Transient Hyperphagia Research Articles

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Dietary protein restriction elicits hyperphagia and increases energy expenditure; however, less is known of whether these responses are a consequence of increasing carbohydrate content. The effects of protein-diluted diets with fixed carbohydrate content on energy balance, hormones, and key markers of protein sensing and thermogenesis in tissues are determined. Obesity-prone rats (n = 13-16 per group) are randomized to diets containing fixed carbohydrate (52% calories) and varying protein concentrations: 15% (control), 10% (mild protein restriction), 5% (moderate protein restriction) or 1% (severe protein restriction) protein calories, or protein-matched to 5% protein, for 21 days. Propranolol and ondansetron are administered to interrogate the roles of sympathetic and serotonergic systems, respectively, in diet-induced changes in energy expenditure. It is found that mild-to-moderate protein restriction promotes transient hyperphagia, whereas severe protein restriction induces hypophagia, with alterations in meal patterns. Protein restriction enhances energy expenditure that is partly attenuated by propranolol, but not ondansetron. Moderate to severe protein restriction decreases gains in body weight, lean and fat mass, decreased postprandial glucose and leptin, but increased fibroblast growth factor-21 concentrations. Protein-matching retains lean mass suggesting that intake of dietary protein, but not calories, is important for preserving lean mass. Notably, protein restriction increases the protein and/or transcript abundance of key amino acid sensing molecules in liver and intestine (PERK, eIF2α, ATF2, CHOP, 4EBP1, FGF21), and upregulated thermogenic markers (β2AR, Klotho, HADH, UCP-1) in brown adipose tissue. Low-protein diets promote hyperphagia and sympathetically mediated increase in energy expenditure, prevent gains in tissue reserves, and concurrently upregulate hepatic and intestinal amino acid sensing intermediaries and thermogenic markers in brown adipose tissue.

Open resection of hypothalamic hamartomas for intractable epilepsy revisited, using intraoperative MRI.

Hypothalamic hamartomas (HHs) are rare non-neoplastic lesions which cause drug-resistant epilepsy with associated behavioural, psychiatric and endocrine issues. With the development of new minimally invasive techniques for the treatment of HH, there is a need to reappraise the effectiveness and safety of each approach. We review the outcomes of HH patients treated surgically, utilizing intraoperative magnetic resonance imaging (IOMRI), by a team of Alder Hey NHS Foundation Trust tumour and epilepsy neurosurgeons since 2011. Patient records of all HH cases operated on since 2011 were reviewed to confirm history of presentation and clinical outcomes. Ten patients have undergone surgery for HH under the dual care of Alder Hey tumour and epilepsy neurosurgeons during this period. Eight cases had a midline transcallosal, interforniceal approach with the remaining 2 having a transcallosal, transforaminal approach. All patients had an IOMRI scan, with 40% needing further tumour resection post-IOMRI. Forty percent had a total resection, 3 patients had near-total resection and 3 patients had subtotal resection (~ 30% tumour residual on post-operative MRI). No new neurological complications developed post-operatively. Hypothalamic axis derangements were seen in 3 cases, including 1 diabetes insipidus with hypocortisolaemia, 1 hypodipsia and 1 transient hyperphagia. Eighty percent are seizure free; the remaining two patients have had significant improvements in seizure frequency. IOMR was used to tailor the ideal tumour resection volume safely based on anatomy of the lesion, which combined with the open transcallosal, interforniceal route performed by surgeons experienced in the approach resulted in excellent, safe and effective seizure control.

Intermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice.

BackgroundIntermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled.MethodsMale C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5–6 consecutive days, and ad libitum intake for 1–3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)–(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding.ResultsMice on the ID showed transient hyperphagia relative to controls during each 1–3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups.ConclusionIntermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice.

Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weight gain

Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100–250mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat.

Maternal perinatal undernutrition programs a “brown-like” phenotype of gonadal white fat in male rat at weaning

Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring.

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

Effect of central administration of QRFP(26) peptide on energy balance and characterization of a second QRFP receptor in rat

The recently identified neuropeptide QRFP(26) is predominantly expressed in the hypothalamus and was suggested to play a role in the regulation of food intake following the observation of an acute orexigenic effect after central administration in mice. QRFP(26) exerts its effect via GPR103 and a newly identified receptor in mouse. The aim of our study was (a) to investigate the distribution of QRFP(26) and a newly discovered QRFP receptor mRNA in rat and (b) to further characterize the effects of central administration of QRFP(26) on energy balance in rats. QRFP(26) mRNA was detected in the retrochiasmatic nucleus, periventricular nucleus, arcuate nucleus and restricted areas of the lateral nucleus of the hypothalamus. We found an additional receptor with high homology for GPR103 in rat. This receptor increases inositol triphosphate production in transfected cells in presence of QRFP(26) and its mRNA was particularly enriched in ventral and posterior thalamic groups, anterior hypothalamus and medulla. When QRFP(26) (10 μg and 50 μg) was administered centrally before the start of the light phase both doses increased food intake for 2 h after injection without reaching statistical significance. QRFP(26) caused no changes in locomotor activity or energy expenditure. In summary, central QRFP(26) injection causes slight and transient hyperphagia in rats without changing any other energy balance parameters after 24 h. We conclude that QRFP(26) has limited impact on the central regulation of energy balance in rats and that its essential function remains to be clarified.

11β-Hydroxysteroid Dehydrogenase Type 1 Induction in the Arcuate Nucleus by High-Fat Feeding: A Novel Constraint to Hyperphagia?

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11 beta-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11 beta-HSD1 null (11 beta-HSD1-/-) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11 beta-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11 beta-HSD1-/- mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript and melanocortin-4 receptor, but higher levels of the orexigenic melanin-concentrating hormone mRNAs than controls (C57BL/6J) on a low-fat diet (11% fat). HF (58% fat) diet promoted transient ( approximately 8 wk) hyperphagia and decreased food efficiency in 11 beta-HSD1-/- mice and decreased melanocortin-4 receptor mRNA expression in control but not 11 beta-HSD1-/- mice. 11 beta-HSD1-/- mice showed a HF-mediated up-regulation of the orexigenic agouti-related peptide (AGRP) mRNA in the arcuate nucleus which paralleled the transient HF hyperphagia. Conversely, control mice showed a rapid (48 h) HF-mediated increase in arcuate 11 beta-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected because glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial colocalization of 11 beta-HSD1 and AGRP in arcuate nucleus cells. One major alternate mechanism governing selective fat ingestion and the AGRP system is endogenous opioids. Treatment of HF-fed mice with the mu opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11 beta-HSD1-/- mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11 beta-HSD1. These data suggest that 11 beta-HSD1 in brain plays a role in the adaptive restraint of excess fat intake, in part by increasing inhibitory opioid tone on AGRP expression in the arcuate nucleus.

Increased Infarct Size and Lack of Hyperphagic Response after Focal Cerebral Ischemia in Peroxisome Proliferator-Activated Receptor β-Deficient Mice

Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPARbeta is the only one to be widely expressed in cortical neurons. Using PPARbeta knockout (KO) mice, we report here a detailed investigation of the role of PPARbeta in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPARbeta KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPARbeta KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPARbeta KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPARbeta plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPARbeta agonists may be of interest for the prevention of central ischemic damage.

Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.

Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17beta-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY). Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations. Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized. Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

Melanocortin signaling is decreased during neurotoxin-induced transient hyperphagia and increased body-weight gain

Hypothalamic neuropeptides play critical roles in the regulation of feeding behavior and body weight (BW). Disruption of signaling in the ventromedial nucleus by microinjection of the neurotoxin, colchicine (COL), produces transient hyperphagia with corresponding BW gain lasting for 4 days. Because the melanocortin system exerts an inhibitory control on food intake, we hypothesized that hyperphagia in COL-treated rats is due to decreased melanocortin-induced restraint on feeding. Melanocortin restraint is exerted through α-melanocortin-stimulating hormone derived from proopiomelanocortin (POMC) and is antagonized by agouti-related peptide produced in neurons located in the arcuate nucleus (ARC). COL (4 μg/0.5 μl saline) or saline was microinjected bilaterally into the ventromedial nucleus of adult male rats. In conjunction with BW gain, blood leptin levels were elevated, whereas POMC mRNA in the ARC was significantly decreased in COL-injected rats. Levels of α-melanocortin-stimulating hormone were also decreased in the micropunched paraventricular nucleus, dorsomedial nucleus, and perifornical hypothalamus, sites implicated in the control of food intake. That diminution in melanocortin signaling underlies hyperphagia was supported by the observation that intracerebroventricular injection of the MC3/MC4 melanocortin receptor agonist, MTII, prevented the hyperphagia and BW gain. Surprisingly, however, mRNA levels of the orexigenic peptide agouti-related peptide in the ARC were decreased perhaps due to the action of elevated leptin. These results show that transient hyperphagia and BW gain induced by disruption of signaling in the ventromedial nucleus results from two neurochemical rearrangements: development of leptin resistance in POMC neurons and diminution in melanocortin signaling as reflected by decreased POMC gene expression in the ARC and decreased availability of α-melanocortin-stimulating hormone for release in feeding relevant sites.

Hypothalamic galanin is up-regulated during hyperphagia and increased body weight gain induced by disruption of signaling in the ventromedial nucleus☆

Disruption of signaling in the ventromedial nucleus (VMN) by colchicine (COL) produces transient (4 days) hyperphagia and weight gain. Microinjection of galanin into various hypothalamic sites stimulates feeding, so we tested the hypothesis that galanin is up-regulated in COL-treated rats by analyzing galanin concentrations in micropunched hypothalamic sites. Galanin was increased in the paraventricular nucleus on Days 1 through 4 after COL-injection. Galanin was also elevated in three other hypothalamic sites, the dorsomedial nucleus, lateral hypothalamic area, and perifornical hypothalamus, on Days 2–4 and in the lateral preoptic area, on Day 1 only. In the median eminence-arcuate nucleus and amygdala an initial decrease on Day 1 was followed by a then progressive increase through Day 4. These increases occurred despite marked elevations in blood insulin and leptin, hormones known to suppress hypothalamic galanin. When COL- or saline-treated rats were injected intracerebroventricularly with galanin, it stimulated feeding further in the hyperphagic COL-treated rats, but the relative response over basal consumption was similar in both COL-treated and control rats. These results in VMN disrupted rats suggest that neurochemical rearrangements, including increased availability of galanin, may contribute to the hyperphagia and increased weight gain; additionally, it seems that neurons in the VMN normally exert a restraint on galanin signaling.

Disruption of neural signaling within the hypothalamic ventromedial nucleus upregulates galanin gene expression in association with hyperphagia: an in situ hybridization analysis

Hypothalamic neuropeptides play critical roles in the regulation of appetite and body weight. We recently reported that disruption of neural signaling in the ventromedial nucleus (VMN) by microinjection of the neurotoxin, colchicine (COL), produced transient hyperphagia with attendant body weight gain lasting for 4 days. The neural mechanism(s) underlying this temporary shift in energy homeostasis is still unknown. Galanin (GAL) is produced in several hypothalamic nuclei and since microinjection of GAL into these sites stimulates feeding, we tested the hypothesis that galaninergic signaling is upregulated in COL-treated rats. COL (4 μg in 0.5 μl saline) or saline alone was microinjected into the VMN of adult male rats and GAL mRNA was evaluated in the basal hypothalamus by ribonuclease protection assay on day 1, day 2 and day 4 after injection. Whereas in saline-treated rats body weight and GAL mRNA remained unaffected, they were significantly increased in COL-injected rats through the period of observation. To identify the specific neuronal subpopulations involved, GAL mRNA levels were analyzed in feeding-related hypothalamic nuclei using semiquantitative in situ hybridization histochemistry on day 4 after microinjection of COL or saline into the VMN. In COL-treated rats, GAL mRNA levels increased dramatically over controls in the supraoptic nucleus, paraventricular nucleus (PVN), dorsomedial nucleus (DMN), arcuate nucleus (ARC) and lateral hypothalamic area (LHA); no significant change was observed in the central nucleus of amygdala. These results indicated that disruption of neurotransmission in the VMN upregulated GAL gene expression in those hypothalamic sites (PVN, DMN, LHA and ARC) that are implicated in regulation of feeding, and since GAL stimulates feeding, this neurochemical rearrangement may contribute to the over-eating in these animals. These results also suggest that, normally, neurons in the VMN may suppress GAL neurotransmission in feeding-regulating hypothalamic neural circuits.

Neuropeptide Y release in the paraventricular nucleus is decreased during transient hyperphagia induced by microinjection of colchicine into the ventromedial nucleus of rats

Disruption of neural signaling in the ventromedial nucleus (VMN) of rats by microinjection of the neurotoxin colchicine (COL) results in transient hyperphagia accompanied by enhanced weight gain. We tested the hypothesis that release of neuropeptide Y (NPY), a potent orexigenic signal is augmented within the paraventricular nucleus (PVN) of COL-treated hyperphagic rats. Adult male rats were microinjected bilaterally with either COL (4 μg/0.5 μl in saline) or saline in the VMN and a push-pull guide cannula aimed at the PVN was implanted for analysis of extra-cellular NPY. COL-injected rats gained 37.8±6.1 g while the saline-injected rats lost 9.3±3.4 g during the 4 days following surgery. On day 4, post-injection, the PVN of these rats was perfused with artificial cerebrospinal fluid via the push-pull cannula. NPY levels in perfusates collected at 10 min intervals from hyperphagic, COL-injected rats were markedly diminished. Cumulative NPY efflux over the 180 min sampling period was significantly less in COL-treated (27.7±6.0 pg) versus saline-injected control rats (110.6±32.2 pg; P<0.05). These results show that impairment of neural signaling in the VMN by COL suppressed NPY release in the PVN. These observations taken together with previous studies showing diminution in preproNPY mRNA in the arcuate nucleus (ARC) and NPY levels in the PVN are in accordance with the thesis that the VMN normally exerts a facilitatory influence on NPYergic signaling in the ARC-PVN axis.

High-Fat Diets and Stress Responsivity

Kamara, K., R. Eskay, and T. Castonguay. High-fat diets and stress responsivity. Physiol Behav 64(1) 1–6, 1998. Adult male rats were fed one of five diets varying in fat composition (Purina Chow or soy bean oil, corn oil, menhaden oil, or olive oil added to chow) for 10 weeks. After 3 days of access, no differences between groups were found in plasma corticosterone measured at light onset and light offset. During Week 2, restraint stress tests were performed. High-fat diets promoted significantly higher stimulated corticosterone levels. During Week 6 all rats were given an oral glucose tolerance test. Rats fed the corn and soybean oil diets had significantly elevated blood glucose 2 h after glucose intubation. Euglycemia was restored after 3 hours in all but the soybean oil group. During Week 9, a second stress test was performed. No differences in initial stress responsivity was observed, but groups fed the menhaden, soybean and olive oil diets had significantly higher corticosterone 1 h after the end of restraint. The corn oil, olive oil and soybean oil diets promoted transient hyperphagia. By the end of the experiment, the group fed the menhaden oil diet weighed significantly less and ate less than the remaining groups. These data demonstrate that stress responsivity is briefly enhanced during initial access to the high-fat regimens. Continued high-fat feeding results in an impaired ability to restore basal corticosterone following stress.

Neuropeptide Y (NPY) Y1 receptor mRNA is upregulated in association with transient hyperphagia and body weight gain: evidence for a hypothalamic site for concurrent development of leptin resistance.

Microinjection of colchicine (COL), a neurotoxin that blocks axoplasmic flow in the neurons, bilaterally into the ventromedial nucleus (VMN) evokes transient hyperphagia and body weight gain. These shifts in energy balance occurred in conjunction with development of increased sensitivity to neuropeptide Y (NPY), the endogenous orexigenic signal. In order to trace the aetiology of NPY supersensitivity, we have evaluated (1) NPY Y1 and Y5 receptor (R) gene expression in the hypothalamus and (2) the possibility of alterations in the inhibitory action of leptin, a hormone produced by lipocytes. Adult male rats were rendered hyperphagic with bilateral microinjections of COL (4 microg/side) into the VMN. We observed that hypothalamic NPY Y1 mRNA levels, as measured by RNAase protection assay, were significantly increased on day 2 and returned to the control level on day 4 in COL-injected rats. The effects on NPY Y5R mRNA were not as clear cut. Interestingly, serum leptin levels increased in association with the hyperphagia and body weight gain, thereby raising the likelihood of development of resistance to the suppressive effect of endogenous leptin on food intake. Indeed, intracerebroventricular injection of 7 microg human recombinant leptin, a dose that attenuated daily food intake in normal and fasted rats, was completely ineffective in attenuating hyperphagia in COL-treated rats. These results show that transient hyperphagia induced by interruption of signalling in the VMN may be caused by increased sensitivity to NPY, which may be caused, in part, by increased expression of NPY Y1R in hypothalamic sites involved in regulation of ingestive behaviour. Additionally, the observation of increased leptin release and concurrent development of leptin resistance suggest that a normally functioning VMN may be necessary for the central inhibitory effects of leptin on food intake.

Increased receptor sensitivity to neuropeptide Y in the hypothalamus may underlie transient hyperphagia and body weight gain

Disruption of neural signaling by microinjection of a neurotoxin, colchicine (COL), in the ventromedial hypothalamus (VMH) of rats results in rapid and transient hyperphagia and body weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal and continuous NPY receptor activation by intracerebroventricular (icv) NPY infusion results in hyperphagia and obesity, we tested the hypothesis that altered NPYergic signaling may underlie the transient hyperphagia in COL-injected rats. Immediately following COL (4 μg) microinjections in the ventromedial nucleus (VMN) rats displayed hyperphagia both during the lights-on and lights-off periods. Concomitant with hyperphagia, preproNPY mRNA levels in the arcuate nucleus and NPY levels in the paraventricular nucleus decreased in a time-dependent manner. However, food intake in response to intracerebroventricular injections of NPY (29, 117 and 470 pmole) was significantly higher in COL-injected rats and the latency to initiation of feeding was markedly reduced as compared to controls. The smallest dose of NPY which was virtually ineffective in control rats, evoked near maximal intake in COL-injected rats. This enhanced response lasted for only 4 days paralleling the transient hyperphagia. The NPY Y1 receptor antagonist 1229U91 (5 or 30 μg/rat, icv) significantly suppressed feeding in COL-treated rats thereby indicating that hyperphagia in these rats was dependent upon endogenous NPY. Overall, these studies demonstrate that not only high levels, but low levels of NPY may also result in hyperphagia and increased body weight and this hyperphagia may be attributed to the rapid development of NPY Y1 receptor hypersensitivity.

Effects of bilateral basomedial hypothalamic lesions on feeding, fattiness, and reproductive functions in the White Leghorn hen

During the last three decades, syndromes caused by bilateral destruction of the basomedial hypothalamus (BMH) were extensively studied in cockerels but not in hens. In the present study bilateral electrolytic lesions in the BMH of White Leghorn (WL) hens produced two main sets of symptoms: (a) Obese, functionally castrated hen (OFC); and (b) Obese, laying hen (OL). Following the placement of the hypothalamic lesion, the OFC hens developed transient hyperphagia, that was followed by hypophagia. Weight gain was accelerated in both periods, and marked obesity developed. These hens had high hematocrit values, and atrophied ovary, oviduct, comb, and adenohypophysis. Plasma estrogen, androgen, and total lipids and liver weight were reduced in the OFC hens. In these hens, the lesioned area included the ventromedial hypothalamic nucleus (VMH), the mammillary nuclei, and in some birds also the arcuate nuclei, and the tuberal nucleus. The OL hens manifested transient hyperphagia that subsided into normophagia with the development of obesity. These hens were less obese than the OFC ones and showed normal reproductive traits. The lesioned area in the OL hens was limited to the VMH. Unlike functionally castrated cockerels, where the induced fattiness is accompanied with higher rate of lipogenesis, the OFC hen manifested a unique syndrome: increased fattiness with arrest in estrogen-dependent lipogenesis.

Meal Pattern of Rats During Hyperphagia Induced by Long-term Food Restriction is Affected by Diet Composition

The influence of diet composition of feeding behavior during the hyperphagia induced by about 15% loss in body weight due to restricted feeding (5 g food/day for 7 days) was investigated in adult male rats. Rats were fed either a low-fat, high-carbohydrate diet (LF diet), a medium-fat diet (MF diet) or a carbohydrate-free, high-fat diet (HF diet). The transient hyperphagia resulting from food restriction was greater in LF- and MF-rats than in HF-rats, in which a mild hypophagia was observed following the hyperphagia. Recovery of body weight was imperfect in the HF-rats in comparison to the unrestricted controls. During the hyperphagia, the meal pattern of LF- and MF-rats was mainly characterized by an increase in meal size, whereas HF-rats showed an increase in meal frequency. These observations indicate that control of food intake by body weight in LF- and MF-rats occurs mainly by modulation of the mechanisms producing meal-ending satiety, whereas in HF-rats the mechanisms eliciting meal initiation seem to be effected by body weight.

Hepatic branch vagotomy enhances glucoprivic feeding in food-deprived old rats

Glucoprivic feeding induced by intraperitoneal (IP) injection of 2-deoxy- d-glucose (2-DG, 250 mg/kg body weight) in the middle of the light phase was investigated in old (age: 15–16 months) and young (age: 2.5–3.5 months) hepatic branch-vagotomized (HBV) and sham-vagotomized (SV) rats. Rats were fed either a carbohydrate-rich diet or a fat-enriched diet a moderate carbohydrate content. The glucoprivic feeding response was greater in 13-h food-deprived old HBV rats than in 13-h food-deprived old SV rats on both diets. 2-Deoxy- d-glucose produced a greater feeding response when rats were fed the fat-enriched diet. Independent of the diet, the transient hyperphagia induced by 2-DG was followed by a long-term hypophagia in old SV rats, but not in old HBV rats. In 13-h food-deprived young rats, hepatic branch vagotomy did not affect the changes in food intake induced by 2-DG. In undeprived old and young rats, the feeding response to 2-DG, exceeding that of deprived rats, was also not affected by HBV. It is concluded that under certain conditions hepatic branch vagotomy eliminates a 2-DG-induced signal inhibiting food intake and thus enhances glucoprivic feeding. The feeding response to 2-DG therefore seems to depend on stimuli affecting food intake in an antagonistic manner.