Alterations in hypothalamus–pituitary–adrenal (HPA) axis activity have been linked to the development of the metabolic syndrome (MetS). Common features of the MetS, like insulin resistance and obesity, are reproducibly induced by high fat diet (HFD) in animal models of diet-induced obesity. These models, hampered by methodological differences, reveal conflicting results with respect to HPA axis activation. This study was aimed to evaluate in detail nonstressed diurnal HPA axis activity in mice during obesity development. Male C57Bl/6J mice were fed high or low fat diet for 12 weeks. HPA axis activity was evaluated by plasma corticosterone concentrations (at 0700, 1200, and 1800 h), corticotropin-releasing hormone (CRH), and glucocorticoid receptor (GR) mRNA expression in the hippocampus, amygdala, and hypothalamus, and 11β-hydroxysteroid dehydrogenase type-1 and -2 (11β-HSD-1 and -2) expression in adipose tissue and liver. Within 1 week, the HFD induced obesity and decreased corticosterone levels at 1200 and 1800 h, which persisted throughout the experiment. Twelve weeks of HFD decreased CRH mRNA in the paraventricular nucleus (PVN) and amygdala and GR mRNA in the PVN at 0900 h. At 1800 h, CRH mRNA expression increased in the PVN and amygdala, and GR mRNA increased in the CA1 region. 11β-HSD-1 expressions decreased in gonadal, visceral, and subcutaneous adipose tissues at 0900 and 1800 h, whereas hepatic 11β-HSD-1 expression increased at 1800 h, whereas 11β-HSD-2 expression was unaffected. The HFD induces complex changes in the diurnal regulation of the different components of the HPA axis. These changes are not unequivocally characterized by increased, but rather by decreased HPA axis activity.
Hanna E Auvinen, Johannes A Romijn, Nienke R Biermasz, Hanno Pijl, Louis M Havekes, Johannes W A Smit, Patrick C N Rensen and Alberto M Pereira
Dieuwertje C E Spaanderman, Mark Nixon, Jacobus C Buurstede, Hetty H C M Sips, Maaike Schilperoort, Eline N Kuipers, Emma A Backer, Sander Kooijman, Patrick C N Rensen, Natalie Z M Homer, Brian R Walker, Onno C Meijer and Jan Kroon
Glucocorticoid signaling is context dependent, and in certain scenarios, glucocorticoid receptors (GRs) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk between glucocorticoids and androgens in metabolic tissues including white adipose tissue, liver and brown adipose tissue. Thereto we exposed male C57BL/6J mice to elevated levels of corticosterone in combination with an androgen receptor (AR) agonist or an AR antagonist. Systemic and local glucocorticoid levels were determined by mass spectrometry, and tissue expression of glucocorticoid-responsive genes and protein was measured by RT-qPCR and Western blot, respectively. To evaluate crosstalk in vitro, cultured white and brown adipocytes were exposed to a combination of corticosterone and an AR agonist. We found that AR agonism potentiated transcriptional response to GR in vitro in white and brown adipocytes and in vivo in white and brown adipose tissues. Conversely, AR antagonism substantially attenuated glucocorticoid signaling in white adipose tissue and liver. In white adipose tissue, this effect could partially be attributed to decreased 11B-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid regeneration upon AR antagonism. In liver, attenuated GR activity was independent of active glucocorticoid ligand levels. We conclude that androgen signaling modulates GR transcriptional output in a tissue-specific manner.
Hannah M Eggink, Lauren L Tambyrajah, Rosa van den Berg, Isabel M Mol, Jose K van den Heuvel, Martijn Koehorst, Albert K Groen, Anita Boelen, Andries Kalsbeek, Johannes A Romijn, Patrick C N Rensen, Sander Kooijman and Maarten R Soeters
Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (i.c.v.) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic i.c.v. infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps. We found that i.c.v. administration of tLCA (final concentration in cerebrospinal fluid: 1 μM) increased fat oxidation (tLCA group: 0.083 ± 0.006 vs control group: 0.036 ± 0.023 kcal/h, F = 5.46, P = 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35 ± 0.13 vs controls: 1.96 ± 0.23 g, P = 0.03). These changes were associated with enhanced uptake of triglyceride-derived fatty acids by brown adipose tissue and with browning of subcutaneous white adipose tissue. I.c.v. administration of GW4064 (final concentration in cerebrospinal fluid: 10 μM) did not affect energy metabolism, body composition nor bile acid levels, negating a role of FXR in the central nervous system in metabolic control. In conclusion, bile acids such as tLCA may exert metabolic effects on fat metabolism via the brain.