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  • In most chronic inflammatory conditions a network

    2019-07-08

    In most chronic inflammatory conditions, a network of cytokines and chemokines play important roles in the initiation and maintenance of the inflammatory activity [13]. With this concept in mind, we hypothesized that chemokines other than fractalkine could be induced in the hypothalamus during early diet-induced obesity and play important roles in the metabolic outcomes of obesity. To test this hypothesis, we determined the landscape of cytokines/chemokines expressed in the hypothalamus of mice fed a HFD, comparing obesity-resistant (OR) versus obesity-prone (OP) mice. We identified the decoy chemokine receptor Ackr2 as one of the transcripts with greatest difference between the two groups, becoming significantly reduced in the hypothalamus of OP mice as early as three days after the introduction of a HFD. The hypothalamic lentiviral overexpression of ACKR2 reduced diet-induced hypothalamic inflammation and reduced obesity-associated glucose intolerance. Thus, the abnormal KRN 7000 of ACKR2 in the hypothalamus of OP mice may contribute to defective whole body glucose tolerance.
    Results
    Discussion Diet-induced hypothalamic inflammation is a hallmark of experimental obesity [1,2]. Here, we investigated chemokine and chemokine-related proteins that could be involved in obesity predisposition by affecting the magnitude of the inflammatory process in the hypothalamus of mice fed a HFD. We show that ACKR2, a decoy chemokine receptor, is induced in the hypothalamus early after the introduction of a HFD both in OP and OR mice; however, in OP mice, the increment of ACKR2 is significantly smaller that in OR mice. Using a lentivirus, we obtained significant increase in hypothalamic ACKR2, which was accompanied by reduced diet-induced hypothalamic inflammation and improved systemic glucose tolerance without affecting caloric intake and body mass. ACKR2 belongs to a small subset of chemokine receptors identified as atypical chemokine receptors, hence the acronym ACKR [14]. According to the HUGO Gene Nomenclature Committee (genenames.org), currently, there are six genes encoding ACKR proteins, namely ACKR1-4, CCRL2, and PITPNM3. Recently, it has been requested that CCRL2 and PITPNM3 be renamed as ACKR5 and ACKR6, respectively, but approval is still pending [15]. Except for PITPNM3, all members of this family exhibit a predicted seven-transmembrane-domain structure; however, none of them is capable of activating signal transduction through the Gi protein [14]. The lack of chemotactic activity and the capacity of scavenging chemokines are the main functional features that characterize the ACKRs [14,15]. Particularly for ACKR2, studies have shown that it can scavenge CCL2-5, CCL3L1, CCL7-8, CCL11, CCL13-14, CCL17, and CCL22 [14,15]. As an important outcome of chemokine scavenging, reduction of inflammatory activity has been reported in different tissues and different experimental and clinical contexts [14,15]. Only a few studies have evaluated the roles of ACKR2 in neuroinflammatory conditions [16,17]. In experimental autoimmune encephalomyelitis, there are controversial data regarding the involvement of ACKR2 in the pathophysiology of the disease [16,17]. Thus, Hansell and coworkers [16] have shown that in the absence of ACKR2, mice develop a more pronounced clinical expression of the condition, which is accompanied by increased expression of IL-17 and increased number of B-lymphocytes expressing granulocyte-macrophage colony-stimulating factor, which is strongly suggestive of enhanced inflammatory activity; conversely, Liu and coworkers [17] have shown that ACKR2 knockout mice exhibit a protective phenotype against the development of autoimmune encephalomyelitis, which was characterized by attenuated interferon-gamma production. No previous study has evaluated the expression and potential roles of ACKR2 in the hypothalamus. In the present study, we showed that there were two major outcomes of the increased expression of ACKR2 in the hypothalamus of mice: i) reduction of diet-induced hypothalamic inflammation and ii) improvement of systemic glucose tolerance. As a decoy receptor that can scavenge a number of chemokines, it was expected that upon increased ACKR2 expression, the inflammatory activity in the hypothalamus could be dampened. Out of the chemokines that can potentially be scavenged by ACKR2, only two, CCL2 and CCL5, have been reported to play a role in hypothalamic function in obesity/diabetes [8,18]. CCL2 expression is increased in the hypothalamus of rodents fed a HFD [8,18] and approaches aimed at reducing the inflammatory activity, such as inhibition of fractalkine [8] or treatment with n3-polyunsaturated fatty acids (PUFAs) [18] result in the reduction of hypothalamic CCL2. Similarly, CCL5 is increased in the hypothalamus of diet-induced obese mice, and treatment with n3-PUFAs reduces its expression [18]; however, at least one study has shown that genetic disruption of the hypothalamic CCL5/CCR5 system leads to systemic glucose intolerance by a mechanism dependent on AMPK-dependent insulin sensing in the hypothalamus [19], suggesting that CCL5 has a beneficial effect on hypothalamic control of systemic metabolism. In the present experimental setting, the increased expression of ACKR2 in the hypothalamus resulted in reduction in the expression of two inflammatory cytokines, TNF-α and IL-1β; one marker of microglia, F4/80; and two markers of chemotaxis, MCP1 and the receptor for fractalkine, CX3CR1. Interestingly, the expression of IL6 was not affected by the overexpression of hypothalamic ACKR2. IL6 can have both pro- and anti-inflammatory actions depending of the anatomical region and context; and, particularly in the hypothalamus, studies have shown that IL6 can act as a protective factor against diet-induced inflammation. Thus, we believe that under increased expression of ACKR2, the fact that IL6 expression was not down-regulated could be an additional evidence of reduced inflammation.