It is currently accepted that neuro-immuno-endocrine disorders can play a role in obesity, hypertension, and insulin resistance, and that neuro-immuno-endocrine dysfunction is associated with abnormalities in the inflammatory response or with the local over-activity of pro-inflammatory factors [
13]. The high systemic levels of IL-6 and CRP in the obese animals of the present study, together with the high concentration of IL-1β also found in this animal model [
35], confirm the low-grade inflammation that occurs in MS [
4‐
6,
36]. Similar results for CRP and IL-6 have been reported in the literature, also in Zucker diabetic rats [
8,
9]. In addition to their "inflammatory status", our obese animals presented a state of hyperglycaemia and systemic stress manifest in their higher concentrations of glucose and NA compared with the lean rats used as controls. We found no differences, however, in CTC concentrations, probably because of the Zucker strain's surprisingly high concentration of this hormone (and of IL-6), which could indicate that this strain has a dysregulated IL-6-CTC loop.
It has been reported that NA affects IL-6 release, in both inhibition and activation [
17,
18]. Although a different behaviour in pathological conditions such as MS cannot be ruled out, in healthy individuals NA generally causes decreases/increases in the systemic concentrations of inflammatory/anti-inflammatory cytokines, respectively [
12,
37]. Also IL-6, together with IL-1β, can stimulate the HPA axis and the SNS, and therefore the release of NA and glucocorticoids [
38,
11,
12]. The stress system activated by the immune system thus stimulates a negative feedback mechanism that protects the organism from an excess of inflammatory proteins. Nonetheless, under conditions of stress and in pathological inflammatory conditions, NA may induce a rise in the systemic levels of IL-6 [
39]. The high levels of NA and IL-6 (and IL-1β [
35]) found in obese animals may reflect defective regulation of the negative inflammatory/stress feedback loop in MS - a physiological state that may in turn be either the cause or the consequence of the diabetes associated with obesity. Although the CTC levels determined in this study do not allow us to clearly conclude that the inflammatory cytokine-HPA axis feedback is dysregulated in obesity, the results do suggest reduced responsiveness to high levels of IL-6 in corticosterone release in the obese Zucker rats.
The multifunctional cytokine IL-6 is clearly involved in the regulation of metabolism, with confirmation of the link between obesity and inflammation [
40‐
42]. Although IL-6 has traditionally been reported to play an important role in the pathogenesis of coronary artery disease and atherosclesoris, the possibility that IL-6 has many beneficial effects on health has been put forward recently. In this sense, IL-6 should not be considered good or bad, but as a molecule with both beneficial (particularly during exercise as discussed below) and destructive effects [
43]. The release of IL-6 into the systemic circulation, and the fact that this release was observed to be greater in the obese Zucker rats, lends support to a recent suggestion that IL-6 plays a role as a systemic regulator of body weight and lipid metabolism [
42]. There is still considerable controversy, however, about the effects of raised systemic levels of IL-6. A few years ago, this situation was linked to the development of diabetes, hypertension, and hyperlipidaemia [
40]. Thus, it has been suggested that circulating IL-6 plays an important role in the development of insulin resistance [
44] and atherosclerosis through its effects on metabolism: reducing hepatic insulin sensitivity and glucose uptake by adipocytes, and causing raised plasma insulin levels, hyperglycaemia, and hyperlipidaemia (reviewed by Eder and co-workers [
42]). Other studies argue for IL-6 having a lipolytic role [
45‐
47,
27], with its participation in lipolysis and fat oxidation [
46,
48]. The controversy was sharpened with the observation that IL-6 knock-out mice develop mature-onset obesity, with hypertriglyceridaemia, glucose intolerance, and other features of MS [
45] and the contrary results of a subsequent study [
49] which observed no such phenomenon, probably because the comparison was made with different control strains [
42]. It is now known that the cellular response to IL-6 depends on the metabolic state of the cell as well as on a combination of other external stimuli [
50,
51]. Therefore, to help resolve this controversy concerning the inflammatory (pro- or anti-inflammatory) and endocrine (whether or not inducive of insulin resistance, and therefore hypo-or hyper-glycaemic) effects of IL-6 in MS, it is vital to clarify whether inflammation is the cause or the consequence of metabolic dysregulation. In view of the overall results of the present study on the systemic levels of stress and inflammation markers, in our opinion it would be most plausible to hypothesize that elevated circulating levels of IL-6 and NA are the origin (and a good marker) of metabolic and "stress/neuroendocrine" inflammatory dysregulation in MS. The elevation of IL-6 would induce increased systemic release of NA (and probably of CTC also), which in turn could stimulate (or at least not inhibit) the release of IL-6 (or
vice versa), and both NA and IL-6 might stimulate the release of glucose into the bloodstream. Elevated levels of IL-6 would also induce an increased hepatic release of CRP, a manifestation of pro-inflammatory status in MS. Therefore, this experimental model of MS presents, in addition to a hyperglycaemic state, a dysregulated inflammatory, neuroendocrine, and stress feedback system. Such dysregulation has already been indicated as present in other diseases of an inflammatory nature, with involvement of the inflammatory cytokines, catecholamines, and glucocorticoids released through the activation of the SNS and the HPA axis [
12,
39,
11].