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Differential modulation of energy balance by leptin, ciliary neurotrophic factor, and leukemia inhibitory factor gene
V Prima1, M Tennant, O S Gorbatyuk
1Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610-0266, USA.
Abstract:
Most obese animal models, whether associated with genetic, diet-induced, or age-related obesity, display pronounced leptin resistance, rendering leptin supplement therapy ineffective in treating obesity. Ciliary neurotrophic factor (CNTF) has been recently used to invoke leptin-like signaling pathways, thereby circumventing leptin resistance. In the current study, we characterize immediate and long-term molecular events in the hypothalamus of rats exposed to the sustained ectopic expression of leptin, CNTF, or leukemia inhibitory factor, another neurocytokine of IL-6 family, all delivered centrally via a viral vector. The respective transgene-encoded ligands induced similar but not identical metabolic responses as assessed by the reduction in body weight gain and changes in food intake. To define molecular mechanisms of weight-reducing and anorexigenic action of cytokines, we have analyzed the gene expression profiles of 1300 brain-specific genes in the hypothalami of normal rats subjected to the prolonged cytokine action for 10 wk. We present evidence that constitutive expression of cytokines in the brain induces changes in gene expression characteristic of chronic inflammation leading to either temporal weight reduction (CNTF) or severe cachexia (leukemia inhibitory factor). Our results convey a cautionary note regarding potential use of the tested cytokines in therapeutic applications.
Insights
Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor show potential for weight management by mimicking leptin signaling. However, sustained brain expression may cause inflammation and adverse effects, cautioning against their therapeutic use.
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Obesity is often linked to leptin resistance, limiting leptin therapy effectiveness in animal models.
- Ciliary neurotrophic factor (CNTF) offers an alternative by activating leptin-like pathways to bypass leptin resistance.
Purpose of the Study:
- To investigate the molecular effects of sustained central expression of leptin, CNTF, and leukemia inhibitory factor (LIF) in the rat hypothalamus.
- To elucidate the mechanisms behind the weight-reducing and anorexigenic actions of these cytokines.
Main Methods:
- Viral vector-mediated central delivery of transgenes encoding leptin, CNTF, and LIF in rats.
- Analysis of body weight gain and food intake to assess metabolic responses.
- Gene expression profiling of 1300 brain-specific genes in hypothalami after 10 weeks of cytokine exposure.
Main Results:
- Leptin, CNTF, and LIF induced comparable, yet distinct, metabolic effects, including reduced weight gain and altered food intake.
- Sustained cytokine expression led to gene expression changes indicative of chronic inflammation in the brain.
- CNTF resulted in temporary weight reduction, while LIF caused severe cachexia.
Conclusions:
- Constitutive brain expression of these cytokines can trigger inflammatory responses.
- While CNTF and LIF show potential for weight management, their use is cautioned due to risks of inflammation and severe cachexia.
- Further research is needed to evaluate the safety and efficacy of cytokine-based therapies for obesity.
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