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Objective Rats were exposed to free‐choice diets (fat plus one of two different sugar solutions, glucose or sucrose), and the metabolic consequences and impact on locomotor activity and anxiety‐like behavior were explored. Methods For 3 weeks, 7‐week‐old male rats were offered either chow only or free‐choice high‐fat diets differing in their added sugar: no sugar, sucrose, or glucose. In a second experiment, after 2 weeks on the diets, rats were switched from high sucrose to high glucose for two additional weeks. Metabolic end points included body weight, food intake, food choice, glycemic control, metabolic hormones, fat pad weight, brown adipose tissue weight, and gene expression. Behavioral analysis included locomotor and anxiety‐like activity in the open field and elevated plus maze. Results Both sugar diets enhanced adiposity and induced hyperphagia, favoring unhealthier dietary selection above that of the control diets (chow or free‐choice high‐fat with no sugar). Despite isocaloric intake in the sugar‐containing diets, offering glucose instead of sucrose was associated with improved insulin sensitivity. The sugar‐containing diets reduced activity (but with movements of increased velocity) and induced an anxiety‐like phenotype. Conclusions Although free‐choice diets negatively impacted on metabolism and anxiety‐like behavior, replacing sucrose with glucose improved insulin sensitivity and may therefore be better for health.

Significance The only known homeostatic regulator of fat mass is the leptin system. We hypothesized that there is a second homeostat regulating body weight with an impact on fat mass. In this study we have added and removed weight loads from experimental animals and measured the effects on the biological body weight. The results demonstrate that there is a body weight homeostat that regulates fat mass independently of leptin. As the body weight-reducing effect of increased loading was dependent on osteocytes, we propose that there is a sensor for body weight in the long bones of the lower extremities acting as “body scales.” This is part of a body weight homeostat, “gravitostat,” that keeps body weight and body fat mass constant., Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass.

Previous studies have shown that mice lacking interleukin-6 (IL-6), an important cytokine in the immune system, develop obesity, and that central, but not peripheral, administration of IL-6 induces energy expenditure. These findings suggest that IL-6 suppresses fat mass through the central nervous system. The mechanism behind this, however, is not understood. The aim of this thesis was to investigate possible neurobiological mechanisms, by which IL-6, during health, could exert its fat suppressing effect. Using immunohistochemistry, we aimed to map the distribution of the IL-6 receptor α (IL-6Rα) in human and mouse hypothalamus. In IL-6 knockout mice, we measured the gene expression of key hypothalamic neuropeptides known to regulate energy homeostasis. In mice, IL-6Rα was present mainly on neurons, and was widely distributed throughout the hypothalamus. IL-6Rα was found in a large number of neurons in the fat suppressing arcuate nucleus (ARC) and paraventricular nucleus (PVN), as well as in the fat promoting lateral hypothalamic area (LHA). We also found the IL-6Rα to be co-localized with several energy balance regulating neuropeptides in these hypothalamic sites, for instance with orexin and melanin concentrating hormone (MCH) in the LHA. In humans, IL-6Rα was only found in MCH neurons, but virtually all MCH neurons contained IL-6Rα. Depletion of IL-6 reduced the expression of the fat suppressing neuropeptides corticotrophin-releasing hormone (CRH) and oxytocin, as well as of arginine-vasopressin (AVP). In addition, we found IL-6Rα on neurons that produce these neuropeptides. This indicates that IL-6 could directly act on these neurons to increase the expression of CRH, oxytocin and AVP. Depletion of IL-6 induced the expression of the fat suppressing cytokine IL-1. In addition, IL-6 expression was reduced in mice with IL-1 receptor 1 knockout. This indicates that, in the hypothalamus, IL-1 receptor 1 signaling increase IL-6 expression, while IL-6 decreases IL-1 expression. Based on our findings in this thesis we speculate that IL-6 could act on several hypothalamic neurons and sites involved in energy homeostasis to increase energy expenditure and eventually weight loss in mice, while a similar effect could by exerted via the pro-obesity neuropeptide MCH in humans. Previous studies show that gut microbiota contributes to obesity, in part by facilitating nutritional uptake, but probably also through other mechanisms. We aimed to investigate possible effects of gut microbiota on central energy balance regulation. We measured the gene expression of several important energy balance regulating neuropeptides in the hypothalamus and brainstem of germ free mice. The fat suppressing neuropeptides glucagon-like peptide-1(GLP-1) and brain-derived neurotrophic factor (BDNF) was downregulated in the presence of gut microbiota, which could explain the elevated fat mass. In addition, we found that mice with gut microbiota were less sensitive to leptin, providing another mechanism by which gut microbiota could increase fat mass. In conclution, our findings are in line the assumption that components of the immune system and the commensal gut microbiota can affect fat mass in part via energy balance-regulating circuits in the brain.