Abstract
Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy) with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (−6.9±1.6% vs. −3.1±2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (−32.2±3.1% vs. −20.8±6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment.
Highlights
Granulocyte-colony stimulating factor (G-CSF) is a cytokine found in vertebrates that primarily acts as a regulator in the formation and development of neutrophils [1]
During the 8 weeks after treatment with G-CSF or saline, body weights gradually decreased in both Otsuka-Long-Evans-Tokushima fatty (OLETF) and Long-Evans Tokushima (LETO) rats; greater body weight reductions were observed in the G-CSF/ OLETF than in the saline/OLETF 4 weeks after treatment
G-CSF is a member of the class-1 cytokine superfamily, many other members of which are known to play a role in energy homeostasis, and its intracellular signal pathways are similar to many cytokines that have known anti-obesity effects [1,2,11]
Summary
Granulocyte-colony stimulating factor (G-CSF) is a cytokine found in vertebrates that primarily acts as a regulator in the formation and development of neutrophils [1]. Many members of this superfamily have anti-obesity properties that take effect through changing appetite, energy expenditure or adipose tissue development Such cytokines include granulocyte monocyte colonystimulating factor (GM-CSF), ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and leptin [2,3,4,5,6,7,8,9]. The molecular structure and intracellular signaling pathway of G-CSF receptors (G-CSFR) are similar to those of leptin, CNTF, LIF and IL-6 receptors [2,10] Their intracellular signaling pathway commonly includes Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK), which are associated with appetite, adipose tissue development and energy homeostasis [2,11,12,13]. We hypothesized that G-CSF might play a role in regulating energy homeostasis and body weight
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