Background and Purpose High‐fat diet consumption results in obesity and chronic low‐grade inflammation in adipose tissue. Whereas glucocorticoid receptor (GR) antagonism reduces diet‐induced obesity, GR agonism reduces inflammation, the combination of which would be desired in a strategy to combat the metabolic syndrome. The purpose of this study was to assess the beneficial effects of the selective GR modulator C108297 on both diet‐induced weight gain and inflammation in mice and to elucidate underlying mechanisms. Experimental Approach Ten‐week‐old C57Bl/6 J mice were fed a high‐fat diet for 4 weeks while being treated with the selective GR modulator C108297, a full GR antagonist (RU486/mifepristone) or vehicle. Key Results C108297 and, to a lesser extent, mifepristone reduced body weight gain and fat mass. C108297 decreased food and fructose intake and increased lipolysis in white adipose tissue (WAT) and free fatty acid levels in plasma, resulting in decreased fat cell size and increased fatty acid oxidation. Furthermore, C108297 reduced macrophage infiltration and pro‐inflammatory cytokine expression in WAT, as well as in vitro LPS‐stimulated TNF‐α secretion in macrophage RAW 264.7 cells. However, mifepristone also increased energy expenditure, as measured by fully automatic metabolic cages, and enhanced expression of thermogenic markers in energy‐combusting brown adipose tissue (BAT) but did not affect inflammation. Conclusions and Implications C108297 attenuates obesity by reducing caloric intake and increasing lipolysis and fat oxidation, and in addition attenuates inflammation. These data suggest that selective GR modulation may be a viable strategy for the reduction of diet‐induced obesity and inflammation.
Conflicting data exist on sensitivity changes of the melanocortin system during diet-induced obesity. We hypothesized that melanocortin sensitivity depends on diet composition, in particular on the fat content rather than the level of obesity. The aim of this study was to determine the influence of diet composition on feeding responses to a melanocortin receptor agonist, using free-choice diets that differ in food components.Male Wistar rats were subjected to a chow (CHOW) diet or a free-choice (fc) diet of either chow, saturated fat and liquid sugar (fcHFHS), chow and saturated fat (fcHF), or chow and liquid sugar (fcHS) for 4 weeks. Melanocortin sensitivity was tested by measuring food intake following administration of the melanocortin 3/4 receptor agonist melanotan II (MTII) or vehicle in the lateral ventricle. In a separate experiment, proopiomelanocortin (POMC) and agouti-related protein (AgRP) mRNA levels were determined in the arcuate nucleus with in situ hybridization in rats subjected to the free-choice diets for 4 weeks.Rats on the fcHFHS diet for 4 weeks show increased caloric intake and body weight gain compared to rats on the CHOW, fcHS and fcHF diet. Caloric intake and body weight gain was comparable between rats on the fcHF, fcHS, and CHOW diet. After 4 weeks diet, POMC and AgRP mRNA levels were not different between diet groups. MTII inhibited caloric intake to a larger extent in rats on the fcHF diet compared to rats on the CHOW, fcHFHS or fcHS diet. Moreover, the fat component was the most inhibited by MTII, and the sugar component the least.Rats on the fcHF diet show stronger food intake inhibition to the melanocortin receptor agonist MTII than rats on the CHOW, fcHS, and fcHFHS diet, which is independent of caloric intake and body weight gain. Our data point toward an important role for diet composition, particularly the dietary fat content, and not obesity in the sensitivity of the melanocortin system.
Objective Butyrate exerts metabolic benefits in mice and humans, the underlying mechanisms being still unclear. We aimed to investigate the effect of butyrate on appetite and energy expenditure, and to what extent these two components contribute to the beneficial metabolic effects of butyrate. Design Acute effects of butyrate on appetite and its method of action were investigated in mice following an intragastric gavage or intravenous injection of butyrate. To study the contribution of satiety to the metabolic benefits of butyrate, mice were fed a high-fat diet with butyrate, and an additional pair-fed group was included. Mechanistic involvement of the gut-brain neural circuit was investigated in vagotomised mice. Results Acute oral, but not intravenous, butyrate administration decreased food intake, suppressed the activity of orexigenic neurons that express neuropeptide Y in the hypothalamus, and decreased neuronal activity within the nucleus tractus solitarius and dorsal vagal complex in the brainstem. Chronic butyrate supplementation prevented diet-induced obesity, hyperinsulinaemia, hypertriglyceridaemia and hepatic steatosis, largely attributed to a reduction in food intake. Butyrate also modestly promoted fat oxidation and activated brown adipose tissue (BAT), evident from increased utilisation of plasma triglyceride-derived fatty acids. This effect was not due to the reduced food intake, but explained by an increased sympathetic outflow to BAT. Subdiaphragmatic vagotomy abolished the effects of butyrate on food intake as well as the stimulation of metabolic activity in BAT. Conclusion Butyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.
Rats on different free‐choice (fc) diets for 1 week of either chow, saturated fat and liquid sugar (fc HFHS ), chow and saturated fat (fc HF ), or chow and liquid sugar (fc HS ) have differential levels of neuropeptide Y ( NPY ) m RNA in the arcuate nucleus. Because these differences were not explained by plasma leptin levels but did predict subsequent feeding behaviour, in the present study, we first examined whether leptin sensitivity could explain these differences. Second, we focused on the role of NPY on feeding behaviour, and measured NPY m RNA levels and sensitivity to NPY after 4 weeks on the different choice diets. To determine leptin sensitivity, we measured food intake after i.p. leptin or vehicle injections in male W istar rats subjected to the fc HFHS , fc HS , fc HF or Chow diets for 7 days. Next, we measured levels of arcuate nucleus NPY m RNA with in situ hybridisation in rats subjected to the choice diets for 4 weeks. Finally, we studied NPY sensitivity in rats subjected to the fc HFHS , fc HS , fc HF or Chow diet for 4 weeks by measuring food intake after administration of NPY or vehicle in the lateral ventricle. Leptin decreased caloric intake in rats on Chow , fc HS and fc HF but not in rats on the fc HFHS diet. After 4 weeks, rats on the fc HFHS diet remained hyperphagic, whereas fc HS and fc HF rats decreased caloric intake to levels similar to rats on Chow . By contrast to 1 week, after 4 weeks, levels of NPY m RNA were not different between the diet groups. Lateral ventricle administration of NPY resulted in higher caloric intake in fc HFHS rats compared to rats on the other choice diets or rats on Chow . Our data show that consuming a combination of saturated fat and liquid sugar results in leptin resistance and increased NPY sensitivity that is associated with persistent hyperphagia.
Significance Steroid hormones coordinate the activity of many brain regions by binding to nuclear receptors that act as transcription factors. This study uses genome-wide correlation of gene expression in the mouse brain to discover ( i ) brain regions that respond in a similar manner to particular steroids, ( ii ) signaling pathways that are used in a steroid receptor and brain region-specific manner, and ( iii ) potential target genes and relationships between groups of target genes. The data constitute a rich repository for the research community to support further new insights in neuroendocrine relationships and to develop novel ways to manipulate brain activity in research or clinical settings.
Adrenal glucocorticoid hormones are potent modulators of brain function in the context of acute and chronic stress. Both mineralocorticoid (MRs) and glucocorticoid receptors (GRs) can mediate these effects. We studied the brain effects of a novel ligand, C118335, with high affinity for GRs and modest affinity for MRs. In vitro profiling of receptor-coregulator interactions suggested that the compound is a “selective modulator” type compound for GRs that can have both agonistic and antagonistic effects. Its molecular profile for MRs was highly similar to those of the full antagonists spironolactone and eplerenone. C118335 showed predominantly antagonistic effects on hippocampal mRNA regulation of known glucocorticoid target genes. Likewise, systemic administration of C118335 blocked the GR-mediated posttraining corticosterone-induced enhancement of memory consolidation in an inhibitory avoidance task. Posttraining administration of C118335, however, gave a strong and dose-dependent impairment of memory consolidation that, surprisingly, reflected involvement of MRs and not GRs. Finally, C118335 treatment acutely suppressed the hypothalamus-pituitary-adrenal axis as measured by plasma corticosterone levels. Mixed GR/MR ligands, such as C118335, can be used to unravel the mechanisms of glucocorticoid signaling. The compound is also a prototype of mixed GR/MR ligands that might alleviate the harmful effects of chronic overexposure to endogenous glucocorticoids.
The incidence of obesity is closely associated with the increased intake of saturated fat and sugar-sweetened beverages, however the mechanisms that regulate the consumption of dietary fat and sugared beverages remain to be determined. We used a novel animal model of obesity that closely resembles the consumption pattern observed in humans, characterized by the abundance of readily available food items containing saturated fat and sugar. In this model, animals are provided with the choice for a fat and sugar component, in addition to a regular nutritionally balanced pellet food and water. This unique animal model with free-choice diets is not only an effective model of diet-induced obesity, but it also characterizes the snacking behavior, increased motivation and alterations in metabolic parameters that closely resemble human obesity and the metabolic syndrome. In this thesis, we show that the composition of the diet, and not the fat mass per se, is important for how the brain responds to diet-induced obesity and subsequently regulates feeding behavior. We found that especially the combination of fat and sugar (and not fat or sugar alone) leads to obesity, insensitivity to the satiety hormone leptin and increased sensitivity for the hunger peptide Neuropeptide Y (NPY). Moreover, we revealed a novel role of NPY in the brain reward center (nucleus accumbens) in the regulation of fat intake, and showed novel anatomical connections of NPY to the nucleus accumbens and how NPY in the nucleus accumbens decreases neuronal activity, leading to increased fat intake. Together, these data lead to a better understanding how the combination of fat and sugar alters certain brain regions and how these changes contribute to chronic overeating and development of obesity.
