Prolonged hyperphagia with high-fat feeding contributes to exacerbated weight gain in rats with adult-onset obesity

Leptin-resistant rats, when given a high-fat (HF) diet, have a delayed normalization of caloric intake and greater weight gain than those on a chow diet. Because aged, obese rats are leptin resistant, these data predict that they will also have a delayed normalization of caloric intake and exacerbated weight gain when provided a HF diet. To investigate this hypothesis, along with the consequences of a HF diet on voluntary wheel running, we compared various ages of rats on a HF or chow diet. HF-fed young rats spontaneously divided into diet-induced obese and diet-resistant rats. However, all aged rats were susceptible to the weight-gaining effects of HF feeding. Rate of initial weight gain was proportional to age, and peak caloric intake on the HF diet and the days required to normalize caloric intake to basal levels increased with age. Responsiveness to peripheral leptin before HF feeding revealed a dose-response decrease in food intake and body weight in the young but no responses in the aged to even the highest dose, 0.5 mg/day. In addition, both age and HF feeding decreased the tendency for wheel running, suggesting the propensity for inactivity with age and HF feeding may contribute to age-related obesity and accelerate the rate of diet-induced obesity. These results demonstrate that aged rats are more susceptible to the detrimental effects of a HF diet.     

Soluble Fermentable Dietary Fibre (Pectin) Decreases Caloric Intake,Adiposity and Lipidaemia in High-Fat Diet-Induced Obese Rats

Consumption of a high fat diet promotes obesity and poor metabolic health, both of which may be improved by decreasing caloric intake. Satiety-inducing ingredients such as dietary fibre may be beneficial and this study investigates in diet-induced obese (DIO) rats the effects of high or low fat diet with or without soluble fermentable fibre (pectin). In two independently replicated experiments, young adult male DIO rats that had been reared on high fat diet (HF; 45% energy from fat) were given HF, low fat diet (LF; 10% energy from fat), HF with 10% w/w pectin (HF+P), or LF with 10% w/w pectin (LF+P) ad libitum for 4 weeks (n = 8/group/experiment). Food intake, body weight, body composition (by magnetic resonance imaging), plasma hormones, and plasma and liver lipid concentrations were measured. Caloric intake and body weight gain were greatest in HF, lower in LF and HF+P, and lowest in the LF+P group. Body fat mass increased in HF, was maintained in LF, but decreased significantly in LF+P and HF+P groups. Final plasma leptin, insulin, total cholesterol and triglycerides were lower, and plasma satiety hormone PYY concentrations were higher, in LF+P and HF+P than in LF and HF groups, respectively. Total fat and triglyceride concentrations in liver were greatest in HF, lower in LF and HF+P, and lowest in the LF+P group. Therefore, the inclusion of soluble fibre in a high fat (or low fat) diet promoted increased satiety and decreased caloric intake, weight gain, adiposity, lipidaemia, leptinaemia and insulinaemia. These data support the potential of fermentable dietary fibre for weight loss and improving metabolic health in obesity.     

Different functional responsibility of the small intestine to high-fat/high-energy diet determined the expression of obesity-prone and obesity-resistant phenotypes in rats

The objective of the present experiment was to assess the involvement of small intestine in expression of susceptibility or resistance to the high-fat/high-energy diet. The investigation was carried out in adult male Sprague-Dawley rats fed either standard laboratory diet (3.2 kcal/g, 9.5 % fat) or high-fat (HF) diet (4.04 kcal/g, 30 % fat) for 4 weeks as well as in HF rats that were retrospectively designated on the bases of their higher or lower weight gain as sensitive (DIO) or resistant (DR) to obesity. Our results revealed in HF group significant increase in energy intake, food efficiency, weight gain and Lee s index of obesity. Moreover, in comparison with controls, a significantly increased duodenal and jejunal alkaline phosphatase (AP) and alpha-glucosidase activity as well as hypertrophy of jejunal mucosa (increased protein/DNA ratio) were observed in HF fed rats. In contrast, intestinal function was inversely related to energy intake or to the development of adiposity in DIO vs. DR rats. The DR rats had significantly greater AP and alpha-glucosidase activity and more pronounced suppression of energy intake than obese DIO rats. It indicates that the increase of enzyme activities and the lowered effectiveness of nutrient absorption might be a significant factor preventing the expression of obesity proneness. This information contributes to a better understanding of a complex interaction between HF diet feeding and small intestinal adaptability, which determines the energy homeostasis and predict the ability to resist or develop obesity in these phenotypes.     

Reduced CCK signaling in obese-prone rats fed a high fat diet

Deficits in satiation signaling during obesogenic feeding have been proposed to play a role in hyperphagia and weight gain in animals prone to become obese. However, whether this impaired signaling is due to high fat (HF) feeding or to their obese phenotype is still unknown. Therefore, in the current study, we examined the effects of CCK-8 (0.5, 1.0, 2.0, and 4.0 μg/kg) on suppression of food intake of HF-fed obese prone (OP) and resistant (OR) rats. Additionally, we determined the role of endogenous CCK in lipid-induced satiation by measuring plasma CCK levels following a lipid gavage, and tested the effect of pretreatment with devazepide, a CCK-1R antagonist on intragastric lipid-induced satiation. Finally, we examined CCK-1R mRNA levels in the nodose ganglia. We show that OP rats have reduced feeding responses to the low doses of exogenous CCK-8 compared to OR rats. Furthermore, OP rats exhibit deficits in endogenous CCK signaling, as pretreatment with devazepide failed to abolish the reduction in food intake following lipid gavage. These effects were associated with reduced plasma CCK after intragastric lipid in OP but not OR rats. Furthermore, HF feeding resulted in downregulation of CCK-1Rs in the nodose ganglia of OP rats. Collectively, these results demonstrate that HF feeding leads to impairments in lipid-induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia and weight gain.     

Behavioral components of high-fat diet hyperphagia: meal size and postprandial satiety

Previously, rats fed a high-fat liquid diet (HF) ad libitum consumed more kilocalories and had greater weight gain than rats fed a liquid high-carbohydrate diet (HC) of equivalent energy density (Warwick, Z. S., and H. P. Weingarten. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 269: R30-R37, 1995). The present series of experiments sought to clarify the behavioral expression of HF hyperphagia by comparing HF and HC with regard to meal size and magnitude of postingestive satiety effect. Meal size of HF was greater than HC at 2.3 kcal/ml and also when diets were formulated at 1.15 kcal/ml. In a preload-test meal paradigm, an orally consumed HF preload was less satiating than a calorically equivalent HC preload across a range of preload volumes and intermeal intervals. Sensory-specific satiety was ruled out as an explanation of the relatively greater intake of test meal after an HF preload meal; an intragastrically delivered HF preload was less satiating than intragastric HC. Furthermore, a fat (corn oil emulsion) preload was less satiating than a carbohydrate (sucrose) preload when an evaporated milk test meal was used. These findings indicate that hyperphagia on an HF diet is expressed in increased meal size and decreased intermeal interval.     

Effects of high-fat diets with different carbohydrate-to-protein ratios on energy homeostasis in rats with impaired brain melanocortin receptor activity

Changes in dietary macronutrient composition and/or central nervous system neuronal activity can underlie obesity and disturbed fuel homeostasis. We examined whether switching rats from a diet with high carbohydrate content (HC; i.e., regular chow) to diets with either high fat (HF) or high fat/high protein content at the expense of carbohydrates (LC-HF-HP) causes differential effects on body weight and glucose homeostasis that depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlay these effects. Chronic third cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol/day) produced obesity and hyperphagia with an increased food efficiency again observed during HF (+19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHU9119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold), and adiponectin levels (2.4-3.7 fold), but diet effects were only observed on plasma adiponectin (HC and LC-HF-HP相似文献   

Sympathetic Activity,Age, Sucrose Preference,and Diet-Induced Obesity

Only half the adult male Sprague-Dawley rats which are placed on a diet relatively high in calories, fat, and sucrose (HE diet) develop diet-induced obesity (DIO). The rest are diet-resistant (DR). Some chowfed rats prone to develop DIO on an HE diet have greater initial food intake of this diet and all have greater glucose-induced plasma norepinephrine (NE) increases than DR-prone rats. Here we looked for a relationship of sucrose preference or 24-hour urinary catecholamine excretion as possible phenotypic markers of the DIO- and DR-prone states before HE diet exposure as a function of age. When begun on an HE diet at 3 months of age, DIO-prone rats gained 30% more weight over 3 months than DR-prone rats and had 35% heavier retroperitoneal fat pads. While still on chow, sucrose preferences were similar, but 24 hour urine NE levels were 29% higher in DIO-than in DR-prone rats. The slope of the curve of urine NE versus body weight gain after 3 months on HE diet was 4-fold greater in DIO- thaain DR-prone rats. After 3 months on the HE diet, there was no statistical relationship between 24-hour urine NE and body weight or prior body weight gain in DIO or DR rats. Six-month-old DIO-prone rats had 126% and 128% more urine NE and gained 112% and 232% more weight after 3 months on HE diet than DR-prone and chowfed rats, respectively. Only DIO-prone rats showed a correlation (r=0.879; p=O.OS) between urine NE levels and subsequent weight gain on HE diet. Thus, 3- or 6- month-old DIO- and DR-prone rats can be identified by their 24-hour basal urine NE levels but not sucrose preference prior to HE diet exposure. While this may suggest higher basal sympathetic activity in DIO-prone rats, other explanations are possible. (OBESITY RESEARCH 1993;1:281–287)     

The H3 receptor is involved in cholecystokinin inhibition of food intake in rats.

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.     

Enterostatin inhibition of dietary fat intake is dependent on CCK-A receptors

Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, selectively inhibits fat intake through activation of an afferent vagal signaling pathway. This study investigated if the effects of enterostatin were mediated through a CCK-dependent pathway. The series of in vivo and in vitro experiments included studies of 1) the feeding effect of peripheral enterostatin on Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors, 2) the effect of CCK-8S on the intake of a two-choice high-fat (HF)/low-fat (LF) diet, 3) the effects of peripheral or central injection of the CCK-A receptor antagonist lorglumide on the feeding inhibition induced by either central or peripheral enterostatin, and 4) the ability of enterostatin to displace CCK binding in a 3T3 cell line expressing CCK-A receptor gene and in rat brain sections. The results showed that OLTEF rats did not respond to enterostatin (300 microg/kg ip) in contrast to the 23% reduction in intake of HF diet in Long Evans Tokushima Otsuka (LETO) control rats. CCK (1 microg/kg ip) decreased the intake of the HF diet in a two-choice diet regime with a compensatory increase in intake of the LF diet. Peripheral injection of lorglumide (300 microg/kg) blocked the feeding inhibition induced by either near-celiac arterial or intracerebroventricular enterostatin, whereas intracerebroventricular lorglumide (5 nmol icv) only blocked the response to intracerebroventricular enterostatin but not to arterial enterostatin. Enterostatin did not bind on CCK-A receptors because neither enterostatin nor its analogs VPDPR and beta-casomorphin displaced [3H]L-364,718 from CCK-A receptors expressed in 3T3 cells or the binding of 125I-CCK-8S from rat brain sections. The data suggest that both the peripheral and central responses to enterostatin are mediated through or dependent on peripheral and central CCK-A receptors.     

A high-fat diet raises fasting plasma CCK but does not affect upper gut motility, PYY, and ghrelin, or energy intake during CCK-8 infusion in lean men

There is evidence from studies in animals that the effects of both fat and CCK on gastrointestinal function and energy intake are attenuated by consumption of a high-fat diet. In humans, the effects of exogenous CCK-8 on antropyloroduodenal motility, plasma CCK, peptide YY (PYY), and ghrelin concentrations, appetite, and energy intake are attenuated by a high-fat diet. Ten healthy lean males consumed isocaloric diets (~15,400 kJ per day), containing either 44% (high-fat, HF) or 9% (low-fat, LF) fat, for 21 days in single-blind, randomized, cross-over fashion. Immediately following each diet (i.e., on day 22), subjects received a 45-min intravenous infusion of CCK-8 (2 ng.kg(-1).min(-1)), and effects on antropyloroduodenal motility, plasma CCK, PYY, ghrelin concentrations, hunger, and fullness were determined. Thirty minutes after commencement of the infusion, subjects were offered a buffet-style meal, from which energy intake (in kilojoules) was quantified. Body weight was unaffected by the diets. Fasting CCK (P < 0.05), but not PYY and ghrelin, concentrations were greater following the HF, compared with the LF, diet. Infusion of CCK-8 stimulated pyloric pressures (P < 0.01) and suppressed antral and duodenal pressures (P < 0.05), with no difference between the diets. Energy intake also did not differ between the diets. Short-term consumption of a HF diet increases fasting plasma CCK concentrations but does not affect upper gut motility, PYY and ghrelin, or energy intake during CCK-8 infusion, in a dose of 2 ng.kg(-1).min(-1), in healthy males.     

Obesity induced by a high-fat diet downregulates apolipoprotein A-IV gene expression in rat hypothalamus

Apolipoprotein A-IV (apo A-IV) is an anorectic protein produced in the intestine and brain that has been proposed as a satiety signal. To determine whether diet-induced obesity alters apo A-IV gene expression in the intestine and hypothalamus, rats were fed a high-fat (HF), low-fat (LF), or standard chow (CHOW) diet for 2, 4, 6, 8, or 10 wk. Rats fed the HF diet had significantly greater body weights than rats given the LF and CHOW diets. Intestinal and plasma apo A-IV levels were comparable across dietary groups and time. LF and CHOW rats had comparable hypothalamic apo A-IV mRNA across the course of the experiment. However, HF rats had a slow and progressive diminution in hypothalamic apo A-IV mRNA over time that became significantly lower than that of LF or CHOW rats by 10 wk. Intragastric infusion of lipid emulsion to animals that were fasted overnight significantly stimulated hypothalamic apo A-IV mRNA in LF and CHOW rats but had no effect in HF rats. These results demonstrate that chronic consumption of a HF diet significantly reduces apo A-IV mRNA levels and the response of apo A-IV gene expression to dietary lipids in the hypothalamus. This raises the possibility that dysregulation of hypothalamic apo A-IV could contribute to diet-induced obesity.     

Regulation of ghrelin gene expression in stomach and feeding response to a ghrelin analogue in two strains of rats

Ghrelin is a peptide produced by the stomach and released into the circulation. As a natural ligand of the growth hormone secretagogue (GHS) receptor, it stimulates growth hormone secretion but it also stimulates feeding in humans and rodents. The orexigenic effect of ghrelin has been related to AgRP/NPY and orexin pathways. We proposed that ghrelin might be involved in the susceptibility to diet induced obesity and in the regulation of macronutrient selection. We have investigated these hypotheses in two strains of rat, the Osborne–Mendel (OM) rat that prefers diets high in fat and is sensitive to dietary obesity and the S5B/P1 (S5B) rat that prefers a low fat diet and is resistant to high fat diet induced obesity.

OM and S5B rats were adapted to a choice of high fat (HF) and low fat (LF) diet for 2 weeks. GHRP-2, an analogue of ghrelin, was injected intraperitoneally into satiated and 24 h fasted rats at doses of 10, 30 and 90 nmol. Food intake was measured over the next 4 h period. In satiated S5B rats, GHRP-2 stimulated intake of the LF diet in a dose dependent manner but did not affect the intake of the HF diet. In satiated OM rats, 90 nmol of GHRP-2 stimulated HF intake. In contrast, neither fasted OM nor S5B rats increased the intake of either HF or LF diet in response to GHRP-2. Fasting for 18 h induced a large rise in ghrelin mRNA in stomach of OM rats but not in S5B rats. There were no significant differences in plasma total ghrelin. An increase in ghrelin mRNA in stomach immediately before the onset of the dark cycle was observed in OM but not in S5B rats. Active ghrelin level was significantly affected by different feeding conditions in both OM and S5B rats adapted on HF diet with a trend to increase after 48 h of fasting and to decline to basal levels following 10 h of refeeding. These data suggest that ghrelin stimulates the intake of the preferred macronutrient. In addition, a differential regulation of ghrelin gene expression between OM and S5B rats may be important in their differential sensitivity to HF diet-induced obesity.     

Intracerebroventricular injections of cholecystokinin octapeptide suppress feeding in rats--pharmacological characterization of this action

Cholecystokinin octapeptide (CCK-8), administered intracerebroventricularly (i.c.v.), will suppress feeding. The aim of the present study was to determine the pharmacological characteristics of this satiety inducing effect in rats. For this purpose, we employed a feeding bioassay model in 24 h fasted rats and examined the effects of CCK-8 and a variety of structurally related analogs on latency to feed after i.c.v. injection and on the amount of food and water consumed as measured after the initiation of feeding in sequential 20-min epochs for 1 h. CCK-8, given in doses of 0.1, 1 and 10 nmol, produced a dose-dependent increase in feeding latency and a reduction of food intake during the first 20 min after initiation of feeding. Food intake during the next 40 min and water consumption were not altered. Plasma levels of CCK-like immunoreactivity after an i.c.v. injection of a dose of CCK-8 which blocked feeding (10 nmol) rose insignificantly from 117 to 125 pg/ml. In contrast, at the minimally effective dose of CCK-8 after i.v. administration (10 nmol), which also produced an inhibition of feeding, the plasma level was 1430 pg/ml. This difference indicates that plasma levels of CCK after i.c.v. CCK-8 are not adequate to produce the observed feeding suppression and suggests that the effects of i.c.v. CCK-8 are not mediated by a peripheral redistribution. Systematic dose response studies revealed the following rank order of potencies: CCK-8 greater than or equal to G-17 II much greater than CCK-8 NS = G-17 I greater than or equal to CCK-4 = CCK 26-29 = 0. Only gastrin-17 II (sulfated) produced an effect comparably significant to CCK-8. I.c.v. proglumide at 2500 nmol failed to modify the effects of CCK-8 at 10 nmol after i.c.v. injection. These data demonstrate that the structural requirements for feeding suppressive activity in rat brain are the carboxyterminus with a sulfated tyrosine residue, located 6 to 7 residues from the carboxyterminus, as present in CCK-8 and gastrin-17 II.     

Cerebral ventricular transport and uptake: Importance for CCK-mediated satiety

Brain cholecystokinin (CCK) peptides have been proposed to be involved in the control of feed intake. We have examined the importance of the cerebral ventricular system in CCK-mediated satiety in sheep. Continuous injection of 0.64 pmol/min CCK-8 into the lateral ventricles (LV) decreased feeding, whereas injection of neither 0.64 nor 2.55 pmol/min CCK-8 into the cisterna magna (CM) significantly affected feeding. Thus, it is likely that the rostral, but not caudal, ventricular compartments and/or adjacent brain areas are involved in CCK-8 mediated satiety. The rate of injection of carrier solution (synthetic cerebrospinal fluid [sCSF]) was found to affect feed intake during a continuous 75 min injection: feed intakes were greater during injection of sCSF at 0.10 ml/min than during either 0.03 ml/min sCSF or no injection (sham). Injection of 0.64 pmol/min CCK-8 in either 0.03 or 0.10 ml/min decreased feeding. The increased feeding during 0.10 ml/min sCSF injection may have been due to dilution of endogenous CCK released into CSF during the meal. To determine the percent recovery from CSF of exogenous CCK-8, CSF samples from CM were collected during 3 hr continuous LV injections of CCK-8 and inulin (for measurement of bulk absorption). Only 20 to 40 percent of administered CCK-8 was recovered in CM CSF. The loss of CCK-8 was probably not due to degradation in the CSF by proteolytic enzymes, since CCK-8 concentrations did not decrease during in vitro incubation at 37°C for up to 24 hr. We propose that CCK-8 is released during feeding into the ventricular system, and subsequently taken up from CSF by specialized ependymal cells for transport to sites of action.     

Suppression of QRFP 43 in the hypothalamic ventromedial nucleus of Long-Evans rats fed a high-fat diet

QRFP 43 is a RFamide peptide present in the ventromedial nucleus (VMN) and lateral hypothalamus. It stimulates food intake in mice and its chronic infusion induces hyperphagia, reduced thermogenesis, and obesity. In this experiment, we measured it in the VMN and lateral hypothalamus of Long-Evans rats fed either a high-fat (HF), control, or low-fat (LF) diet in parallel with plasma leptin, adiposity, and energy intake. After 8 weeks of ad libitum diet intake, energy intake of HF rats was similar to that of control rats. In the VMN, QRFP 43 was completely undetectable in HF rats and its tissue concentration in control rats was significantly lower than in LF rats (p < 0.03). HF rats had higher levels of leptin than control rats (+24%; p < 0.03) and than LF rats (+42%; p < 0.002). The QRFP 43 concentration in the VMN was inversely correlated with plasma leptin (r = −0.34; P < 0.04) and with the adipogenic index of the diet (p < 0.02) but not with insulin. We conclude that the decrease of the orexigenic drive mediated by QRFP 43 could contribute to the normalization of caloric intake in HF diet fed rats. QRFP 43 might play a role downstream of leptin in the regulation of feeding behavior.     

MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCK_A) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCK_A receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 μg/kg) followed by CCK-8 (0 or 4 μg/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 μg/kg, and increased food intake, in females and males at 100 and 200 μg/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCK_A receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCK_A receptors.     

Feeding Response to Mercaptoacetate in Osborne-Mendel and S5B/PL Rats

SINGER, LORI K, DAVID A YORK, GEORGE A BRAY. Feeding response to mercaptoacetate in Osborne-Mendel and S5B/PL Rats. The purpose of this experiment was to determine if Osborne-Mendel (OM) rats, which are susceptible to dietary-induced obesity, and S5B/PL (S5B) rats, which are resistant to dietary-induced obesity, differ in their feeding responses to mercaptoacetate (MA), which blocks fatty acid oxidation, or 2-deoxy-D-glucose (2DG), which blocks glucose utilization. 2DG (100 mg/kg or 200 mg/ kg) increased food intake in both strains of rats on a high-fat diet (56% energy from fat). Mercaptoacetate (600 umol/kg) increased food intake in OM but not S5B rats on a high-fat diet. When maintained on a low-fat diet (10% energy from fat), MA (400 umol/kg or 600 umol/kg) stimulated food intake in OM rats, whereas S5B rats increased food intake only after the highest dose of MA (600 umol/kg). MA stimulated carbohydrate and protein intake in OM rats maintained on a macro-nutrient selection diet, whereas S5B rats maintained on this diet did not significantly increase intake of any mac-ronutrient after MA. These results demonstrate that OM and S5B rats have a similar food intake response to 2DG but a dissimilar response to MA. The variable response to MA in these strains may be due to a difference in peripheral or central signaling systems related to fatty acid oxidation or a difference in metabolic environments between the strains, which in turn affects the feeding response to MA. These studies suggest that a difference in control of fatty acid oxidation may account for the difference in susceptibility to obesity when eating a high-fat diet.     

The intestinal peptide transporter PEPT1 is involved in food intake regulation in mice fed a high-protein diet

High-protein diets are effective in achieving weight loss which is mainly explained by increased satiety and thermogenic effects. Recent studies suggest that the effects of protein-rich diets on satiety could be mediated by amino acids like leucine or arginine. Although high-protein diets require increased intestinal amino acid absorption, amino acid and peptide absorption has not yet been considered to contribute to satiety effects. We here demonstrate a novel finding that links intestinal peptide transport processes to food intake, but only when a protein-rich diet is provided. When mice lacking the intestinal peptide transporter PEPT1 were fed diets containing 8 or 21 energy% of protein, no differences in food intake and weight gain were observed. However, upon feeding a high-protein (45 energy%) diet, Pept1(-/-) mice reduced food intake much more pronounced than control animals. Although there was a regain in food consumption after a few days, no weight gain was observed which was associated with a reduced intestinal energy assimilation and increased fecal energy losses. Pept1(-/-) mice on high-protein diet displayed markedly reduced plasma leptin levels during the period of very low food intake, suggesting a failure of leptin signaling to increase energy intake. This together with an almost two-fold elevated plasma arginine level in Pept1(-/-) but not wildtype mice, suggests that a cross-talk of arginine with leptin signaling in brain, as described previously, could cause these striking effects on food intake.     

Effect of Enterostatin on the Feeding Responses to Galanin and NPY

We have investigated the possibility that enterostatin may inhibit the intake of dietary fat by inhibiting either galanin or NPY-induced feeding pathways. Rats, adapted to either high fat (HF) or low fat-high carbohydrate (HC) diets and fitted with third ventricular cannulas were used to study the effects of intracerebroventricular (icv) enterostatin on icv NPY and galanin induced feeding responses in satiated rats. An equimolar dose of enterostatin (0.1nmoles) inhibited, while a tenfold excess of entersotatin abolished the feeding response to galanin in rats adapted to a HF diet. The galanin stimulation of food intake was reduced in rats adapted to the HC diet and this response was less sensitive to inhibition by enterostatin. Enterostatin had no inhibitory effects on NPY-induced feeding in rats adapted to the HC diet and only a small inhibitory effect, at tenfold molar excess, in rats adapted to the HF diet. The ability of enterostatin to bind to galanin or NPY Y-1 receptors was investigated in lig and binding studies. Enterstatin fialed to dispace ¹²⁵I-galanin or ¹²⁵I-PYY from specific binding sites in rat forebrain homogenates or SK-N-MC cells respectively. The data provide support for the hypothesis that enterostatin specifically inhibits a galanin-responsive fat intake system, but indicate that this effect is not modulated by direct interaction with either galanin or NPY-Y1 receptors.     

High-fat diet prevents eating response and attenuates liver ATP decline in rats given 2,5-anhydro-D-mannitol

Administration of the fructose analog 2,5-anhydro-D-mannitol (2,5-AM) stimulates eating in rats fed a low-fat diet but not in those fed a high-fat diet that enhances fatty acid oxidation. The eating response to 2,5-AM treatment is apparently triggered by a decrease in liver ATP content. To assess whether feeding a high-fat diet prevents the eating response to 2,5-AM by attenuating the decrease in liver ATP, we examined the effects of the analog on food intake, liver ATP content, and hepatic phosphate metabolism [using in vivo 31P-NMR spectroscopy (NMRS)]. Injection (intraperitoneal) of 300 mg/kg 2,5-AM increased food intake in rats fed a high-carbohydrate/low-fat diet, but not in those fed high-fat/low-carbohydrate (HF/LC) food. Liver ATP content decreased in all rats given 2,5-AM compared with saline, but it decreased about half as much in rats fed the HF/LC diet. NMRS on livers of anesthetized rats indicated that feeding the HF/LC diet attenuates the effects of 2,5-AM on liver ATP by reducing phosphate trapping. These results suggest that rats consuming a high-fat diet do not increase food intake after injection of 2,5-AM, because the analog is not sufficiently phosphorylated and therefore fails to decrease liver energy status below a level that generates a signal to eat.