Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight*

Despite numerous experiments showing that administration of neuropeptide Y (NPY) to rodents stimulates feeding and obesity, whereas acute interference with NPY signaling disrupts feeding and promotes weight loss, NPY-null mice have essentially normal body weight regulation. These conflicting observations suggest that chronic lack of NPY during development may lead to compensatory changes that normalize regulation of food intake and energy expenditure in the absence of NPY. To test this idea, we used gene targeting to introduce a doxycycline (Dox)-regulated cassette into the Npy locus, such that NPY would be expressed until the mice were given Dox, which blocks transcription. Compared with wild-type mice, adult mice bearing this construct expressed Ϸ4-fold more Npy mRNA, which fell to Ϸ20% of control values within 3 days after treatment with Dox. NPY protein also fell Ϸ20-fold, but the half-life of Ϸ5 days was surprisingly long. The biological effectiveness of these manipulations was demonstrated by showing that overexpression of NPY protected against kainateinduced seizures. Mice chronically overexpressing NPY had normal body weight, and administration of Dox to these mice did not suppress feeding. Furthermore, the refeeding response of these mice after a fast was normal. We conclude that, if there is compensation for changes in NPY levels, then it occurs within the time it takes for Dox treatment to deplete NPY levels. These observations suggest that pharmacological inhibition of NPY signaling is unlikely to have long-lasting effects on body weight. body weight regulation ͉ conditional knockout ͉ feeding behavior N umerous studies using a variety of approaches have implicated neuropeptide Y (NPY) in the regulation of body weight. Injection of NPY or NPY-related peptides intracranially (either into the hypothalamus or cerebral ventricles) stimulates robust feeding (1-6); conditions of energy deprivation (starvation) or increased energy demand (lactation) induce NPY expression in the hypothalamus (7,8); most genetic models of obesity exhibit hyperphagia and an increase in hypothalamic NPY levels (9-13); and various pharmacological treatments that enhance feeding are accompanied by an increase in NPY (14). In addition, various methods (antisense oligonucleotides, antibodies, or receptor antagonists) aimed at blocking NPY actions in the hypothalamus have been shown to inhibit feeding (15)(16)(17)(18)(19)(20)(21)(22). Moreover, there is anatomical and electrophysiological evidence that NPY neurons in the arcuate (ARC) region of the hypothalamus have direct inhibitory inputs onto proopiomelanocortin (POMC) cells that form part of the melanocortin-signaling pathway, which suppresses feeding (23). Thus, current models for hypothalamic control of energy balance suggest that activation of POMC cell signaling to cells bearing melanocortin-4 receptors (MC4R) suppresses feeding, whereas NPY and various other hormones and neurotransmitters stimulate feeding by antagonizing this melanocortin-signaling pathway. NPYexpressing n...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Modulation of neuropeptide Y expression in adult mice does not affect feeding

Marie

Luquet²,

Cole³

et al. 2005

“…To maintain body weight, caloric intake and energy expenditure must be balanced, and excessive caloric intake is a leading cause of obesity (1). There is growing evidence that the brain receives and integrates information related to energy status from peripheral tissues and that appetite is under the control of numerous neurotransmitters and hormones, such as neuropeptide Y, melanocortin, leptin, and ghrelin (2,3) Histamine is a classical inflammatory mediator in peripheral tissues and also functions as a neurotransmitter in the brain. Histamine plays a pivotal role in various physiological functions, such as feeding behavior and energy homeostasis (4).…”

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confidence: 99%

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

Yoshimoto

Miyamoto

Shimamura

et al. 2006

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with ␣-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.autoreceptor ͉ heteroreceptor ͉ appetite regulation O besity has recently become a matter of great concern, because it is considered one of the highest risk factors for diabetes mellitus, hyperlipidemia, and arteriosclerosis. To maintain body weight, caloric intake and energy expenditure must be balanced, and excessive caloric intake is a leading cause of obesity (1). There is growing evidence that the brain receives and integrates information related to energy status from peripheral tissues and that appetite is under the control of numerous neurotransmitters and hormones, such as neuropeptide Y, melanocortin, leptin, and ghrelin (2, 3)Histamine is a classical inflammatory mediator in peripheral tissues and also functions as a neurotransmitter in the brain. Histamine plays a pivotal role in various physiological functions, such as feeding behavior and energy homeostasis (4). Intracerebroventricular administration of histamine consistently decreases appetite in several species (4). Mice with genes disrupted for histamine H1 receptor or histidine decarboxylase (HDC), a ratelimiting enzyme for histamine synthesis, are prone to becoming obese on a high-fat diet or at advanced age (5-8). Furthermore, several antipsychotic drugs with high affinities for H1 receptors are known to cause weight gain in rodents and humans (9). These results suggest a significant role for histamine and H1 receptors in feeding behavior and body-weight regulation.Histamine H3 receptors (H3Rs) were pharmacologically identified more than a decade ago and recently cloned (10, 11). They are predominantly ex...

“…NPY is widely expressed in the brain, including the cerebral cortex, the hippocampus, the hypothalamus, the septum, and the brainstem (4). Central NPY systems are known to be involved in the regulation of feeding and energy homeostasis, growth, reproductive behavior and physiology, circadian rhythms, gastrointestinal motility, memory, nociception, and blood pressure regulation (5)(6)(7). NPY is found in major brain structures implicated in the regulation of emotionality and aggression, including the prefrontal cortex, the amygdala, the medial hypothalamus, and midbrain regions such as the dorsal periaqueductal gray.…”

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confidence: 99%

Y1 receptors regulate aggressive behavior by modulating serotonin pathways

Karl

Lin

Schwarzer

et al. 2004

Neuropeptide Y (NPY) is pivotal in the coordinated regulation of food intake, growth, and reproduction, ensuring that procreation and growth occur only when food is abundant and allowing for energy conservation when food is scant. Although emotional and behavioral responses from the higher brain are known to be involved in all of these functions, understanding of the coordinated regulation of emotion͞behavior and physiological functions is lacking. Here, we show that the NPY system plays a central role in this process because ablation of the Y1 receptor gene leads to a strong increase in territorial aggressive behavior. After exposure to the resident-intruder test, expression of c-fos mRNA in Y1-knockout mice is significantly increased in the medial amygdala, consistent with the activation of centers known to be important in regulating aggressive behavior. Expression of the serotonin [5-hydroxytryptamine (5-HT)] synthesis enzyme tryptophan hydroxylase is significantly reduced in Y1-deficient mice. Importantly, treatment with a 5-HT-1A agonist, (؎)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, abolished the aggressive behavior in Y1-knockout mice. These results suggest that NPY acting through Y1 receptors regulates the 5-HT system, thereby coordinately linking physiological survival mechanisms such as food intake with enabling territorial aggressive behavior. Aggression is a fundamental behavior that has evolved to help organisms compete for limited resources and, therefore, to guarantee survival of the species. Behavioral, pharmacological, and genetic studies have shown that specific neuronal circuits and various neurotransmitters and hormones modulate impulsiveness and aggressiveness in animal models as well as humans (1, 2). In particular, brain areas such as the olfactory bulb, the prefrontal cortex, the amygdala, several hypothalamic structures, and the area of the periaqueductal gray have been implicated in the regulation of emotion-and aggression-related behavior (3).Although science has begun to reveal these neuronal circuits involved in regulating aggression, little is known about the molecular mechanisms that link particular physiological events with appropriate aggressive behavior. For example, aggressive behavior could be advantageous for hunting or defending a territory, especially when an individual is hungry and there is competition for a limited food supply. Similarly, aggression in males of many species can be advantageous in attracting the fittest partner. However, the mechanisms by which aggression and appetite or aggression and sexual drive are coordinately regulated are unknown.We hypothesized that the evolutionary conserved neuropeptide Y (NPY) and its Y-receptor system may fulfill this important role of integrating aggressive behavior, especially territorial aggressive behavior, with other survival-related physiological functions. NPY is widely expressed in the brain, including the cerebral cortex, the hippocampus, the hypothalamus, the septum, and the brainstem (4). Central NPY syst...