The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis

Francesconi, Walter; Sanchez‐Alavez, Manuel; Berton, Fulvia; Alboni, Silvia; Benatti, Cristina; Mori, Simone; Nguyen, William; Zorrilla, Eric P.; Moroncini, Gianluca; Tascedda, Fabio; Conti, Bruno

doi:10.1523/jneurosci.3919-15.2016

Cited by 30 publications

(22 citation statements)

References 67 publications

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“…The pattern of changes recorded in the hypothalamus was consistent with the pattern expected when animals experience a reduction in appetite. These effects were abolished in brain slices from the IL-18 knock-out mouse (Francesconi et al, 2016).…”

Section: Dual-intervention Point Model and 'Drifty Gene' Hypothesismentioning

confidence: 95%

“…Injection of IL-18 directly into this area of the brain in mice resulted in a significant reduction in food intake, but interestingly had no impact on physical activity levels, body temperature or energy expenditure (Francesconi et al, 2016). Brain slice work showed that neurons in the BST that project to the hypothalamus were strongly activated by glutamate, but that this excitatory effect was reduced when they were treated with IL-18.…”

Section: Dual-intervention Point Model and 'Drifty Gene' Hypothesismentioning

confidence: 99%

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The evolution of body fatness: trading off disease and predation risk

Speakman

2018

Journal of Experimental Biology

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Human obesity has a large genetic component, yet has many serious negative consequences. How this state of affairs has evolved has generated wide debate. The thrifty gene hypothesis was the first attempt to explain obesity as a consequence of adaptive responses to an ancient environment that in modern society become disadvantageous. The idea is that genes (or more precisely, alleles) predisposing to obesity may have been selected for by repeated exposure to famines. However, this idea has many flaws: for instance, selection of the supposed magnitude over the duration of human evolution would fix any thrifty alleles (famines kill the old and young, not the obese) and there is no evidence that hunter-gatherer populations become obese between famines. An alternative idea (called thrifty late) is that selection in famines has only happened since the agricultural revolution. However, this is inconsistent with the absence of strong signatures of selection at single nucleotide polymorphisms linked to obesity. In parallel to discussions about the origin of obesity, there has been much debate regarding the regulation of body weight. There are three basic models: the setpoint, settling point and dual-intervention point models. Selection might act against low and high levels of adiposity because food unpredictability and the risk of starvation selects against low adiposity whereas the risk of predation selects against high adiposity. Although evidence for the latter is quite strong, evidence for the former is relatively weak. The release from predation ∼2-million years ago is suggested to have led to the upper intervention point drifting in evolutionary time, leading to the modern distribution of obesity: the drifty gene hypothesis. Recent critiques of the dual-intervention point/ drifty gene idea are flawed and inconsistent with known aspects of energy balance physiology. Here, I present a new formulation of the dual-intervention point model. This model includes the novel suggestion that food unpredictability and starvation are insignificant factors driving fat storage, and that the main force driving up fat storage is the risk of disease and the need to survive periods of pathogen-induced anorexia. This model shows why two independent intervention points are more likely to evolve than a single set point. The molecular basis of the lower intervention point is likely based around the leptin pathway signalling. Determining the molecular basis of the upper intervention point is a crucial key target for future obesity research. A potential definitive test to separate the different models is also described.

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Section: Dual-intervention Point Model and 'Drifty Gene' Hypothesismentioning

confidence: 95%

Section: Dual-intervention Point Model and 'Drifty Gene' Hypothesismentioning

confidence: 99%

The evolution of body fatness: trading off disease and predation risk

Speakman

2018

Journal of Experimental Biology

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“…Energy expenditure was determined by using a computer-controlled open-circuit system (Oxymax System) that is part of an integrated Comprehensive Lab Animal Monitoring System (Columbus Instruments), as previously described (54).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction

Cintrón-Colón

Sanchez‐Alavez

Nguyen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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When food resources are scarce, endothermic animals can lower core body temperature (T b ). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrusspecific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent T b regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.IGF-1R | temperature | calorie restriction | energy homeostasis | aging

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“…There is recent evidence to suggest this may be the case. A recent study by Francesconi et al (33) reported that IL-18 reduces food intake by actions in the bed nucleus of the stria terminalis. The authors concluded that this is mediated via IL-18Ra, as these effects were not observed in IL-18Ra 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor

Booker

Grattan

2017

The Journal of Immunology

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The IL-1 families of ligands and receptors exhibit similarity of coding sequences, protein structures, and chromosomal positions, suggesting that they have arisen via duplication of ancestral genes. Within these families there is selectivity in ligand-receptor interactions as well as promiscuity. IL-18 and its receptor are members of these families. IL-18 is recognized as binding to the protein products of the IL18R1 and IL18RAP genes, and with high affinity to a separate IL-18 binding protein (IL-18BP). However, IL-18BP is anomalous, as it exhibits little resemblance to IL-18R proteins. Additionally, IL-18 is produced in the brain in medial habenula neurons, which project IL-18-containing axons to the interpeduncular nucleus. However, there is a lack of focal IL-18R expression in their terminal field. Given these anomalies, we hypothesized that another receptor for IL-18 may exist, and that IL18BP is evolutionarily related to this receptor. We examined Ensembl and National Center for Biotechnology Information databases to identify available IL18BP records (n = 86 species) and show through bioinformatics approaches that across mammalian species with IL18BP genes, IL-18BP is consistently most similar to IL-1R9 (IL-1R accessory protein-like 2), another member of the IL-1R family. IL-1R9 and the related IL-1R8, but not other IL-1R family members, exhibit an amino acid sequence similar to binding site A of human and viral IL-18BPs. Conserved intron/exon boundaries, protein structure, and key binding site amino acids suggest that IL18BP and IL1R9 are evolutionarily related, and that IL-1R9 and IL-1R8 may bind IL-18.

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The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis

Cited by 30 publications

References 67 publications

The evolution of body fatness: trading off disease and predation risk

The evolution of body fatness: trading off disease and predation risk

Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction

IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor

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