Different Responses to a High-Fat Diet in IL-6 Conditional Knockout Mice Driven by Constitutive GFAP-Cre and Synapsin 1-Cre Expression

Background/Aims: Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, at least in part through actions in the central nervous system (CNS) from local sources. Methods: We herewith report results obtained in conditional IL-6 KO mice for brain cells (Il6(Delta Gfap) and Il6(Delta Syn)). Results: The reporter RiboTag mouse line demonstrated specific astrocytic expression of GFAP-dependent Cre in the hypothalamus but not in other brain areas, whereas that of synapsin 1-dependent Cre was specific for neurons. Feeding a high-fat diet (HFD) or a control diet showed that Il6(Delta Gfap) and Il6(Delta Syn) mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6(Delta Syn) male mice following a 24-h fast. HFD increased circulating insulin, leptin, and cholesterol levels, decreased triglycerides, and caused impaired responses to the insulin and glucose tolerance tests. In Il6(Delta Gfap) mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6(Delta Syn) mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6(Delta Gfap), and increased in Il6(Delta Syn) female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6(Delta Syn) mice and even increased in Il6(Delta Gfap)male mice. Microarray analysis of hypothalamic RNA showed that female Il6(Delta Gfap) mice had increased interferon-related pathways and affected processes in behavior, modulation of chemical synaptic transmission, learning, and memory. Conclusion: The present results demonstrate that brain production of IL-6 regulates body weight in the context of caloric excess and that the cellular source is critical.