Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice

Tan, Ying; Hang, F; Liu, Zhongwu; Stoiljković, Milan; Wu, Mingxing; Tu, Yue; Han, Wenfei; Lee, Angela M.; Kelley, Craig; Hajós, Mihály; Lu, Lingeng; Lecea, Luı́s de; Araújo, Ivan de; Picciotto, Marina R.; Horváth, Tamas L.; Gao, Xiao‐Bing

doi:10.1172/jci130889

Cited by 22 publications

(15 citation statements)

References 90 publications

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“…Increased tissue inflammation in Titan mice might contribute to tissue damage 40 . Notably, one identified RDD contained the Hcrt gene, which is a hypothalamic neuropeptide that can regulate feeding behavior and metabolic homeostasis 51 , 52 . While we did not evaluate gene expression levels in the brain area that may account for metabolic alterations in the Titan mice, we observed a significant reduction of Hcrtr2 in the liver.…”

Section: Discussionmentioning

confidence: 99%

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

et al. 2022

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Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world’s longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and tests its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

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Section: Discussionmentioning

confidence: 99%

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

et al. 2022

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“…Notably, one identified RDD contained the Hcrt gene, which is a hypothalamic neuropeptide that can regulate feeding behavior and metabolic homeostasis 48,49 . While we did not evaluate gene expression levels in the brain area that may account for metabolic alterations in the Titan mice, we observed a significant reduction of Hcrtr2 in the liver.…”

Section: Discussionmentioning

confidence: 99%

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

Mueller-Eigner

Sanz-Moreno

de-Diego

et al. 2020

Preprint

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Metabolic syndrome is widespread and negatively impacts healthy longevity but takes years to study in mammalian models, delaying translational applications. To address this, we characterized the unique polygenic "Titan" mouse (110 grams average) with a healthy lifespan of only 4 months that was generated by 45 years of breeding selection. Titan mice displayed increased plasma leptin, insulin, IL-6 and fasting triglycerides. Also, pancreatic fat cell accumulation and thymic medullary hyperplasia were detected in Titan animals. Liver transcriptome and proteome analysis demonstrated alterations in lipid metabolism, the methionine cycle, and cytochrome P450 regulation in Titan mice. Late dietary intervention in Titan mice reduced fat content and improved expression of genes involved in lipid synthesis and cytochrome P450 detoxification, altering the abundance of metabolites, including malonyl-CoA and dimethylglycine. Strikingly, late dietary intervention at 3 months of age almost doubled the healthy lifespan of Titan mice. This powerful model of metabolic disorders, systemic inflammation, and early aging will enable to provide uniquely rapid results for translational intervention.

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“…In the lateral hypothalamus, no altered mRNA expression of orexin was observed in mice exposed to transient peripubertal diet-induced obesity [98]. In obese animals, a deficiency in orexins could be the cause of behavioral changes (decreased reward seeking, altered stress response, and lowered arousal) [80]. In fact, the activity of neuronal networks (hippocampus and lateral hypothalamus) was impaired when a decrease in the action mediated by orexin occurred [80] (Table 3).…”

Section: Mousementioning

confidence: 99%

“…Differential roles in food consumption at different feeding periods Rat [78] High-fat diet: activation of neurons expressing orexin and increase in consumption of a high-fat diet by activating the mesolimbic reward pathway Rat [79] Obese animals: a deficiency in orexins promote behavioral changes. Impaired activity of neuronal networks by a decrease in the action medited by orexin Mouse [80] Orexin A: decreased adiposity, intraperitoneal fat deposit and expression of several receptors in the brain. Not effect on glucose metabolism and energy expenditure Mouse [21] Table 3.…”

Section: Effects Species Referencesmentioning

confidence: 99%

“…In obese animals, a deficiency in orexins could be the cause of behavioral changes (decreased reward seeking, altered stress response, and lowered arousal) [80]. In fact, the activity of neuronal networks (hippocampus and lateral hypothalamus) was impaired when a decrease in the action mediated by orexin occurred [80] (Table 3). Finally, in mice, it was reported that orexin A decreased adiposity, intraperitoneal fat deposit and the expression of several receptors in the brain but did not affect glucose metabolism and energy expenditure [21] (Table 3).…”

Section: Mousementioning

confidence: 99%

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Involvement of the Orexinergic System in Feeding

Marcos

Coveñas

2021

Applied Sciences

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To know the processes involved in feeding, the dysregulation of hypothalamic neuropeptides promoting anorexigenic/orexigenic mechanisms must be investigated. Many neuropeptides are involved in this behavior and in overweight/obesity. Current pharmacological strategies for the treatment of obesity are unfortunately not very effective and, hence, new therapeutic strategies must be investigated and developed. Due to the crucial role played by orexins in feeding behavior, the aim of this review is to update the involvement of the orexinergic system in this behavior. The studies performed in experimental animal models and humans and the relationships between the orexinergic system and other substances are mentioned and discussed. Promising research lines on the orexinergic system are highlighted (signaling pathways, heterogeneity of the hypothalamic orexinergic neurons, receptor-receptor interaction, and sex differences). Each of the orexin 1 and 2 receptors plays a unique role in energy metabolism, exerting a differential function in obesity. Additional preclinical/clinical studies must be carried out to demonstrate the beneficial effects mediated by orexin receptor antagonists. Because therapies applied are in general ineffective when they are directed against a single target, the best option for successful anti-obesity treatments is the development of combination therapies as well as the development of new and more specific orexin receptor antagonists.

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Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice

Cited by 22 publications

References 90 publications

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

Involvement of the Orexinergic System in Feeding

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