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

Abstract

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 (Il6ΔGfap and Il6ΔSyn). 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 Il6ΔGfap and Il6ΔSyn mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6ΔSyn 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 Il6ΔGfap mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6ΔSyn mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6ΔGfap, and increased in Il6ΔSyn female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6ΔSyn mice and even increased in Il6ΔGfapmale mice. Microarray analysis of hypothalamic RNA showed that female Il6ΔGfap 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.

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

“…DNA recombination in liver and tail indicates a total body recombination in the germline, and these samples must be discarded. In contrast to the astrocytic and neuronal Cre models that we have used previously (Fernández‐Gayol et al, ), the microglial Cre model did not suffer of ectopic DNA recombination in noticeable amounts.…”

“…The generation of tissue/cell-specific KO mice is a very powerful approach, but a thorough assessment of specific and unspecific gene recombination derived from the Cre-lox system errors is a mandatory step (Fernández-Gayol et al, 2019;Song & Palmiter, 2018). Moreover, Cx3Cr1 CreER mice could have genetic rearrangements without any dose of TAM (Haimon et al, 2018).…”

“…As expected, most (82%) of the CD11b + alive single-cells were double positive for CX3CR1 and CD45, whereas 3.2 | Role of microglial IL-6 in some behavioral traits and in body weight growth Different studies have highlighted the role of IL-6 both in the control of body weight (Señarís et al, 2011;Wallenius et al, 2002) and behavior (Armario et al, 1998;Baier et al, 2009;Butterweck et al, 2003). The analysis of cell-specific IL-6 deficiency has shown that its source has a major impact in the phenotype of the animals, and that it is not simply a quantitative change (Erta et al, 2015;Fernández-Gayol et al, 2019;Quintana et al, 2013). Therefore, it was important to study the behavioral phenotype of Il6 ΔMic mice as well.…”

Fat food exacerbates post-prandial hypothalamic inflammation involving GFAP+ cells and microglia

“…In fact, modulation of GFAP-positive cellular activity decreases IL-6 mRNA hypothalamic levels only in HFD-treated mice. This is consistent with recent discoveries demonstrating that IL-6 produced by astrocytes is a major actor in central energy balance regulation and plays a protective role against obesity development during HFD exposure (Fernandez-Gayol et al, 2019; Quintana et al, 2013; Timper et al, 2017). On the other hand, modulation of GFAP-positive cellular activity does not dramatically affect hypothalamic neuropeptide mRNA levels and does not change HFD intake.…”

“…Interestingly, brain inflammatory responses in the HT were also observable after only one day of HFD consumption (Buckman et al, 2015) or 24h of lipid perfusion to the brain (Dalvi et al, 2017), well before the development of obesity. Moreover, inhibition of brain inflammatory responses to HFD leads to energy balance dysregulation (Buckman et al, 2015; Fernandez-Gayol et al, 2019). In humans, studies have described acute post-prandial inflammation associated to increased levels of circulating inflammatory markers in response to HFD (Emerson et al, 2017; Herieka and Erridge, 2014).…”