In this report, we provide evidence that IL-7 targets hypothalamic brain areas to regulate body weight and feeding behavior. IL-7 not only protected from obesity development but also reduced food intake by directly targeting the hypothalamus, and more precisely the ARC. This work and our recent description of a new role of IL-7 in the regulation of energy homeostasis (Wolowczuk et al. submitted) identify the novel role for this cytokine in body weight and metabolic regulation.
Interestingly, while as previously described, MSG treatment was associated to significant neural cell-loss in the ARC leading to the obesity development, a single injection of IL-7 completely protected the mice from gaining weight. Moreover, IL-7 treatment also greatly improved obesity-associated disorders with a complete restoration of insulin sensitivity, and a partial improvement of the glucose tolerance in adulthood. These metabolic changes were associated with a partial protection of the mediobasal part of the ARC, where are located NP-Y and somatostatin neurons 
, underlying a potential central role of IL-7. This protection was correlated with the pro-survival effects of IL-7 on neural cells since we showed that a single injection of IL-7 was sufficient to increase neural cell-survival without affecting their proliferation rate. In accordance with its pro-survival effects on lymphocytes 
, IL-7 might exert its neural protective role through the up-regulation of the anti-apoptotic factor bcl-2, and thus counteract or compensate for bcl-2 down-regulation in MSG-induced apoptosis 
. However, despite this central effect, a peripheral role of IL-7 in the protection against MSG-induced obesity and metabolic alterations could not be excluded. Indeed, a protective effect by targeting the white adipose tissue was previously described with the pro-inflammatory cytokine IL-1 
and our previous report showed the critical role of IL-7 on white adipose tissue (Wolowczuk et al
Here we demonstrate that IL-7 has a central hypothalamic effect. Indeed, as mentioned earlier, a single injection of IL-7 was sufficient to trigger neuronal activation in the adult mice ARC, but we also showed that IL-7 induced the expression of the early activation marker c-Fos in the ventromedial area of the ARC. As c-Fos activation might involve multisynaptic neuronal relay 
, its expression can be due to a direct but also by an indirect effect of IL-7. However, the direct effect was strengthened by our demonstration of the presence of both chains of the IL-7 receptor in this area, respectively the IL-7Rα and the γc
chains, distributed in the ventromedial part of the ARC and in the median eminence. IL-7 signaling during B and T lymphopoiesis involves primarily STAT5 phosphorylation 
, although a specific role for STAT3 phosphorylation has been reported in mediating early B-cell progenitor survival 
. Based on the knowledge that IL-7R (our results) and STAT5 
are present in hypothalamic neurons, we asked whether STAT5A/B and/or STAT3 contributed to IL-7-mediated regulation of hypothalamic arcuate nucleus cells. Interestingly, we showed that while IL-7 administration did not modify STAT5 activation when compared with PBS-treated animals, it significantly increased the number of p-STAT3-IR cells. Although IL-7R signaling is known to induce STAT1, STAT3 and STAT5 phosphorylation 
, our results suggest that STAT3 plays the dominant role in IL-7-mediated arcuate nucleus neuronal activation and/or survival. This result is similar to the reported effects of leptin in hypothalamic neurons in which it induced STAT3 phosphorylation through leptin receptor prior to c-Fos induced expression 
. Strikingly, IL-7-treatment induced the expression of c-Fos in the ventromedial part of the ARC, close to the third ventricle, precisely where IL-7 induced p-STAT3 activated cells were located. The p-STAT5 staining was more homogeneously distributed in this area, with a highest number of p-STAT5-IR cells located caudally in the dorsal ARC. Altogether, this further supported our demonstration of a preferential activation of STAT3 in IL-7-responsive hypothalamic cells. Moreover, few p-STAT5-IR cells were also detected in paraventricular hypothalamus, periventricular nuclei and lateral hypothalamus, areas where anorexigenic and orexigenic neurons were found (data not shown).
Since the ARC modulates body weight and feeding behavior through the differential expression of anorexigenic and orexigenic neuropeptides, we further investigated the central effect of IL-7 on these key hypothalamic neuropeptides in adult mice. In condition of ad libitum
feeding with a normal chow diet, we found that a single administration of IL-7 in mice drastically increased the expression of hypothalamic POMC, a major anorexigenic neuropeptide 
without affecting food intake. However, we show that under re-feeding conditions after fasting, IL-7 treatment significantly decreased mice food intake showing the potent anorectic effect of this cytokine. Like IL-7, the mammalian target of rapamycin (mTOR) is an anti-apoptotic factor promoting cell-growth 
and regulates food intake 
. Thus, as previously reported in lymphocytes, IL-7 might mediate its central effect on neuronal cell-survival and on feeding behavior via
mTOR. Interestingly, this inhibitory effect of IL-7 on food intake was correlated with a specific inhibition of AgRP as described in a transactivation-deficient FoxO1 (F
containing protein, O
subfamily1) mutant mice 
, with no change of expression of the other key neuropeptides studied. Importantly, contrary to other cytokines described to induce anorexia secondary to nausea 
, we demonstrate that this modulation of feeding is mediated by IL-7 per se
and not by sickness.
In conclusion, we show here for the first time the potent central role of IL-7 on energy regulation by directly signaling in the ARC, key hypothalamic area controlling feeding behavior and metabolism. Our initial work, in which we used a model of IL-7 overexpressing mice 
, revealed a novel aspect of IL-7 biology, namely its role in the regulation of whole-body metabolism (Wolowczuk et al., submitted). Indeed, beside defective white adipose tissue formation and functionality in IL-7 transgenic animals, we also observed evidence of IL-7's central action. The present work furthered these initial observations, notably regarding the effects of IL-7 on the hypothalamus. Altogether, our results suggest that IL-7 acts as a novel key regulator of food intake under specific conditions like re-feeding after fasting (present paper), feeding with sucrose-enriched regimen (Viltart et al
., manuscript in preparation) or feeding with a high-fat diet (Wolowczuk et al
., submitted). We thus propose IL-7 as a new essential factor participating in the complex integration of peripheral hormonal-immune signals in the central nervous system to control body weight.
Our work thereby opens a wide avenue for identifying novel targets to improve the existing treatment and/or to develop new treatments for obesity and/or appetite disorders.