Some endocrine influences on hypothalamic hyperphagia

After combined ovariectomy and adrenalectomy, rats with ventromedial hypothalamic lesions did not express hyperphagia if offered standard pelleted diet. A high-fat diet or a liquid diet would induce them to do so, however, Therefore, adrenal (and ovarian) secretions are not necessary for the expression of hyperphagia. When hyperphagia occurred, it showed the characteristic stasis in body weight at an elevated level. This implies that even after ovariectomy, adrenalectomy, and damage to the brain, the capacity for weight regulation survives.     

Hyperphagia of hyperthyroidism: is neuropeptide Y involved?

The possible role of neuropeptide Y (NPY) was studied in rats with hypermetabolism and hyperphagia induced by thyroxine (50-100-200 microg/day s.c. for 3-4 weeks). Both metabolic rate and body temperature increased quickly with thyroxine treatment, while hyperphagia started to develop only after 2 weeks of treatment. The weight gain rate progressively decreased or stopped. The NPY-induced hyperphagia was not altered significantly during thyroxine treatment (in severe thyrotoxicosis it was rather suppressed); the fasting-induced hyperphagia was smaller than in controls following 1 week of treatment, and it became enhanced only after 3 weeks, when the deficit in body weight indicated a certain level of starvation already prior to the food deprivation. The NPY-antagonist D-Tyr27,36,D-Thr32-NPY27,36 suppressed this fasting-induced hyperphagia, suggesting that endogenous NPY is involved in this late phase. In conclusion, hyperthyroidism per se does not increase the NPY activity, instead the quickly developing hyperthermia may inhibit the NPY actions; NPY may, however, be activated by a concurrent hypermetabolism-induced starvation.     

The effects of a constant T3 level and thermoneutrality in diet-induced hyperphagia

Rats were thyroidectomized, then fitted with a miniosmotic pump infusing T3, thereby assuring a constant circulating level of T3. After a ten-day recovery period, they were submitted either to a chow or to a cafeteria diet. Body weight, food intake, and energy expenditure were recorded during a thirty day period. Thyroidectomized T3 supplemented rats did not exhibit hyperphagia when fed a cafeteria diet. Despite this puzzling normophagia, they still chose nutrients in a distribution similar to that of other cafeteria-fed rats and, though maintaining the same weight as chow-fed rats, increased their proportion of fatty weight compared to these rats. The relationship between energy expenditure, T3 concentration, and cafeteria diet are discussed.     

Combination unilateral amygdaloid and ventromedial hypothalamic lesions: evidence for a feeding pathway

Previous studies have reported hyperphagia and obesity in female rats with bilateral lesions of the most posterodorsal part of the amygdala. In rats with unilateral posterodorsal amygdaloid lesions, a dense pattern of anterograde degeneration appears in the ipsilateral ventromedial hypothalamus, but not the contralateral nucleus. In the present study, female rats with unilateral ventromedial hypothalamic lesions or sham lesions were given either sham lesions or unilateral lesions of the posterodorsal amygdala (PDA) 20 days later. Unilateral lesions of the ventromedial hypothalamus resulted in hyperphagia and excessive weight gain. Subsequent amygdaloid lesions that were contralateral to the initial hypothalamic lesions resulted in hyperphagia and additional excessive weight gains, but amygdaloid lesions ipsilateral to the initial hypothalamic lesions did not. It is concluded that the effects of the two lesions on body weight are not additive and that the PDA and ventromedial hypothalamus are part of the same ipsilateral pathway regulating feeding behavior and body weight regulation.     

Low abundance of NPY in the hypothalamus can produce hyperphagia and obesity

States of increased metabolic demand are associated with up-regulation of NPY and hyperphagia. However, we present some instances of hyperphagia in which NPY is not up-regulated. Ablation or functional disruption of specific sites in the hypothalamus, such as the ventromedial or paraventricular nuclei, or transection of inputs to the hypothalamus from the hindbrain results in hyperphagia and excess body weight gain. However, NPY expression and concentration in these experimental models is either decreased or unchanged. While there is no up-regulation of NPY in these models, there is increased sensitivity to the orexigenic effects of NPY. This enhanced responsiveness to NPY may more than compensate for the reduced levels of NPY and result in hyperphagia and excess body weight gain. The hyper-responsiveness may be due either to an increase in NPY receptors or to other changes in target cells and response pathways that may result from the treatments used in these models.     

A mechanism underlying mature-onset obesity: evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants

Mice deficient in brain-derived neurotrophic factor (BDNF) develop mature-onset obesity, primarily due to overeating. To gain insight into the mechanism of this hyperphagia, we characterized food intake, body weight, meal pattern, and meal microstructure in young and mature mice fed balanced or high-fat diets. Hyperphagia and obesity occurred in mature but not young BDNF mutants fed a balanced diet. This hyperphagia was mediated by increased meal number, which was associated with normal meal size, meal duration, and satiety ratio. In contrast, the high-fat diet induced premature development of hyperphagia and obesity in young BDNF mutants and a similar magnitude hyperphagia in mature mutants. This hyperphagia was supported by increased meal size and was accompanied by a reduced satiety ratio. Thus the mechanism underlying hyperphagia was present before significant weight gain, but whether it occurred, and whether meal frequency or meal size was altered to support it, was modulated by a process associated with aging and by diet properties. Meal pattern changes associated with the balanced diet suggested meal initiation, and the oropharyngeal positive feedback that drives feeding, were enhanced and might have contributed to overeating in BDNF mutants, whereas negative feedback was normal. Consistent with this hypothesis, meal microstructure revealed that all hyperphagic mutant groups exhibited increased intake rates at meal onset. Therefore, the central nervous system targets of BDNF actions may include orosensory brain stem neurons that process and transmit positive feedback or forebrain neurons that modulate its strength.     

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   

Even a mild spell of cold weather affects feeding in migrating redheaded buntings

We investigated whether a climatic change in temperature affected daily food intake in migrating male redheaded buntings. Groups of adult male birds (n = 18) were photoinduced into migratory phenotype under increasing spring daylengths (NDL); as the birds began to exhibit night restlessness, Zugunruhe, these were allocated into groups, either with ambient (NDL, variable daily temperature: maximum – 29–44 °C and minimum – 16–33 °C; for food intake (six birds) and activity recording, six birds) until 2 weeks after they concluded migration or with constant temperature (NDT, 22 ± 1 °C; for food intake (six birds)) conditions. As day length increased March onwards, daily food intake increased (hyperphagia) in NDL and NDT groups. However, hyperphagia was slower in NDT birds as compared to NDL birds, suggesting that altered ambient temperature affects daily food intake in migrating buntings. Another group of 12 birds were held under constant daylengths (12L:12D; EDT and constant temperature 22 ± 1 °C). Although the onset of Zugunruhe was delayed under EDT, the day of onset of Zugunruhe was taken as day 0. Daily food intake and body weight before and during migration of EDT birds were compared with that of NDT and NDL groups. Daily food intake and body weight increased in all migrating birds, but hyperphagia continued post-migration in NDT birds. The study suggests that constantly suboptimal temperature despite increasing daylength, NDT, appeared to affect feeding and body weight of migratory buntings as evident from continued hyperphagia and body weight gain, even after concluding migrating activity.     

Development of insulin resistance and hyperphagia in Zucker fatty rats

The onset of hyperphagia in the Zucker fatty (fa/fa) rat occurs on a single day in postnatal development and could be driven by an increase in insulin sensitivity. To test this hypothesis, we performed insulin tolerance tests at several points in development. In rapidly growing juvenile rats, fatty rats are as insulin sensitive as lean rats at 4 wk of age but become increasingly insulin resistant as they became obese. During the suckling to weaning transition, fatty rats are insulin resistant at 2 wk of age, when they are exclusively suckling; they are also insulin resistant at 3 wk of age, when they are suckling and consuming solid food, but not hyperphagic. By 4 wk of age, when fatty rats are hyperphagic, they are as insulin sensitive as their lean littermates. These data indicate that fatty rats experience two phases of insulin resistance, punctuated by a brief period of insulin sensitivity that follows the onset of hyperphagia. To determine whether the increase in insulin sensitivity could be driving the onset of hyperphagia, insulin tolerance tests were performed from 21 to 27 days of age. Obese and lean rats became increasingly insulin resistant from 21 to 23 days of age and then became as insulin sensitive as lean rats by 25 days of age. These data show that increased insulin resistance precedes the onset of hyperphagia and increased insulin sensitivity follows the onset of hyperphagia. This pattern suggests that developmental perturbations in insulin signaling are likely to be involved in the onset of hyperphagia.     

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.     

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

Neural sites that interact with the suprachiasmatic nuclei (SCN) to generate rhythms of unrestricted feeding remain unknown. We used the targeted toxin, leptin conjugated to saporin (Lep-SAP), to examine the importance of leptin receptor-B (LepR-B)-expressing neurons in the arcuate nucleus (Arc) for generation of circadian feeding rhythms. Rats given Arc Lep-SAP injections were initially hyperphagic and rapidly became obese (the "dynamic phase" of weight gain). During this phase, Lep-SAP rats were arrhythmic under 12:12-h light-dark (LD) conditions, consuming 59% of their total daily intake during the daytime, compared with 36% in blank-SAP (B-SAP) controls. Lep-SAP rats were also arrhythmic in continuous dark (DD), while significant circadian feeding rhythms were detected in all B-SAP controls. Approximately 8 wk after injection, Lep-SAP rats remained obese but transitioned into a "static phase" of weight gain marked by attenuation of their hyperphagia and rate of weight gain. In this phase, Arc Lep-SAP rats exhibited circadian feeding rhythms under LD conditions, but were arrhythmic in continuous light (LL) and DD. Lep-SAP injections into the ventromedial hypothalamic nucleus did not cause hyperphagia, obesity, or arrhythmic feeding in either LD or DD. Electrolytic lesion of the SCN produced feeding arrhythmia in DD but not hyperphagia or obesity. Results suggest that both Arc Lep-SAP neurons and SCN are required for generation of feeding rhythms entrained to photic cues, while also revealing an essential role for the Arc in maintaining circadian rhythms of ad libitum feeding independent of light entrainment.     

Effect of gonadectomy on AgRP-induced weight gain in rats

Agouti-related peptide (AgRP), the endogenous antagonist to the melanocortin 3 and 4 receptors, elicits robust hyperphagia and weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause weight gain in rodents partially depends on the activity level of the melanocortin agonist-producing proopiomelanocortin neurons. Both proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as leptin and insulin. Another modulator of AgRP activity includes the cell surface molecule syndecan-3. Because leptin and insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days (P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of hyperphagia (P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure (Vo2) following AgRP compared with male rats (P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in Vo2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats.     

Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.     

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats.     

Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats

Dapagliflozin is a potent and selective sodium glucose cotransporter-2 (SGLT2) inhibitor which promotes urinary glucose excretion and induces weight loss. Since metabolic compensation can offset a negative energy balance, we explored the potential for a compensatory physiological response to the weight loss induced by dapagliflozin. Dapagliflozin was administered (0.5-5 mpk; p.o.) to diet-induced obese (DIO) rats with or without ad libitum access to food for 38 days. Along with inducing urinary glucose excretion, chronic administration of dapagliflozin dose-dependently increased food and water intake relative to vehicle-treated controls. Despite this, it reduced body weight by 4% (relative to controls) at the highest dose. The degree of weight loss was increased by an additional 9% if hyperphagia was prevented by restricting food intake to that of vehicle controls. Neither oxygen consumption (vO2) or the respiratory exchange ratio (RER) were altered by dapagliflozin treatment alone. Animals treated with dapagliflozin and pair-fed to vehicle controls (5 mpk PF-V) showed a reduction in RER and an elevation in nonfasting β-hydroxybutyrate (BHBA) relative to ad libitum-fed 5 mpk counterparts. Fasting BHBA was elevated in the 1 mpk, 5 mpk, and 5 mpk PF-V groups. Serum glucose was reduced in the fasted, but not the unfasted state. Insulin was reduced in the non-fasted state. These data suggest that in rodents, the persistent urinary glucose excretion induced by dapagliflozin was accompanied by compensatory hyperphagia, which attenuated the weight loss induced by SGLT2 inhibition. Therefore, it is possible that dapagliflozin-induced weight loss could be enhanced with dietary intervention.     

Triiodothyronine (T3) stimulates food intake via enhanced hypothalamic AMP-activated kinase activity

Thyroid hormone regulates food intake. We previously reported that rats with triiodothyronine (T3)-induced thyrotoxicosis display hyperphagia associated with suppressed circulating leptin levels, increased hypothalamic neuropeptide Y (NPY) mRNA and decreased hypothalamic pro-opiomelanocortin (POMC) mRNA. AMP-activated kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular energy is depleted. We hypothesized that T3 causes an increase in hypothalamic AMPK activity, which in turn contributes to the development of T3-induced hyperphagia. Rats that were given s.c. injections of T3 (4.5 nmol/kg) had increased food intake 2 h later without alterations in NPY and POMC mRNA levels, but with increased hypothalamic phosphorylated AMPK (169%) and phosphorylated acetyl-CoA carboxylase (194%). To determine the more chronic effects of T3, rats were given 6 daily s.c. injection of T3 or the vehicle. Food intake was significantly increased. Multiple T3 injections increased hypothalamic phosphorylated AMPK (278%) and phosphorylated acetyl-CoA carboxylase (335%) compared to the controls. Intracerebroventricular administration of compound C, an AMPK inhibitor, blocked the food intake induced by a single or multiple injections of T3. Taken together, these results suggest that enhanced hypothalamic AMPK phosphorylation contributes to T3-induced hyperphagia. Hypothalamic AMPK plays an important role in the regulation of food intake and body weight.     

Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse

The melanocortin system is involved in hypothalamic regulation of energy homeostasis. The melanocortin-4 receptor (MC4R) has been linked to both obesity and reproductive dysfunction. Deletion of the MC4R from the mouse genome has resulted in phenotypes including adult onset obesity, hyperphagia, and difficulty in reproducing when homozygote parents are bred. Additionally, polymorphisms of the human MC4R have been identified in morbidly obese children and adults. Herein, we have identified that voluntary exercise, provided via the presence of a running wheel, impedes the monogenetic obesity (at 20 weeks of age running wheel housed body weight=31+/-1.8 g versus conventionally housed body weight=41+/-2.3 g, a 25% decrease in body weight p<0.01), hyperphagia (average cumulative food intake is not statistically different than wild type mice housed in running wheel cages), and reproductive dysfunction phenotypes associated with the MC4R knockout mice housed by conventional means. These data demonstrate the novel finding that voluntary exercise at a young age may hinder genetically induced obesity.     

A Role for Hypothalamic AMP-Activated Protein Kinase in the Mediation of Hyperphagia and Weight Gain Induced by Chronic Treatment with Olanzapine in Female Rats

Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.     

Pancreatic hydrolases in cold-induced hyperphagia of rats fed a low or high-fat diet

Rats fed either a low (2p. 100) or high (40 p. 100)-fat diet were exposed to 22 or 5 degrees C. The resulting hyperphagia adequately compensated energy losses as judged from body weight. The cold-induced hyperphagia was accompanied by a non-parallel increase in pancreatic hydrolases. Amylase and lipase were not increased above the adaptive levels they had respectively reached in the heat with a high-starch or high-lipid diet. Chymotrypsinogen, on the contrary, responded to increased intake of both diets. It also responded to the higher protein concentration in the high-fat diet caused by isocaloric replacement of starch by fat. Colipase varied independently of lipase and was increased additively by fat and protein intakes. Consequently, although limiting for lipase in the warm, colipase rose to a 1:1 ratio in the cold. Increased intake had a consistent pleiotropic effect evidenced by an increase of amylase with the high-fat diet and of lipase with the low-fat diet. The net effect was a significant increase in the lipid-digesting potential of the organism of lipid-fed animals upon exposure to cold, while the starch-digesting potential remained unaffected in starch-fed animals.     

Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.