Single gene deletions of orexin, leptin, neuropeptide Y, and ghrelin do not appreciably alter food anticipatory activity in mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA.     

Overexpression of APOC1 in obob mice leads to hepatic steatosis and severe hepatic insulin resistance

Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1(+/-)) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1(+/-) mice showed reduced body weight (-25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%), and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1(+/-) mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1(+/-) mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver.     

Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatin-deficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (+0.81 ± 0.28 kcal/day, P = 0.004) and HET controls (+0.92 ± 0.31 kcal/day, P = 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 ± 1.1% vs. WT: 14.5 ± 1.3%, P = 0.003) and circulating leptin levels (KO: 0.7 ± 0.2 ng/ml vs. WT: 1.9 ± 0.3 ng/ml, P = 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (-50% vs. WT, P < 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: -17 ± 1.2% vs. WT: -5 ± 0.3%) and weight loss (KO: -2.2 ± 0.2 g vs. WT: -1.6 ± 0.1, P < 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin.     

Decreased food intake rather than zinc deficiency is associated with changes in plasma leptin, metabolic rate, and activity levels in zinc deficient rats( small star, filled)

This study investigated the hypothesis that the reduced food intake and poor weight gain in zinc deficient rats is due to: increased plasma leptin concentration, increased physical activity and/or increased metabolic rate. Weanling rats were assigned to three groups: controls fed ad libitum (C), zinc deficient (ZD), and pair-fed controls (PF), and tested in a metabolic chamber and activity monitor at baseline and weekly for four weeks. At the end of the study, all groups were compared for differences in plasma leptin concentrations. ZD and PF animals had markedly reduced food intake and weight gain. ZD had reduced stereotypic and locomotor activity compared to PF animals and both groups demonstrated an abolished peri-nocturnal activity spike and were much less active than controls. This was associated with a reduced total metabolic rate by day 30: ZD (0.73 +/- 0.07 kcal/hr, p = 0.0001) and PF (0.83 +/- 0.06 kcal/hr, p = 0.0001) groups vs. controls (1.82 +/- 0.09 kcal/hr). Plasma leptin concentrations in ZD (1.55 +/- 0.06 &mgr;g/L) were lower than controls (2.01 +/- 0.18 &mgr;g/L, p < 0.03), but neither ZD nor controls were statistically different from PF (1.68 +/- 0.05 &mgr;g/L). Both low leptin concentrations and low metabolic rates in the ZD and PF rats were associated with decreased food intake rather than zinc deficiency. The reduced food intake and poor weight gain observed in zinc deficient rats could not be explained by elevated leptin concentrations, hypermetabolism, or increased activity. Low serum leptin concentrations, hypometabolism, and decreased activity are more likely the result of the anorexia of zinc deficiency.     

Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice

Mechanisms regulating spontaneous physical activity remain poorly characterized despite evidence of influential genetic and acquired factors. We evaluated ambulatory activity and wheel running in leptin-deficient ob/ob mice and in wild-type mice rendered hypoleptinemic by fasting in both the presence and absence of subcutaneous leptin administration. In ob/ob mice, leptin treatment to plasma levels characteristic of wild-type mice acutely increased both ambulatory activity (by 4,000 ± 200 beam breaks/dark cycle, P < 0.05) and total energy expenditure (TEE; by 0.11 ± 0.01 kcal/h during the dark cycle, P < 0.05) in a dose-dependent manner and acutely increased wheel running (+350%, P < 0.05). Fasting potently increased ambulatory activity and wheel running in wild-type mice (AA: +25%, P < 0.05; wheel running: +80%, P < 0.05), and the effect of fasting was more pronounced in ob/ob mice (AA: +400%, P < 0.05; wheel running: +1,600%, P < 0.05). However, unlike what occurred in ad libitum-fed ob/ob mice, physiological leptin replacement attenuated or prevented fasting-induced increases of ambulatory activity and wheel running in both wild-type and ob/ob mice. Thus, plasma leptin is a physiological regulator of spontaneous physical activity, but the nature of leptin's effect on activity is dependent on food availability.     

Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin_2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.     

Unique food-entrained circadian rhythm in cysteine414-alanine mutant mCRY1 transgenic mice

Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Daily scheduled restricted feeding (RF), in which the food available time is restricted for several hours each day, elicits anticipatory activity. This food-anticipatory activity (FAA) is controlled by a food-entrainable oscillator (FEO) that is distinct from the suprachiasmatic nucleus (SCN), the master pacemaker in mammals. In an earlier report, we described generation of transgenic (Tg) mice ubiquitously overexpressing cysteine414-alanine mutant mCRY1. The Tg mice displayed long locomotor free-running periods (approximately 28 h) with rhythm splitting. Furthermore, their locomotor activity immediately re-adjusted to the advance of light–dark cycles (LD), suggesting some disorder in the coupling of SCN neurons. The present study examined the restricted feeding cycle (RF)-induced entrainment of locomotor activity in Tg mice in various light conditions. In LD, wild-type controls showed both FAA and LD-entrained activities. In Tg mice, almost all activity was eventually consolidated to a single bout before the feeding time. The result suggests a possibility that in Tg mice the feeding cycle dominates the LD cycle as an entrainment agent. In constant darkness (DD), wild-type mice exhibited robust free-run activity and FAA during RF. For Tg mice, only the rhythm entrained to RF was observed in DD. Furthermore, after returning to free feeding, the free-run started from the RF-entrained phase. These results suggest that the SCN of Tg mice is entrainable to RF and that the mCRY1 mutation alters the sensitivity of SCN to the cycle of nonphotic zeitgebers.

     

Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice

Mch1r-deficient (Mch1r(-/-)) mice are hyperphagic, hyperactive, lean, and resistant to diet-induced obesity. To examine whether the MCH1R is involved in regulating activity-based energy expenditure, we investigated voluntary wheel running (WR) activity of wild-type (WT) and Mch1r(-/-) mice basally, in response to diets with different caloric density and with different feeding schedules. We also evaluated WR activity of mice with ablation of the prepro-MCH gene (Pmch(-/-) mice). Dark cycle WR activity of Mch1r(-/-) mice fed low fat (LF) chow was increased significantly relative to WT mice. Transition to moderate high-fat (MHF) diet was associated with an increase in nocturnal WR activity in both genotypes. Both Mch1r(-/-) and WT mice exhibited food anticipatory activity (FAA) before the daily scheduled feeding time, indicating that MCH1R is not required for FAA. Naloxone (3 mg/kg, i.p.) suppressed WR activity of both genotypes, suggesting opioid regulation of locomotor activity. WR increased nocturnal dynorphin mRNA levels in Mch1r(-/-) brain. Importantly, Pmch-deficient mice had significantly enhanced WR activity relative to WT controls. These results suggest that endogenous MCH plays an inhibitory role in regulating locomotor activity. In summary, we demonstrated enhanced WR activities in mice lacking either MCH or its cognate receptor.     

Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure

The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (T(C)), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b(-/-) mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in T(C). Interestingly, POMC-Ptp1b(-/-) mice had increased BAT weight and elevated plasma triiodothyronine (T(3)) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis.     

Cachexia in MAC16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin and hypothalamic neuropeptide Y

Weight loss normally stimulates hunger, through mechanisms that include falls in circulating leptin and insulin, leading to stimulation of hypothalamic neuropeptide Y (NPY). Here, we investigated the leptin, insulin and NPY to clarify why hunger is suppressed in mice with severe cachexia due to the MAC16 adenocarcinoma. MAC16-bearing mice progressively lost weight (19% below controls) and fat (- 61%) over 16 days after tumour transplantation, while total food intake fell by 10%. Pair-fed mice showed less wasting, with final weight being 9% and fat mass 25% below controls. Plasma leptin fell by 85% in MAC16 and 51% in pair-fed mice, in proportion to loss of fat. Plasma insulin was also reduced by 49% in MAC16 and 53% in pair-fed groups. Hypothalamic leptin receptor (OB-Rb) mRNA was significantly increased in both MAC16 (+ 223%) and pair-fed (+192%) mice. Hypothalamic NPY mRNA was also significantly raised in MAC16 (+152%) and pair-fed (+ 99%) groups, showing negative correlations with plasma leptin and insulin, and a positive association with OB-Rb mRNA. In MAC16-induced cachexia, leptin production and hypothalamic OB-Rb and NPY expression are regulated appropriately in response to fat depletion. Therefore, suppression of hunger is probably due to tumour products that inhibit NPY transport or release, or that interfere with neuronal targets downstream of NPY.     

Photic and Pineal Modulation of Food Anticipatory Circadian Activity Rhythms in Rodents

Restricted daily feeding schedules entrain circadian oscillators that generate food anticipatory activity (FAA) rhythms in nocturnal rodents. The location of food-entrainable oscillators (FEOs) necessary for FAA remains uncertain. The most common procedure for inducing circadian FAA is to limit food access to a few hours in the middle of the light period, when activity levels are normally low. Although light at night suppresses activity (negative masking) in nocturnal rodents, it does not prevent the expression of daytime FAA. Nonetheless, light could reduce the duration or magnitude of FAA. If so, then neural or genetic ablations designed to identify components of the food-entrainable circadian system could alter the expression of FAA by affecting behavioral responses to light. To assess the plausibility of light as a potential mediating variable in studies of FAA mechanisms, we quantified FAA in rats and mice alternately maintained in a standard full photoperiod (12h of light/day) and in a skeleton photoperiod (two 60 min light pulses simulating dawn and dusk). In both species, FAA was significantly and reversibly enhanced in the skeleton photoperiod compared to the full photoperiod. In a third experiment, FAA was found to be significantly attenuated in rats by pinealectomy, a procedure that has been reported to enhance some effects of light on behavioral circadian rhythms. These results indicate that procedures affecting behavioral responses to light can significantly alter the magnitude of food anticipatory rhythms in rodents.     

The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity

Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Lepr(neo/neo) mice). Similar to Lepr(db/db) mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Lepr(neo/neo) mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity.     

Neotomodon alstoni mice present sex differences between lean and obese in daily hypothalamic leptin signaling

This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex.     

Behavioral and Neural Correlates of Acute and Scheduled Hunger in C57BL/6 Mice

In rodents, daily feeding schedules induce food anticipatory activity (FAA) rhythms with formal properties suggesting mediation by food-entrained circadian oscillators (FEOs). The search for the neuronal substrate of FEOs responsible for FAA is an active area of research, but studies spanning several decades have yet to identify unequivocally a brain region required for FAA. Variability of results across studies leads to questions about underlying biology versus methodology. Here we describe in C57BL/6 male mice the effects of varying the ‘dose’ of caloric restriction (0%, 60%, 80%, 110%) on the expression of FAA as measured by a video-based analysis system, and on the induction of c-Fos in brain regions that have been implicated in FAA. We determined that more severe caloric restriction (60%) leads to a faster onset of FAA with increased magnitude. Using the 60% caloric restriction, we found little evidence for unique signatures of neuronal activation in the brains of mice anticipating a daily mealtime compared to mice that were fasted acutely or fed ad-libitum–even in regions such as the dorsomedial and ventrolateral hypothalamus, nucleus accumbens, and cerebellum that have previously been implicated in FAA. These results underscore the importance of feeding schedule parameters in determining quantitative features of FAA in mice, and demonstrate dissociations between behavioral FAA and neural activity in brain areas thought to harbor FEOs or participate in their entrainment or output.     

Effect of delta22-5beta-taurocholenic acid on hepatic cholesterol and fatty acid in gold thioglucose obese mice fed low- or high-fat diets

We previously demonstrated that hyperglycemic-obese (obob) mice fed a 1% corn oil diet accumulated 10 times as much hepatic cholesterol as did their non-obese (+/?) littermates fed this diet because of difficulty in removal of cholesterol from the liver rather than from increased synthesis. Furthermore, feeding the bile acid analog Delta(22)-5beta-taurocholenic acid completely prevented the accumulation of hepatic cholesterol in obob mice fed the 1% corn oil diet. The hypothesis to be tested in the current study is that these aspects of cholesterol metabolism in the obob mouse do not occur in the hyperinsulinemic and insulin-resistant gold thioglucose obese mouse. Gold thioglucose obese (gtgo) and non-obese (ngtgo) mice were fed diets containing either 1% corn oil or 40% lard each with or without added taurocholenic acid for 6 weeks and then given a 250 mg meal of [U-(14)C]-glucose with incorporation of label into hepatic cholesterol and fatty acid measured 2 hours later. Consistent with earlier results in the obob model, incorporation of labeled glucose was significantly increased in obese compared with non-obese mice fed 1% corn oil and significantly reduced either by feeding 40% lard or by adding taurocholenic acid to the diet. In addition, taurocholenic acid greatly increased incorporation of labeled glucose into hepatic cholesterol in obese or non-obese mice fed either diet. In contrast to obob mice, the percentage of fat in the liver of gtgo mice was increased only 50% compared with ngtgo mice. The comparable increase in obob mice was 480%. Hepatic cholesterol did not increase significantly in the liver of gtgo mice fed 1% corn oil when compared with the ngtgo controls. The comparable increase in obob mice fed 1% corn oil was 350%. Also in marked contrast to obob mice, feeding taurocholenic acid increased hepatic cholesterol compared with non-obese controls fed either diet. The results are discussed in the light of the presence of circulating leptin in gtgo but not in obob mice.     

Activation of the central melanocortin system contributes to the increased arterial pressure in obese Zucker rats

We have previously demonstrated that leptin-mediated activation of the central nervous system (CNS) melanocortin system reduces appetite and increases sympathetic activity and blood pressure (BP). In the present study we examined whether endogenous melanocortin system activation, independent of leptin's actions, contributes to the regulation of BP and metabolic functions in obese Zucker rats, which have mutated leptin receptors. The long-term cardiovascular and metabolic effects of central melanocortin-3/4 receptor (MC3/4R) antagonism with SHU-9119 were assessed in lean (n = 6) and obese (n = 8) Zucker rats. BP and heart rate (HR) were measured 24-h/day by telemetry and an intracerebroventricular cannula was placed in the brain lateral ventricle. After stable control measurements, SHU-9119 was infused intracerebroventricularlly (1 nmol/h) for 10 days followed by a 10-day recovery period. Chronic CNS MC3/4R antagonism significantly increased food intake and body weight in lean (20 ± 1 to 45 ± 2 g and 373 ± 11 to 432 ± 14 g) and obese (25 ± 2 to 35 ± 2 g and 547 ± 10 to 604 ± 11 g) rats. No significant changes were observed in plasma glucose levels in lean or obese rats, whereas plasma leptin and insulin levels markedly increased in lean Zucker rats during CNS MC3/4R antagonism. Chronic SHU-9119 infusion in obese Zucker rats reduced mean arterial pressure (MAP) and HR by 6 ± 1 mmHg and 24 ± 5 beats/min, whereas in lean rats SHU-9119 infusion reduced HR by 31 ± 9 beats/min while causing only a transient decrease in MAP. These results suggest that in obese Zucker rats the CNS melanocortin system contributes to elevated BP independent of leptin receptor activation.     

PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure

Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.     

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   

Intracerebroventricular leptin administration reduces food intake in pregnant and lactating mice

Leptin acts within the hypothalamus to diminish food intake. During pregnancy and lactation, both circulating leptin concentrations and food intake are elevated, suggesting an ineffectiveness of leptin to reduce food intake in these mice. Thus, this study tested the ability of intracerebroventricular (ICV) leptin administration to alter food intake during pregnancy and lactation. Mice during the first, second, and third trimesters of pregnancy, lactating mice on postpartum Day 7, and age-matched female mice were used. Plasma leptin concentrations averaged 2.9 +/- 0.3 ng/ml in control mice, increased steadily as pregnancy progressed (3.4 +/- 0.7, 29.8 +/- 4.5, and 40.5 +/- 0.7 ng/ml during the first, second, and third trimesters, respectively), and remained elevated on Day 7 postpartum (26.4 +/- 7.8 ng/ml). Mice were food deprived for 4 h, injected ICV with vehicle or leptin (1 micro g), and food intake was subsequently measured hourly for 3 hr, and after 24 hr. Vehicle-treated pregnant mice consumed marginally more food than cycling control mice, whereas nursing dams ate two to three times as much food as controls. As expected, ICV leptin administration reduced 24-hr food intake of control mice by 2 g, or approximately 50%. ICV-administered leptin was as effective in reducing food intake of pregnant and lactating mice as observed in control mice. Thus, the elevated circulating leptin concentrations observed in pregnant and nursing mice did not alter the ability of ICV-administered leptin to diminish food intake. High plasma concentrations of leptin-binding proteins observed during pregnancy, and probably during lactation, may limit the amount of endogenous leptin reaching the hypothalamus, and may consequently enable increases in food intake concomitant with elevated plasma leptin during these nutritionally demanding periods.     

The effect of meal size and meal duration on food anticipatory activity in greenback flounder

Latency of food anticipatory activity (FAA) in greenback flounder Rhombosolea tapirina was about 21 days. Fish fed at meal sizes of 0·25 and 0·5% W day⁻¹ exhibited FAA under meal durations of 1, 3 and 7 h. Fish fed at 1·5% W day⁻¹ showed FAA only at a meal duration of 1 h. At each meal size, FAA was shorter and lower the longer the duration of the meal. The mean durations of FAA and post-feeding activity were correlated positively ( r =0·87; P <0·01; n =7). FAA persisted for <3 days during food deprivation. It is suggested that greenback flounder was capable of evaluating the energetic and temporal impacts of a single daily meal.