Modulation of Brain Reward Circuitry by Leptin

Fulton, Stephanie; Woodside, Barbara; Shizgal, Peter

doi:10.1126/science.287.5450.125

Cited by 377 publications

(261 citation statements)

References 31 publications

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“…17 It is interesting that obese rats showed increased motivation for sucrose while having increased leptin concentrations. Leptin has been shown to reduce the rewarding effect of lateral hypothalamic self stimulation at food sensitive sites, 31,32 and recently it has been shown that leptin affects mesoaccumbens dopamine signaling. 33,34 This suggests a role for leptin in the modulation of brain reward mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…35 Rats that were relatively insensitive to leptin's anorexigenic effect were more prone to obesity when fed a high-fat diet. 36 Because leptin-sensitive neurons are also present in areas important for reward mechanisms, 31,32,37 it would be interesting to study whether the leptin sensitivity and the motivation to press for sucrose that both predict future obesity are related.…”

Section: Discussionmentioning

confidence: 99%

“…Under a PR schedule, the cost of a reward is progressively increased over successive trials, to determine the effort the rat will emit for it. The response requirement increased according to the following equation 19,20,27 : response ratio ¼ (5e(0.2 Â infusion number)) -5 through the following series: 1,2,4,9,12,15,20,25,32,40,50,62,77,95,118,145,178,219,268,328,402,492,603, 737. The session ended when the rat had failed to earn a reward within 60 min.…”

Section: Methodsmentioning

confidence: 99%

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A reciprocal interaction between food-motivated behavior and diet-induced obesity

et al. 2007

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Objectives: One of the main causes of obesity is overconsumption of diets high in fat and sugar. We studied the metabolic changes and food-motivated behavior when rats were subjected to a choice diet with chow, lard and a 30% sucrose solution (high fat high sugar (HFHS)-choice diet). Because rats showed considerable variations in the feeding response to HFHS-choice diet and in food-motivated behavior, we investigated whether the motivation to obtain a sucrose reward correlated with the development of obesity when rats were subsequently subjected to HFHS-choice diet. Method: We first studied feeding, locomotor activity and body temperature, fat weights and hormonal concentrations when male Wistar rats were subjected to HFHS-choice diet for 1 week. Second, we studied sucrose-motivated behavior, using a progressive ratio (PR) schedule of reinforcement in rats that were subjected to the HFHS-choice diet for at least 2 weeks, compared to control rats on a chow diet. Third, we measured motivation for sucrose under a PR schedule of reinforcement in rats that were subsequently subjected to HFHS-choice diet or a chow diet for 4 weeks. Fat weights were measured and correlated with the motivation to obtain sucrose pellets. Results: One week on the HFHS-choice diet increased plasma concentrations of glucose and leptin, increased fat stores, but did not alter body temperature or locomotor activity. Moreover, consuming the HFHS-choice diet for several weeks increased the motivation to work for sucrose pellets. Furthermore, the motivation to obtain sucrose pellets correlated positively with abdominal fat stores in rats subsequently subjected to the HFHS-choice diet, whereas this correlation was not found in rats fed on a chow diet. Conclusion: Our data suggest that the motivation to respond for palatable food correlates with obesity due to an obesogenic environment. Conversely, the HFHS-choice diet, which results in obesity, also increased the motivation to work for sucrose. Thus, being motivated to work for sucrose results in obesity, which, in turn, increases food-motivated behavior, resulting in a vicious circle of food motivation and obesity. IntroductionObesity is one of the fastest growing medical problems in modern society. It contributes to the development of chronic disorders such as cardiovascular disease, type 2 diabetes, hypertension and some cancers. 1 For healthy body weight regulation, it is important to balance energy intake and energy expenditure. Modern society, however, is characterized by a sedentary lifestyle and a calorie intake, which is not adjusted for that. Although regulatory mechanisms that balance intake and expenditure are known , 2,3 it still remains unclear why this fails in obese individuals. It has been postulated that the ability to overconsume high-energy dense foods (in the face of plentiful food availability) was selected during evolution. Thus, under conditions when food availability is uncertain and scarce, consuming highenergy dense foods is an adequate adaptation (for a review see Uli...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A reciprocal interaction between food-motivated behavior and diet-induced obesity

et al. 2007

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“…Additionally, the lateral hypothalamic area (LHA) is well known as a region containing peptides important in feeding (e.g., melanin concentrating hormone, orexin) as well as a region that potently supports electrical self-stimulation. In fact, leptin, the anorectic hormone released from adipocytes, attenuates the ability of fasting to increase self-stimulation of the LHA (Fulton, et al, 2000). Interactions between the LHA and regions important for reward behaviors such as the nucleus accumbens have yet to be described but it is likely that dopaminergic and serotonergic pathways are critical for food reward.…”

Section: Discussionmentioning

confidence: 99%

Differential involvement of endogenous opioids in sucrose consumption and food reinforcement

Hayward

Schaich-Borg

Pintar

et al. 2006

Pharmacology Biochemistry and Behavior

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Endogenous opioids within the central nervous system are postulated to mediate hedonic aspects of feeding behavior. To identify the relevant endogenous opioid receptor ligands, mice lacking one or two of the opioid peptide families β-endorphin, enkephalins or dynorphins were tested for sucrose preference in a two-bottle free-choice drinking paradigm under drug-naïve conditions and following treatment with an opioid antagonist (1 mg/kg naloxone i.p.) or saline. Basal sucrose consumption was unaltered in all of the knockout genotypes compared to their congenic wild-type C57BL/6 littermates during 0.5 and 6 h access to a bottle containing 2, 4, 8, or 16% sucrose and a second bottle containing water. Moreover, all mutant genotypes and wildtype mice exhibited a similar compensatory decrease in overnight food intake following the extra caloric load from 6 h sucrose access. Although these basal responses to sucrose were unaffected by the knockout genotypes, naloxone reduced sucrose consumption by 50% compared to saline treatment during the first 0.5 h in wild-type and β-endorphin knockout mice, but had no effect in enkephalin knockouts, β-endorphin and enkephalin double knockouts, or dynorphin knockouts. These data suggest that naloxone reduces sucrose consumption in wild-type mice by blocking endogenous enkephalin and/or dynorphin signaling, but not β-endorphin. Dynorphin knockouts in the current study had bar-pressing responses for a palatable food reinforcer in an operant procedure under free-feeding conditions similar to wildtype mice while we found in a previous study that β-endorphin and enkephalin knockout mice had reduced motivation to respond (Hayward, et al., 2002). We conclude from these studies directly comparing three strains of opioid peptide knockout mice that enkephalin and dynorphin can modulate sucrose preference but are not necessary to support sucrose consumption. However, dynorphin was not necessary to support wildtype levels of operant responding suggesting that only enkephalin and β-endorphin modulate conditioned food reinforcement. KeywordsOperant behavior; β-endorphin; enkephalin; dynorphin; knockout mice; ingestive behavior * Corresponding author phone: 609-235-1430 fax: 609-235-1498 e-mail: Michael.Hayward@Xenogen.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe plentiful access to calorically dense and highly palatable food choices is a likely contributor to the current obesity epidemic. How ingestion of palatable food is regulated is of great i...

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“…In normal individuals, the orexin modulation of VTA neurons may be important in transmitting information about the availability of primary rewards to the mesocorticolimbic reward system (Schultz, 1998). A subpopulation of orexin neurons possess leptin receptors (Willie et al, 2001), and leptin administration is known to modulate the rewarding effect of lateral hypothalamic stimulation (Fulton et al, 2000). Furthermore, orexin neurons are sensitive to metabolic state, receiving input from glucose-sensitive neurons (Liu et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Excitation of Ventral Tegmental Area Dopaminergic and Nondopaminergic Neurons by Orexins/Hypocretins

et al. 2003

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Orexins/hypocretins are involved in mechanisms of emotional arousal and short-term regulation of feeding. The dense projection of orexin neurons from the lateral hypothalamus to mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) is likely to be important in both of these processes.We used single-unit extracellular and whole-cell patch-clamp recordings to examine the effects of orexins (A and B) and melaninconcentrating hormone (MCH) on neurons in this region. Orexins caused an increase in firing frequency (EC 50 78 nM), burst firing, or no change in firing in different groups of A10 dopamine neurons. Neurons showing oscillatory firing in response to orexins had smaller afterhyperpolarizations than the other groups of dopamine neurons. Orexins (100 nM) also increased the firing frequency of nondopaminergic neurons in the VTA. In the presence of tetrodotoxin (0.5 M), orexins depolarized both dopaminergic and nondopaminergic neurons, indicating a direct postsynaptic effect. Unlike the orexins, MCH did not affect the firing of either group of neurons. Single-cell PCR experiments showed that orexin receptors were expressed in both dopaminergic and nondopaminergic neurons and that the calcium binding protein calbindin was only expressed in neurons, which also expressed orexin receptors.In narcolepsy, in which the orexin system is disrupted, dysfunction of the orexin modulation of VTA neurons may be important in triggering attacks of cataplexy.

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Modulation of Brain Reward Circuitry by Leptin

Cited by 377 publications

References 31 publications

A reciprocal interaction between food-motivated behavior and diet-induced obesity

A reciprocal interaction between food-motivated behavior and diet-induced obesity

Differential involvement of endogenous opioids in sucrose consumption and food reinforcement

Excitation of Ventral Tegmental Area Dopaminergic and Nondopaminergic Neurons by Orexins/Hypocretins

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