IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Abstract

<jats:p>Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.</jats:p>

Brain-Restricted Inhibition of IL-6 Trans-Signaling Mildly Affects Metabolic Consequences of Maternal Obesity in Male Offspring

“…Additionally, as mentioned above, Escrig and colleagues also observed a lower body weight in GFAPsgp130 mice on a standard diet. Even if the lower body weight was not to a significant extent, this effect was also blunted after feeding an HFD [42]. In line with Escrig et al, food intake in male mice was not altered by centrally blocking IL-6tS.…”

“…This is in accordance with findings by colleagues. Escrig et al revealed higher blood glucose levels in female GFAPsgp130 SD to SD mice, an effect that was also visible in male GFAPsgp130 mice [42]. This finding is supported by Timper et al, who revealed that central injection of IL-6 improved hepatic insulin action and glucose tolerance in obese mice [75].…”

“…Escrig et al analyzed the effects of GFAPsgp130 mice in the context of maternal high-fat diet (HFD) and Alzheimer's disease. In their study, in which they performed crossbreeding, the bodyweight of 17-month-old male and female offspring was consistently lower than the respective control group, but not to a significant extent [42]. Taking into account that Escrig et al showed similar observations, effects based on the lack of crossbreeding are unlikely.…”

Olfactory Signatures in the Food Finding Test in Mice With Normal and Alzheimer’s Disease-Pathological Aging With Special Concerns on the Effects of Social Isolation

“…In the context of aging, body weight also serves as a good indicator of the health status of the animal ( Barron et al, 2013 ). In the case of 3xTg-AD mice, we have shown that weight loss depends on intrinsic factors such as increased nocturnal activity ( Baeta-Corral et al, 2018b ) and hypermetabolic state ( Escrig et al, 2020 ) compared to age-matched NTg mice. We have also shown that weight loss is useful to monitor the aggravation of the AD-pathogenic processes ( Torres-Lista et al, 2019 ).…”

Sympathetic nerve-adipocyte interactions in response to acute stress

“…Qing and colleagues demonstrate that after acute stress sympathetic nerves induce the increase in the levels of IL-6 which leads to other pathophysiologic effects [14]. It will be interesting to determine whether sympathetic nerves are also responsible for IL-6 increase in other pathological conditions, in which the role of this cytokine is well characterized, such as Alzheimer's disease [75][76][77], Asthma [78,79], atherosclerosis [80,81], inflammatory bowel disease [82,83], nephropathy [84], liver diseases [85], and others [38] (Fig. 2).…”