A putative physiological role of hypothalamic CNTF in the control of energy homeostasis

Vacher, Claire-Marie; Crépin, Delphine; Aubourg, Alain; Couvreur, Odile; Bailleux, Virginie; Nicolas, Valérie; Férézou, Jacqueline; Gripois, D.; Gertler, Arieh; Taouis, Mohammed

doi:10.1016/j.febslet.2008.10.018

Cited by 11 publications

(11 citation statements)

References 43 publications

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“…5A, lane M). The fact that CNTFR␣ was not detected in the membrane fraction, although functional after an intraperitoneal injection of CNTF (34,57), may be due to its labile glycosyl-phosphatidylinositol anchorage to the cell membrane (14). Moreover, JAK2 and Akt were detected in both cytoplasmic and nuclear fractions (Fig.…”

Section: Cntf and Its Receptor Subunits Are Expressed In Anorexigenicmentioning

confidence: 99%

“…We have demonstrated previously that CNTF was expressed in 90% of astrocytes and 75% of neurons in the rat ARC (57). Because CNTF administration decreases food intake, we addressed the possibility for the cytokine to be produced in anorexigenic neurons.…”

Section: Cntf and Its Receptor Subunits Are Expressed In Anorexigenicmentioning

confidence: 99%

“…Human CNTF and ovine leptin were produced by Protein Laboratories Rehovot as described previously and validated (16,18,57).…”

Section: Animals and Housingmentioning

confidence: 99%

“…Recently, the contribution of endogenous CNTF to the physiological control of energy homeostasis has been proposed with the finding of a body weight-dependent production of CNTF in the rat ARC (57). Nevertheless, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide (49) and thus may not be secreted by the classical exocytosis pathways.…”

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confidence: 99%

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The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons

Couvreur

Aubourg

Crépin

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several signaling proteins, including Akt, as well as the transcription of the POMC gene. These data strongly suggest that intracellular CNTF may directly modulate POMC gene expression via the activation of receptors localized in the cell nucleus, providing a novel plausible mechanism of CNTF action in regulating energy homeostasis.

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Section: Cntf and Its Receptor Subunits Are Expressed In Anorexigenicmentioning

confidence: 99%

Section: Cntf and Its Receptor Subunits Are Expressed In Anorexigenicmentioning

confidence: 99%

“…Human CNTF and ovine leptin were produced by Protein Laboratories Rehovot as described previously and validated (16,18,57).…”

Section: Animals and Housingmentioning

confidence: 99%

mentioning

confidence: 99%

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The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons

Couvreur

Aubourg

Crépin

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…The protein encoded by ZFP91 is a potent survival factor for neurons and also acts as a regulator of the noncanonical NF-κβ pathway. In addition, a read-through transcript variant composed of ZFP91 and the downstream ciliary neurotrophic factor (CNTF) gene, an endogenous modulator of energy homeostasis in the arcuate nucleus (35), has been reported. We observed that male offspring of HFD-fed dams, which were born large according to the mean weight of their littermates (above 80th percentile), had higher levels of DNA methylation in the ZFP91 promoter (data not shown).…”

Section: Reviewmentioning

confidence: 99%

Fetal metabolic programming and epigenetic modifications: a systems biology approach

et al. 2013

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A growing body of evidence supports the notion that epigenetic changes such as DNA methylation and histone modifications, both involving chromatin remodeling, contribute to fetal metabolic programming. We use a combination of gene-protein enrichment analysis resources along with functional annotations and protein interaction networks for an integrative approach to understanding the mechanisms underlying fetal metabolic programming. systems biology approaches suggested that fetal adaptation to an impaired nutritional environment presumes profound changes in gene expression that involve regulation of tissue-specific patterns of methylated cytosine residues, modulation of the histone acetylation-deacetylation switch, cell differentiation, and stem cell pluripotency. The hypothalamus and the liver seem to be differently involved. In addition, new putative explanations have emerged about the question of whether in utero overnutrition modulates fetal metabolic programming in the same fashion as that of a maternal environment of undernutrition, suggesting that the mechanisms behind these two fetal nutritional imbalances are different. In conclusion, intrauterine growth restriction is most likely to be associated with the induction of persistent changes in tissue structure and functionality. conversely, a maternal obesogenic environment is most probably associated with metabolic reprogramming of glucose and lipid metabolism, as well as future risk of metabolic syndrome (Ms), fatty liver, and insulin (INs) resistance.L arge amounts of epidemiological data showed that impaired intrauterine growth and adult metabolic and cardiovascular disorders, including coronary heart disease, type 2 diabetes, and insulin (INS) resistance, are strongly associated (1-4). Actually, the first exploration of a putative connection between environmental influence in early life and the risk of cardiovascular disease in adulthood was done by David Barker and coworkers, who followed-up a cohort of 499 men and women born in Preston (Lancashire, UK) during 1935-1943, and observed that as adults the highest blood pressures occurred in people who had been small babies with large placentas (5).Of note, the concept of a relationship between birth weight and adult chronic diseases initially described in low-birthweight babies was further extended to large-for-gestational age (LGA) babies, and the term of inappropriate gestational weight gained acceptance to better illustrate changes in earlylife metabolic environment that contribute to the risk of metabolic syndrome (MS) in adulthood (6).Barker and Hales also provided the initial answer to the question of how birth weight and adult chronic diseases are connected. They explained that fetuses adapt to an impaired supply of nutrients by changing their physiology and metabolism, and altering the sensitivity of tissues causes an abnormal structure and function in adult life; thereby, they formulated the "thrifty phenotype hypothesis" (7,8).Altogether, the above-mentioned clinico-epidemiological evidence str...

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Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy

Arch

2011

Diabetes - Perspectives in Drug Therapy

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Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.

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A putative physiological role of hypothalamic CNTF in the control of energy homeostasis

Cited by 11 publications

References 43 publications

The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons

The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons

Fetal metabolic programming and epigenetic modifications: a systems biology approach

Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy

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