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.

Digestive physiology of the pig symposium: secretion of gastrointestinal hormones and eating control.

Nutrient ingestion triggers numerous changes in gastrointestinal (GI) peptide hormone secretion that affect appetite and eating. Evidence for these effects comes from research in laboratory animals, healthy humans, and, increasingly, obese patients after Roux-en-Y gastric bypass (RYGB) surgery, which has marked effects on GI hormone function and is currently the most effective therapy for morbid obesity. Increases in cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (PYY) and decreases in ghrelin secretion after meals are triggered by changes in the nutrient content of the intestine. One apparent physiological function of each is to initiate a reflex-like feedback control of eating. Here we briefly review this function, with an emphasis on the controls of their secretion. Each is secreted from enteroendocrine cells that are directly or indirectly affected by caloric load, macronutrient composition, and other characteristics of ingested food such as fatty acid chain length. In addition, digestive hydrolysis is a critical mechanism that controls their secretion. Although there are relatively few data in agricultural animals, the generally consistent results across widely divergent mammals suggests that most of the processes described are also likely to be relevant to GI hormone functions and eating in agricultural animals.

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.

The biomechanics and clinical efficacy of footwear adapted with rocker profiles--evidence in the literature.

BACKGROUND: Rocker profiles are the most commonly prescribed external therapeutic shoe modification. However, the prescription criteria for rocker profiles have historically been based on theoretical considerations with minimal scientific study and validation. OBJECTIVE: Rocker profiles are used to afford pressure relief for the plantar surface of the foot, to limit the need for sagittal plane motion in the joints of the foot and to alter gait kinetics and kinematics in proximal joints. This paper reviews the literature relating to biomechanical and clinical efficacy. METHOD: A literature search was undertaken in Medline, PubMed, Recal, Cochrane database and Scopus. RESULTS AND CONCLUSIONS: Efficacy is demonstrated with regards to relief of forefoot plantar pressures. However, the definitive profile shape has not been demonstrated. The effectiveness of rocker-soled shoes in restricting sagittal plane motion in individual joints of the foot is unclear. Rocker profiles have minimal effect on the kinetics and kinematics of the more proximal joints of the lower limb, but more significant effects are seen at the ankle. Further research is warranted on the effects of rocker profiles on individual joints of the foot and the manner in which they effect lower limb muscle activity and gait patterns.

Perioperative changes in the microcirculation in feet after foot and ankle surgery.

The senior author (N.P.G.) observed that if the foot became dependent in the first 48 hours after foot surgery, the patient had swelling and pain. This effect seemed less after about 48 hours. The authors set out to see if there was a scientific basis for this. Laser Doppler was used to assess blood flow in 14 patients. Flow was recorded in the big toe, at heart level, and on dependency, preoperatively and postoperatively. Postural vasoconstriction was calculated, and time for blood flow to normalize was recorded. Mean postural vasoconstriction preoperatively was 51.31%; postoperative mean at 24 hours was 23.05%, at 48 hours 36.62%, and at 72 hours 44.24%. There was a difference between the preoperative levels and the 24-, 48-, and 72-hour postoperative levels (P < .05). Results showed that it takes longer than 72 hours rather than 48 hours for microcirculation to return to normal. The results emphasized the importance of postoperative foot elevation for at least 48 hours because of this phenomenon.

The modified McBride procedure: clinical, radiological, and pedobarographic evaluations.

Nineteen patients (27 feet) with symptomatic hallux valgus who underwent modified McBride procedure were studied prospectively. The outcome measures included preoperative and postoperative American Orthopaedic Foot and Ankle Society's Hallux Metatarsophalangeal-Interphalangeal scoring, weight-bearing radiographs, and pedobarography using the EMED-SF*6 System. The average patient age was 49.7 years, and all patients were women. The average follow-up was 7 months. Results showed an average improvement in rating scale score from 53 to 87/100, in the hallux valgus angle from 32 degrees to 15 degrees, and in the first intermetatarsal angle from 15 degrees to 10 degrees. Pedobarographic analysis showed a statistically significant increase in the contact area of the hallux by 17.5% (P<.001), with a reduction of peak pressures of the hallux by 29% from 67.5+/-29.5 N/cm2 to 48+/-34 N/cm2 (P<.001; confidence interval, 9.887, 29.233) and the total foot by 8% from 89+/-26 N/cm2 to 82+/-25 N/cm2 (P<.05; CI, 0.727, 14.900). The overall satisfaction rate was 96%. We conclude that the modified McBride procedure has a role in patients with passively correctable hallux valgus and a supple metatarsocuneiform joint.

Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation.

The relative potencies of cholecystokinin (CCK)-8 and CCK-33 for decreasing meal size depend on the route of administration. Inhibitory potencies are equal after intraperitoneal administration, but CCK-33 is significantly more potent after intraportal administration. This suggests that CCK-33 is a more effective stimulant of hepatic afferent vagal nerves than is CCK-8. To investigate this possibility, we administered both peptides intraperitoneally in rats with abdominal vagotomies that spared only the hepatic proper vagal nerves (H) and in rats with abdominal vagotomies that spared the common hepatic branch that contains the fibers of the hepatic proper and gastroduodenal nerves (HGD). The vagal afferent innervation in H and HGD rats was verified with a wheat germ agglutinin-horseradish tracer strategy. Intraperitoneal administration of CCK-33 decreased 30-min intake of 10% sucrose in H rats as much as in sham rats, but CCK-8 decreased intake significantly less in H rats than in sham rats. The larger inhibitory effect of CCK-33 than of CCK-8 in H rats is consistent with the hypothesis that CCK-33 is a more effective stimulant of the hepatic proper vagal afferent nerves than CCK-8. In contrast to the results in H rats, the inhibitory potencies of both peptides were significantly and equivalently reduced in HGD rats compared with sham rats. This suggests that there is an inhibitory interaction between the stimulation of the gastroduodenal and hepatic proper afferent fibers by CCK-33.

Antipsychotic drug-induced weight gain: development of an animal model.

OBJECTIVE: Weight gain is a prominent effect of most atypical antipsychotic drugs (AAPDs); yet, the mechanisms are not fully understood and no well-established mouse models exist for investigating the mechanisms. Thus, we developed a mouse model to evaluate the effects of AAPDs on eating, body weight (BW), and body composition. METHODS: Female C57BL/6J mice were used to test olanzapine, quetiapine, ziprasidone, and risperidone. Mice were acclimated to individual housing, given ad libitum access to chow and water, dosed with placebo peanut butter pills for 1 week, and then dosed daily with AAPD-laced peanut butter pills for 4 weeks. Weekly food intakes and BWs were measured, and body compositions were determined at the end of each experiment. RESULTS: After 4 weeks of treatment, olanzapine, quetiapine, ziprasidone, and risperidone caused significant weight increases, but only olanzapine and quetiapine were associated with significantly increased food intake. Body composition data revealed that olanzapine-treated mice had more relative fat mass and risperidone-treated mice had more relative lean mass than did control mice. Quetiapine and ziprasidone did not significantly affect relative body composition even though BW was increased. CONCLUSIONS: Oral AAPD administration causes increased BW in female mice. Our mouse model of AAPD-induced weight gain resembles the human response to these medications and will be used to investigate the mechanisms for weight gain and fat accumulation.

Physiological effect of circulating glucagon on the hepatic membrane potential.

The pancreatic hormone glucagon hyperpolarizes the liver cell membrane under various conditions. Here we investigated the physiological relevance of this effect by testing the influence of infusions of glucagon antiserum on the liver cell membrane potential in vivo. Intracellular microelectrode recordings of liver cells (up to 60/rat over 2 h) were done in anesthetized male rats. Livers were fixed in place, and recordings were done 10-30 min after intraperitoneal injections of glucagon or hepatic portal vein infusions of glucagon or specific polyclonal glucagon antibodies raised in rabbits. The isotonic lactose vehicle was used as a control for glucagon, and equal amounts of nonimmunized rabbit IgG were used as a control for glucagon antibodies. Intraperitoneal glucagon (400 microg/kg) hyperpolarized the liver cell membrane up to 12 mV, and intraportal glucagon (10 or 60 microg/kg) dose dependently hyperpolarized the liver cell membrane by 3-7 mV. Intraportal infusion of glucagon antiserum (in vitro binding capacity of 4 ng glucagon/rat) significantly depolarized the liver cell membrane by approximately 2.5 mV. The effects of both glucagon and glucagon antiserum reversed after 60-90 min. We conclude that glucagon is a physiologically important modulator of the liver cell membrane potential.

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.

Intrameal hepatic-portal infusion of glucose reduces spontaneous meal size in rats.

To test whether glucose (GLC) or insulin (INS) acutely reduces spontaneous meal size, we tested the effects of remotely controlled, intrameal hepatic-portal vein infusions of GLC or INS on rats' spontaneous feeding patterns. Experiment 1 included four blocks of three test infusions and one control infusion. The test infusions in each block were 0.25, 0.5, 1.0 or 1.5 mmol GLC; 2, 4, 6, or 8 mU INS; or the four combinations with dose ratios of 1 mmol GLC/8 mU INS, respectively. Control infusions and the INS vehicle were saline infusions that were equiosmotic to the GLC infusion used in that block. Infusions (0.1 ml x 5 min) were done during the first spontaneous dark-phase meal. None of the test infusions affected meal size, meal duration or the duration of the subsequent intermeal interval. In Experiment 2, a similar design was used to test infusions of 1 mmol GLC, 2 mU INS and GLC/INS. Both GLC alone and GLC/INS reduced the size and duration of the first spontaneous dark-phase meal. The subsequent intermeal interval was unaffected, but GLC alone also increased the satiety ratio (min/g) of the meal. The size and duration of the second dark-phase meal were unaffected. INS alone did not affect any meal parameters. In Experiment 3, infusions of 1 mmol GLC and 2 mU INS were repeated during each of the first three meals of the dark phase. These infusions reduced the size and duration of each meal, as well as 6-h cumulative food intake, but did not affect any other meal parameter. These experiments demonstrate for the first time that intrameal hepatic-portal infusions of GLC or of GLC and INS is sufficient to acutely and selectively reduce spontaneous meal size in the rat. The findings are consistent with the idea that meal-contingent changes in hepatic-portal GLC concentration contribute to satiation.

Estradiol treatment increases feeding-induced c-Fos expression in the brains of ovariectomized rats.

The steroid hormone estradiol decreases meal size by increasing the potency of negative-feedback signals involved in meal termination. We used c-Fos immunohistochemistry, a marker of neuronal activation, to investigate the hypothesis that estradiol modulates the processing of feeding-induced negative-feedback signals within the nucleus of the solitary tract (NTS), the first central relay of the neuronal network controlling food intake, and within other brain regions related to the control of food intake. Chow-fed, ovariectomized rats were injected subcutaneously with 10 microg 17-beta estradiol benzoate or sesame oil vehicle on 2 consecutive days. Forty-eight hours after the second injections, 0, 5, or 10 ml of a familiar sweet milk diet were presented for 20 min at dark onset. Rats were perfused 100 min later, and brain tissue was collected and processed for c-Fos-like immunoreactivity. Feeding increased the number of c-Fos-positive cells in the NTS, the paraventricular nucleus of the hypothalamus (PVN), and the central nucleus of the amygdala (CeA) in oil-treated rats. Estradiol treatment further increased this response in the caudal, subpostremal, and intermediate NTS, which process negative-feedback satiation signals, but not in the rostral NTS, which processes positive-feedback gustatory signals controlling meal size. Estradiol treatment also increased feeding-induced c-Fos in the PVN and CeA. These results indicate that modest amounts of food increase neuronal activity within brain regions implicated in the control of meal size in ovariectomized rats and that estradiol treatment selectively increases this activation. They also suggest that estradiol decreases meal size by increasing feeding-related neuronal activity in multiple regions of the distributed neural network controlling meal size.

Estradiol, CCK and satiation.

Estradiol has long been known to inhibit feeding in animals, but the mechanism(s) mediating its effects have not been clear. Demonstrations that estradiol's feeding effects are expressed as decreases in meal size coupled with the emerging consensus that cholecystokinin (CCK) released from the small intestines during meals is a physiological negative-feedback signal controlling meal size (i.e. satiation) suggested a new approach to the problem of the mechanisms of estradiol's inhibitory effect on feeding. Progress on this approach is reviewed here. Experimental manipulations of exogenous and endogenous CCK and estradiol have produced converging evidence that estradiol cyclically increases the activity of the CCK satiation-signaling pathway so that meal size and food intake decrease during the ovulatory or estrus phase of the ovarian cycle. This is a striking example of the modulation of the operation of a control of meal size by the physiological context in which the meal occurs. Estradiol also produces a tonic decrease in meal size, but this apparently does not involve the CCK satiation-signaling pathway. Where and how estradiol acts to increase the potency of the CCK satiating-signaling pathway are not known. Several possible sites are suggested by the observations that estradiol treatment increases feeding- and CCK-induced expression of c-Fos in ovariectomized animals in brain areas including the nucleus tractus solitarius, paraventricular nucleus of the hypothalamus, and central nucleus of the amygdala. Tests with null mutation mice indicate that estrogen receptor-alpha is necessary for estradiol's feeding effects. Finally, the possibilities that estradiol exerts important influences on normal or disordered eating in women are discussed. It is concluded that estradiol exerts a biologically significant action on CCK satiation in animals. Further research to determine whether this action of estradiol has a role in the pathogenesis, course, or treatment of disordered eating in women is indicated.

Sex differences in disease anorexia.

Sexually differentiated responses occur in molecular, cellular, physiologic, and organismic aspects of immune-system function in relation to acquired and innate immunities. These sex differences apparently include activational effects, which depend on gonadal hormone levels in adults, and lifelong effects, which arise directly from genetic differences or organizational effects of gonadal hormones early in development that lead to lifelong sex differences. Sex differences in immune function also can have great biological significance. Despite this, the mechanisms of these effects rarely have been analyzed extensively. This is especially true of anorexia during illness or disease. Therefore, this review briefly considers 1) the biological mechanisms of sex differences; 2) sex differences in immune function; 3) clinical and experimental data related to sex differences in four diseases or disease models that involve anorexia, Crohn's inflammatory-bowel disease, cancer, turpentine inflammation, and lipopolysaccharide bacteremia; and 4) sex differences in anorexia after interleukin-1 administration.

Dopamine D(2) receptors mediate amylin's acute satiety effect.

The anorectic effect of the pancreatic peptide amylin has been established in numerous studies. Here, we investigated the influence of a pretreatment with dopamine (DA) D(1)- and D(2)-receptor antagonists on the anorectic effect of intraperitoneally injected amylin in rats fed a medium-fat (18% fat) diet. In 24-h food-deprived rats, pretreatment with the DA D(2)-receptor antagonist raclopride [100 microg/kg (0.2 micromol/kg) ip] significantly attenuated amylin's (5 microg/kg ip) anorectic effect, whereas raclopride alone had no effect on food intake [i.e., food intakes 1 h after injection were (n = 12): NaCl/NaCl 7.3 +/- 0.5 g; NaCl/amylin 3.9 +/- 0.6; raclopride/NaCl 7.7 +/- 0.7; raclopride/amylin 5.6 +/- 0.7]. Pretreatment with another DA D(2) receptor antagonist, sulpiride [50 mg/kg (154 micromol/kg) ip], similarly reduced amylin's satiety effect, whereas pretreatment with the DA D(1)-receptor antagonist SCH-23390 [10 microg/kg (0.03 micromol/kg) ip] did not influence amylin's effect. SCH-23390, however, completely blocked the anorexia induced by D-amphetamine (0.3 mg/kg ip). These results suggest that, under the present feeding conditions, the dopaminergic system mediates part of amylin's inhibitory effect on feeding in rats when administered intraperitoneally. This seems to involve DA D(2) receptors but not D(1) receptors.