The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

Chronic unpredictable stress and long-term ovariectomy affect arginine-vasopressin expression in the paraventricular nucleus of adult female mice

Arginine-Vasopressin (AVP) may regulate the hypothalamic-pituitary-adrenal axis (HPA) and its effects on depressive responses. In a recent study, we demonstrated that Chronic Unpredictable Stress (CUS) depressive effects are enhanced by long-term ovariectomy (a model of post-menopause). In the present study, we investigated the effects of long-term ovariectomy and CUS on AVP expression in different subdivision of the paraventricular nucleus (PVN) of female mice. Both long-term ovariectomy and CUS affect AVP immunoreactivity in some of the PVN subnuclei of adult female mice. In particular, significant changes on AVP immunoreactivity were observed in magnocellular subdivisions, the paraventricular lateral magnocellular (PaLM) and the paraventricular medial magnocellular (PaMM), the 2 subnuclei projecting to the neurohypophysis for the hormonal regulation of body homeostasis. AVP immunoreactivity was decreased in the PaLM by both the long-term deprivation of ovarian hormones and the CUS. In contrast, AVP immunoreactivity was increased in the PaMM by CUS, whereas it was decreased by ovariectomy. Therefore, present results suggest morphological and functional differences among the PVN's subnuclei and complex interactions among CUS, gonadal hormones and AVP immunoreactivity.Depto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEpu

Liraglutide Enhances the Activity of the ACE-2/Ang(1–7)/Mas Receptor Pathway in Lungs of Male Pups from Food-Restricted Mothers and Prevents the Reduction of SP-A

In utero growth restriction and being born small for gestational age are risk factors for respiratory morbidity. IUGR (in utero growth retardation) is associated to overall reduction in lung weight, surfactant content and activity, impaired maturation of the alveolar type II cells, and decreased alveolar formation. The renin-angiotensin system (RAS) may be a key target underlying pathophysiological lung alterations. GLP-1 and agonists of its receptor modulate the expression levels of different components of RAS and also are very important for lung maturation and the production of surfactant proteins. The aim of this study was to elucidate the effects of IUGR induced by perinatal food restriction of the mother in the lung function of pups at early stages of life (PD21) and to determine if liraglutide had any effect during gestational period. Sprague-Dawley pregnant rats were randomly assigned to 50% food restriction (MPFR) or ad libitum control (CT) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant MPFR and CT rats were treated with liraglutide or vehicle. At postnatal day 21 and before weaning, 20 CT and 20 FR male pups were sacrificed and lungs were analyzed by RT-PCR. Liraglutide restored surfactant protein A (SP-A) mRNA expression in pup lungs from food-restricted mothers. Surfactant protein B (SP-B) mRNA expression is not affected by neither IUGR nor liraglutide treatment. Moreover, liraglutide modulated different elements of RAS, increasing angiotensin-converting enzyme 2 (ACE2) and MasR mRNA expression only in pups from food-restricted mothers (MPFR), despite food restriction had not any direct effect at this early stage. Liraglutide also increased endothelial nitric oxide synthase (eNOS) expression in MPFR lungs, reflecting the activation of MasR by angiotensin 1–7. In conclusion, liraglutide prevented the alteration in lung function induced by IUGR and promoted the positive effects of ACE2-Ang(1–7)-MasR in restoring lung function

Supplementary Material for: Short-Term High-Fat Diet Feeding Provides Hypothalamic but Not Hippocampal Protection against Acute Infection in Male Mice

<p>Obesity is associated with increased fever and sickness behavior in response to infection. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the reaction to immune stimuli. Bacterial infection, or bacterial lipopolysaccharide (LPS), induces the expression of peripheral cytokines that stimulate the hypothalamus and the hippocampus and activate the HPA axis. In this study, we explored whether the hypothalamic and hippocampal responses to infection are altered during the development of diet-induced obesity. Male mice were exposed to a high-fat diet (HFD) or a low-fat diet (LFD) for 15 days. They were then administered a single intraperitoneal injection of bacterial LPS or vehicle and sacrificed 24 h later. LPS increased circulating levels of insulin and leptin, but only in LFD animals. LPS induced a significant decrease in hypothalamic corticotrophin-releasing hormone and glucocorticoid receptor mRNA levels in LFD animals but exerted the opposite effect in HFD-fed mice. LPS increased the hypothalamic expression of molecules involved in the leptin signaling pathway (SOCS3 and STAT3), nuclear factor-κB pathway members, inflammatory mediators (tumor necrosis factor-a and interleukin-6) and glial proliferation markers (Emr1 and CD68) in LFD animals. These effects were dampened in HFD-fed mice. In contrast, the hippocampal responses to LPS were largely insensitive to HFD. These results suggest that HFD feeding reduced the inflammatory response induced by LPS in the hypothalamus but not in the hippocampus.</p

Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a "thrifty gene".

International audienceUsing pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the mu-opioid receptor (MOR) gene (MOR-/-), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR-/- mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR-/- mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets

The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.

OBJECTIVES: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. METHODS: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1(-/-)) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. RESULTS: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1(-/-) mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1(-/-) mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1(-/-) mice. CONCLUSIONS: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity