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Principles for interactions among the multiple systems that influence food intake. Am J Physiol Regulatory Integrative Comp Physiol 283: R46-R53, 2002; 10.1152/ajpregu.00021.2002.--The widespread use of molecular biological has led to a pronounced increase in the number of signals that are now implicated in the controls of food intake and body weight. However, a complete understanding of the roles of these multiple signals requires that we assess how they interact with one another to alter ingestive behavior. Although many such experiments are being conducted, methods employed to delineate these interactions are often fraught with interpretive difficulties. The purpose of this article is to explore these difficulties and offer practical advice for minimizing these issues in experiments that seek to explore the important interactions among these signals. In particular, the issues of additive vs. nonadditive results, the use of sub- or suprathreshold dose combinations, and the choosing of multiple-dose analyses are all addressed. Furthermore, the possibilities of using intake measures other than cumulative intake and complementary nonbehavioral endpoints are encouraged. dose-effect curve; leptin; multiple-dose combination; obesity; peptide

Midlife weight gain occurs in many species, suggesting that leptin signaling is impaired at middle age. To test this hypothesis, we measured changes in food intake and body composition in young (Y) and middle-aged (MA) C57BL/6 male mice infused subcutaneously with phosphate-buffered saline or leptin. Leptin-induced decreases in food intake and body fat were delayed in MA mice and associated with catabolism after longer treatment periods. Endogenous plasma leptin levels did not correlate with body fat in MA mice. Calorie restriction (CR) reduced body fat, plasma leptin, and insulin in MA mice to levels in Y mice but did not upregulate leptin sensitivity. CR mice did not respond to leptin doses that inhibited food intake in MA mice and reduced food intake and body fat in Y mice significantly below levels in CR mice. Plasma corticosterone was significantly higher in leptin-treated CR vs. MA mice. We conclude that MA C57BL/6 mice exhibit impaired leptin signaling and that CR, possibly by elevating glucocorticoids, impairs appetite control without improving the metabolic actions of leptin. weight gain; food intake; glucocorticoids; insulin; longevity

Inhibition of a signal that generates positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus to paraventricular nucleus is a possible mechanism for leptin action. It is hypothesized that reduced NPY activity is needed for the satiety and thermogenic effects of leptin. Findings showed that repletion of NPY in the paraventricular nucleus by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin.

The mechanism of modified human OB protein (Mod-OB) regulation of food intake was investigated in female rats by monitoring the effect of subcutaneous administration of Mod-OB on food intake and weight gain. Results reveal that treated subjects have significant reductions in nighttime meal size. There is also a significant decrease in weight gain among treated subjects. Mod-OB administration did not alter physical activity and ovarian cycle in treated subjects.

The mechanism whereby leptin modulates feeding in rats was investigated by monitoring the feeding behavior of rats given leptin via ventricular administration. Results show a reduction of nighttime meal size but not meal frequency and duration. Similar observations were seen during the day and during 24-hour periods. Satiety ratio doubled among experimental subjects. The mechanism governing leptin regulation of feeding is meal size reduction.

The mechanism of modified human OB protein (Mod-OB) regulation of food intake was investigated in male rats by monitoring the effect of subcutaneous administration of Mod-OB on food intake and weight gain. Results reveal that treated subjects have significant reductions in nighttime meal size. There is also a significant decrease in weight gain among treated subjects. Further, the subjects did not exhibit compensatory hyperphagia.

The effects of leptin on food intake and energy balance was evaluated in intact mice, adrenalectomized mice and corticosterone-treated adrenalectomized mice. Results reveal that leptin and corticosterone reduced and increased food intake, respectively, independent of each other. There were no significant interactions identified between them in the experiments conducted. Further, leptin is able to exert its effects even in the absence of an intact adrenal gland.

Transgenic brown adipose tissue-ablated uncoupling protein diphtheria toxin A chain mice were used in the investigation of the dependence of feeding on temperature and the function of leptin in the regulation of food intake. Results reveal that the adjustment of food intake among control subjects during acclimation to cold temperature is not regulated by leptin. Further, the adjustment in food intake among transgenic mice is impaired.

The idea that the nonspecific melanocortin agonist MTII may affect eating behavior of rats through mechanisms similar to those that mediate the effects of leptin was tested. Findings revealed that unlike leptin, MTII caused conditioned taste aversions. Data are in agreement with the hypothesis that MTII may affect regulatory behavior through processes which are similar to those that mediate the effects of leptin.

The effects of beta3-adrenergic receptor stimulation on the modulation of leptin gene expression were analyzed in fasted F-344 rats. The administration of CGP-12177 beta3-adrenergic anatagonists in fasted F-344 rats reduced food consumption and leptin messenger RNA levels. The activation of beta3-adrenergic receptors by CGP-12177 also increased the levels of uncoupling proteins in the brown adipose tissues of the fasted rats.

The effects of single intraperitoneal injections of mouse leptin on the time course of food intake and gastric emptying were analyzed in obese and fasted, lean C57BL/6 +/+ mice. Acute injection of recombinant murine leptin reduced cumulative food intake in fasted, lean C57BL/6 +/+ mice strains without altering the rate of gastric emptying after a solid meal. Furthermore, the rate of gastric emptying overlapped with the kinetics of the food intake-reducing effects of leptin.

The effects of reduced short-term food intake due to leptin and glucagon-like peptide-1 (7-36) amide (GLP-1) infusions into the third ventricle (i3vt) on taste aversion reactions were analyzed in rats. Administration of GLP-1 in the i3vt of rats exposed to saccharine taste elicited conditioned taste aversion compared to leptin. Analysis of leptin and GLP-1 activity in i3vt based on c-Fos immunoreactivity indicated the presence of different mechanisms that mediate the anoretic action GPT-1 and leptin.

The role of leptin in mammalian thermoregulation or homeostasis was analyzed in seasonally hyperphagic arctic ground squirrels after infusions of leptin via miniosmotic pumps. Administration of leptin in arctic squirrels during prehibernation hyperphagia reduced food intake and body weight by altering feeding behavior. Furthermore, the hyperphagic arctic squirrels exhibited reduced body fat indicating the role of leptin in the regulation of satiety expenditure of energy during hibernation.

The activities of the limbic, hypothalamic and hindbrain regions of rats were analyzed by c-Fos-like immunoreactivity after the third ventricular administration of leptin and glucagon-like peptide-1-(7-36) amide (GLP-1). The rats exhibited reduced food intake after two treatments of leptin and GLP-1 due to alterations in neural patterns. Furthermore, consumption of meals did not alter the plasma leptin concentrations indicating the role of leptin in controlling the termination of ingestive episodes. However, elevated levels of GLP-1 were detected during meal consumption.

Leptin may rapidly inhibit food intake by altering the secretion of hypothalamic neuropeptides such as neuropeptide Y (NPY), a stimulator of food intake, and/or corticotropin-releasing hormone (CRH), an inhibitor of food intake. We measured concentrations of NPY and CRH in specific hypothalamic regions [i.e., arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus and dorsomedial nucleus] of 7- to 8-wk-old lean and ob/ob mice at 1 or 3 h after intracerebroventricular leptin administration. No rapid-onset effects of leptin on hypothalamic NPY or CRH concentrations were observed in intact mice. The addition of leptin to hypothalamic preparations from intact mice also did not alter NPY or CRH secretion. Glucocorticoids may oppose leptin actions. Consistent with this, leptin administration to adrenalectomized mice markedly reduced CRH concentrations in the ARC within 3 h after injection. This rapid reduction in CRH concentration in the ARC after leptin administration is more likely due to stimulated CRH release from this region than to decreased synthesis/transport from the PVN because leptin stimulates CRH synthesis in the PVN. Within 20 min after exposure to leptin, NPY secretion from hypothalamic preparations obtained from adrenalectomized mice was lowered by 27% and CRH secretion was elevated by 51%. The current study demonstrates that leptin rapidly influences the secretion of hypothalamic NPY and CRH and that these actions of leptin within the hypothalamus are restrained by the presence of endogenous corticosterone. J. Nutr. 130: 2813-2820, 2000. KEY WORDS: * neuropeptide Y * corticotropin-releasing hormone * leptin * glucocorticoids * hypothalamus * ob/ob mice

Ammar, A. A., F. Sederholm, T. R. Saito, A. J. W. Scheurink, A. E. Johnson, and P. Sodersten. NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior. Am J Physiol Regulatory Integrative Comp Physiol 278: R1627-R1633, 2000.--Many studies have indicated that neuropeptide Y (NPY) stimulates and leptin inhibits food intake. In line with this, intracere-broventricular injection of NPY (10 [micro]g) stimulated and leptin (10 [micro]g) inhibited intake of a sucrose solution when female rats were required to obtain the solution from a bottle. However, NPY inhibited and leptin stimulated intake if the solution was infused intraorally. Thus NPY stimulates the responses used to obtain food but inhibits those used to consume food, and leptin has the opposite effects. To test the specificity of these responses the sexual behavior of male rats was examined. NPY-treated males showed minor deficits in sexual behavior but chose to ingest a sucrose solution rather than copulate with a female if offered the choice. By contrast, leptin-treated males ingested little sucrose and displayed an increase in ejaculatory frequency if given the same choice. It is suggested that NPY is not merely an orexigenic peptide, but one that directs attention toward food. Similarly, leptin may not be an anorexic peptide, but one that diverts attention away from food toward alternate stimuli. food intake; reproduction; peptides; behavioral choice

Studies examining the effects of low-protein diets on food intake and body weight have shown varied results. Many researchers have found low dietary protein to increase food intake, while others have found no effect or even a decrease. In 63 male Sprague-Dawley rats, we examined several low levels of dietary protein (2%, 5%, 8%, 10%, 15% vs. 20% casein) to determine the dose-response relationships between low dietary protein and food intake, body composition, energy balance and serum leptin concentrations. Food intake, over the range of low dietary protein, showed a quasi bell-shaped response curve with peak intake occurring in rats fed 8-10% casein. Peak feeding occurred at or just below the estimated protein requirement of the rats (10-12.5% casein). Compared to the 20% casein controls, food intake was severely reduced in rats fed 2% casein, while it was greater in the other low-protein groups. The amount of body fat steadily increased between the 15% casein group and the 8% casein group, and sharply declined between the 5% casein group and 2% casein group. The change in body fat reflected both the change in food intake and altered energy partitioning. Serum leptin concentrations were greater in rats fed the 5 and 8% casein diets than in control rats fed 20% casein. Serum leptin concentrations were positively associated with body fat content ([r.sup.2] = 0.763, P [is less than] 0.001). Increased serum leptin concentrations in the presence of increased food intake is suggestive of a state of leptin resistance. This animal model may provide important insights into diet-induced obesity. J. Nutr. 130: 514-521, 2000. KEY WORDS: * protein restriction * food intake * body composition * leptin * rats