feeding by amylin.

To further characterize amylin's inhibitory action on feeding, we examined the effects of intraperitoneal injections of amylin on sham feeding of sucrose in food-deprived male rats with chronic gastric cannulas. Thirty and 100 microg/kg amylin reduced sham feeding, but did not terminate it or elicit the behavioral sequence of satiety. Real feeding of sucrose, but not sham feeding, was reduced after injection of 10 microg/kg amylin. Amylin's inhibitory effect on sham feeding appeared behaviorally specific because neither 30 nor 100 microg/kg amylin affected sham drinking of water in thirsty rats and because no abnormal behaviors occurred. We conclude that amylin has a behaviorally specific satiating effect on sucrose sham feeding that is insufficient to elicit satiety in absence of gastric or postgastric food stimulation.

The satiating potency of hepatic portal glucagon in rats is not affected by [corrected] insulin or insulin antibodies.

To characterize the interactive effects of acute prandial manipulations of insulin and glucagon on spontaneous feeding in adult male rats fed ad lib, glucagon (G) and insulin (1) or insulin antibodies (IAb) were confused into the hepatic portal vein during the first meal of the dark phase. Infusions (3-6 min, 33 microliters/min) were remotely controlled, and a computerized system recorded meal patterns. In Experiment 1, five separate factorial designs were used to test the effects of G (1.3 or 13 micrograms/meal) alone, I (1.3 or 2.7 mU/meal) alone, or both G + I. The peptides were infused either simultaneously or sequentially (G before I). The larger dose of G alone reduced meal size. I neither inhibited feeding nor increased the effects of either G dose. In one test, 13 micrograms/meal G did not block meal size when followed by 2.7 mU I, but this antagonism did not occur in a replication. In several tests, there was a trend for I to decrease the size of the spontaneous meal that followed the meal during which I was infused, but this was statistically significant only once. Intermeal intervals were not affected in any test. Experiment 2 tested coinfusions of 20 micrograms G and polyclonal IAb with an in vitro binding capacity of 40 mU rat insulin. G alone reduced meal size, IAb alone increased meal size, and G + IAb produced an additive effect. These data extend previous investigations of the satiating action of G and I in the rat and indicate 1. that exogenous I does not affect the satiating potency of G; 2. that exogenous G and endogenous I elicit an additive synergistic inhibition of spontaneous meal size; and 3. that G-induced I secretion does not mediate the satiating effect of G.