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Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.

ABSTRACT: Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance.

SUBMITTER: Gloaguen I

PROVIDER: S-EPMC21071 | biostudies-literature | 1997 Jun

REPOSITORIES: biostudies-literature

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Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.

Gloaguen I I Costa P P Demartis A A Lazzaro D D Di Marco A A Graziani R R Paonessa G G Chen F F Rosenblum C I CI Van der Ploeg L H LH Cortese R R Ciliberto G G Laufer R R

Proceedings of the National Academy of Sciences of the United States of America 19970601 12

Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNT ...[more]

PMID: 9177239

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Project description:In humans and experimental animals, the administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. To gain further insights into the mechanism(s) underlying its satiety effect, we: (i) evaluated the CNTF-dependent activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway in mouse models where neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons can be identified by green fluorescent protein (GFP); and (ii) assessed whether CNTF promotes leptin signaling in hypothalamic feeding centers. Immunohistochemical experiments enabled us to establish that intraperitoneal injection of mouse recombinant CNTF activated the JAK2-STAT3 pathway in a substantial proportion of arcuate nucleus (ARC) NPY neurons (18.68% ± 0.60 in 24-h fasted mice and 25.50% ± 1.17 in fed mice) but exerted a limited effect on POMC neurons (4.15% ± 0.33 in 24-h fasted mice and 2.84% ± 0.45 in fed mice). CNTF-responsive NPY neurons resided in the ventromedial ARC, facing the median eminence (ME), and were surrounded by albumin immunoreactivity, suggesting that they are located outside the blood-brain barrier (BBB). In both normally fed and high-fat diet (HFD) obese animals, CNTF activated extracellular signal-regulated kinase signaling in ME ?1- and ?2-tanycytes, an effect that has been linked to the promotion of leptin entry into the brain. Accordingly, compared to the animals treated with leptin, mice treated with leptin/CNTF showed: (i) a significantly greater leptin content in hypothalamic protein extracts; (ii) a significant increase in phospho-STAT3 (P-STAT3)-positive neurons in the ARC and the ventromedial hypothalamic nucleus of normally fed mice; and (iii) a significantly increased number of P-STAT3-positive neurons in the ARC and dorsomedial hypothalamic nucleus of HFD obese mice. Collectively, these data suggest that exogenously administered CNTF reduces food intake by exerting a leptin-like action on distinctive NPY ARC neurons and by promoting leptin signaling in hypothalamic feeding centers.

Project description:Administration of ciliary neurotrophic factor (CNTF) to experimental animals exerts anti-obesity effects by acting on multiple targets. In white adipose tissue CNTF reduces lipid content, promotes fatty acid (FA) oxidation and improves insulin sensitivity. This study was performed to establish whether CNTF exerts similar effects on human white adipocytes. To this end, adipose differentiation was induced in vitro in human multipotent adipose-derived stem (hMADS) cells. CNTF receptor ? (CNTFR?) expression was assessed in hMADS cells and adipocytes by qRT-PCR, Western blotting, and immunocytochemistry. After administration of human recombinant CNTF, signaling pathways and gene expression were evaluated by Western blotting and qRT-PCR. Glucose uptake was assessed by measuring 2-nitrobenzodeoxyglucose uptake with a fluorescence plate reader. Lastly, CNTF-induced anti-inflammatory responses were evaluated in hMADS adipocytes stressed with tumor necrosis factor ? (TNF?) for 24 h. Results showed that CNTFR? protein expression was higher in undifferentiated hMADS cells than in hMADS adipocytes, where it was however clearly detectable. In hMADS adipocytes, 1 nM CNTF strongly activated the JAK-STAT3 (Janus kinase-signaling transducer and activator of transcription 3) pathway and acutely and transiently activated the AMPK (AMP-activated protein kinase) and AKT (protein kinase B) pathways. Acute CNTF treatment for 20 min significantly increased basal glucose uptake and was associated with increased AKT phosphorylation. Longer-term (24 and 48 h) treatment reduced the expression of lipogenic markers (FA synthase and sterol regulatory element-binding protein-1) and increased the expression of lipolytic [hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL)] and mitochondrial (peroxisome proliferator-activated receptor ? coactivator-1? and carnitine palmitoyltransferase 1) markers. In TNF?-treated hMADS adipocytes, CNTF significantly reduced the expression of monocyte chemoattractant protein 1 and TNF?-induced AKT inhibition. Collectively, these findings demonstrate for the first time that CNTF plays a role also in human adipocytes, driving their metabolism toward a less lipid-storing and more energy-consuming phenotype.

Project description:Despite treatment with agents that enhance beta-cell function and insulin action, reduction in beta-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3beta (Gsk-3beta). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3beta to regulation of beta-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/-) exhibit insulin resistance and a doubling of beta-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3beta (Gsk-3beta+/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced beta-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2-/-), like the Ir+/- mice, are insulin resistant, but develop profound beta-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3beta activity associated with a marked reduction of beta-cell proliferation and increased apoptosis. Irs2-/- mice crossed with Gsk-3beta+/- mice preserved beta-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2-/- mice had increased cyclin-dependent kinase inhibitor p27(kip1) that was limiting for beta-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of beta-cell mass in Gsk-3beta+/- Irs2-/- mice was accompanied by suppressed p27(kip1) levels and increased Pdx1 levels. To separate peripheral versus beta-cell-specific effects of reduction of Gsk3beta activity on preservation of beta-cell mass, mice homozygous for a floxed Gsk-3beta allele (Gsk-3(F/F)) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce beta-cell-specific knockout of Gsk-3beta (betaGsk-3beta-/-). Like Gsk-3beta+/- mice, betaGsk-3beta-/- mice also prevented the diabetes of the Irs2-/- mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within beta-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of beta-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve beta-cells and prevent diabetes onset.

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Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.

Publications

Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.

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