Abstract
BackgroundInterleukin-6 (IL6) produced in the context of exercise acts in the hypothalamus reducing obesity-associated inflammation and restoring the control of food intake and energy expenditure. In the hippocampus, some of the beneficial actions of IL6 are attributed to its neurogenesis-inducing properties. However, in the hypothalamus, the putative neurogenic actions of IL6 have never been explored, and its potential to balance energy intake can be an approach to prevent or attenuate obesity.MethodsWild-type (WT) and IL6 knockout (KO) mice were employed to study the capacity of IL6 to induce neurogenesis. We used cell labeling with Bromodeoxyuridine (BrdU), immunofluorescence, and real-time PCR to determine the expression of markers of neurogenesis and neurotransmitters. We prepared hypothalamic neuroprogenitor cells from KO that were treated with IL6 in order to provide an ex vivo model to further characterizing the neurogenic actions of IL6 through differentiation assays. In addition, we analyzed single-cell RNA sequencing data and determined the expression of IL6 and IL6 receptor in specific cell types of the murine hypothalamus.ResultsIL6 expression in the hypothalamus is low and restricted to microglia and tanycytes, whereas IL6 receptor is expressed in microglia, ependymocytes, endothelial cells, and astrocytes. Exogenous IL6 reduces diet-induced obesity. In outbred mice, obesity-resistance is accompanied by increased expression of IL6 in the hypothalamus. IL6 induces neurogenesis-related gene expression in the hypothalamus and in neuroprogenitor cells, both from WT as well as from KO mice.ConclusionIL6 induces neurogenesis-related gene expression in the hypothalamus of WT mice. In KO mice, the neurogenic actions of IL6 are preserved; however, the appearance of new fully differentiated proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons is either delayed or disturbed.
Highlights
Interleukin-6 (IL6) produced in the context of exercise acts in the hypothalamus reducing obesityassociated inflammation and restoring the control of food intake and energy expenditure
Exogenous IL6 protects against diet-induced body mass gain The consumption of large portions of dietary fats can induce hypothalamic inflammation, affecting the function and viability of critical neurons involved in the control of caloric intake and energy expenditure [43, 44]
IL6 induces hypothalamic neurogenesis, as well as expression of neurogenesis-related transcripts in the hypothalamus we evaluated the effect of IL6 to induce the expression of neurogenesis-related genes in the hypothalamus
Summary
Interleukin-6 (IL6) produced in the context of exercise acts in the hypothalamus reducing obesityassociated inflammation and restoring the control of food intake and energy expenditure. Of the pattern of production in infectious and chronic inflammatory conditions, during exercise, IL6 is produced for a short period of time, independently of a previous stimulation by tumor necrosis factor-alpha (TNFα) and accompanied by only moderate/low increase of other inflammatory substances [14]. This particular mode of IL6 production has been shown to mediate some of the health promoting actions of exercise, such as increasing systemic insulin action [15,16,17], reducing hepatic steatosis [18], and reducing hepatic glucose production [17]
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