Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.ISSN:0092-8674ISSN:1097-417

Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding

Objective: The critical role of adipose tissue in energy and nutrient homeostasis is influenced by many external factors, including overnutrition, inflammation, and exogenous hormones. Prior studies have suggested that glucocorticoids (GCs) in particular are major drivers of physiological and pathophysiological changes in adipocytes. In order to determine whether these effects directly require the glucocorticoid receptor (GR) within adipocytes, we generated adipocyte-specific GR knockout (AGRKO) mice. Methods: AGRKO and control mice were fed chow or high fat diet (HFD) for 14 weeks. Alternatively, AGRKO and control mice were injected with dexamethasone for two months. Glucose tolerance, insulin sensitivity, adiposity, lipolysis, thermogenesis, and insulin signaling were assessed. Results: We find that obesity, insulin resistance, and dysglycemia associated with high fat feeding do not require an intact GR in the adipocyte. However, exogenous dexamethasone (Dex) promotes metabolic dysfunction in mice, and this effect is reduced in mice lacking GR in adipocytes. The ability of Dex to promote “whitening” of brown fat is also reduced in these animals. We also show that GR is required for β-adrenergic and cold stimulation-mediated lipolysis via expression of the key lipolytic enzyme ATGL. Conclusion:s Our data suggest that the GR plays a role in normal adipose physiology via effects on lipolysis and mediates at least some of the adverse effects of exogenous steroids on metabolic function. The data also indicate that intra-adipocyte GR plays less of a role than previously believed in the local and systemic pathology associated with overnutrition

Detection of District Heating Pipe Network Leakage Fault Using UCB Arm Selection Method

District heating networks make up an important public energy service, in which leakage is the main problem affecting the safety of pipeline network operation. This paper proposes a Leakage Fault Detection (LFD) method based on the Linear Upper Confidence Bound (LinUCB) which is used for arm selection in the Contextual Bandit (CB) algorithm. With data collected from end-users’ pressure and flow information in the simulation model, the LinUCB method is adopted to locate the leakage faults. Firstly, we use a hydraulic simulation model to simulate all failure conditions that can occur in the network, and these change rate vectors of observed data form a dataset. Secondly, the LinUCB method is used to train an agent for the arm selection, and the outcome of arm selection is the leaking pipe label. Thirdly, the experiment results show that this method can detect the leaking pipe accurately and effectively. Furthermore, it allows operators to evaluate the system performance, supports troubleshooting of decision mechanisms, and provides guidance in the arrangement of maintenance

Impact of caregivers' psychological and caregiving status on recruitment, conversion, and retention in stem cell therapy trials for cerebral palsy: A prospective survey analysis

Abstract Aim To examine specific correlates that may affect retention outcomes of neural stem cell therapy trials in families screened for cerebral palsy. Design A prospective correlational study. Methods Primary caregivers completed surveys of psychological resilience, care burden and family caregiver tasks. The overall data and differences between groups were analysed and compared. Results Resilience was negatively correlated with the care ability and closely related to the monthly household income and educational level of the caregivers. Factors affecting the final retention rate included the type of disease, number of combined disorders, monthly household income, primary caregivers' education level and resilience. Conclusion Economic level, literacy and psychological status may affect trial retention. These findings can provide tips for preparing for subsequent screening, identification and intervention in stem cell clinical trials. Implication for the Profession and/or Patient Care The study results may provide nursing care tips to make recruitment more efficient, reduce trial costs, support patient‐centredness and accelerate trial progress. No Patient or Public Contribution The target population involves the primary caregivers of children living with cerebral palsy. However, neither patients nor the public contributed to the design or conduct of the study, analysis, or interpretation of the data, or preparation of the manuscript

Administration of uric acid to mice results in an abnormal response to glucose.

<p>(<b>A</b>) Serum uric acid levels of mice were significantly increased after daily injection of uric acid (250 mg/kg) for 4 weeks. (<b>B</b>) This figure showed the results of glucose tolerance test. The glucose tolerance test (2 mg/kg) led to significantly elevated blood glucose levels in hyperuricemic mice compared to controls. (<b>C</b>) This figure showed the results of insulin tolerance test. In the insulin tolerance test (0.75 U/kg), there was no difference in blood glucose levels between hyperuricemic mice and control mice. (<b>D</b>) Plasma insulin level was significantly lower in hyperuricemic mice at 30 min than in the control group. (<b>E</b>) Immunohistology using antibody to insulin showed reduced insulin content in islets from hyperuricemic mice compared with that of control mice (original magnification,×200). (<b>F</b>) Fold changes in insulin content were determined in hyperuricemic mice and control mice. Insulin content was significantly reduced in hyperuricemic mice. (<b>G</b>) Fold changes in islet area were determined in hyperuricemic mice and control mice. Islet area was significantly reduced in hyperuricemic mice. *<i>P</i><0.05, **<i>P</i><0.01.</p

Uric acid causes excessive nitric oxide production in pancreatic β-cells via the NF-κB signaling pathway.

<p>(<b>A</b>) The NO content, determined by a Griess assay kit, of Min6 cells treated with different concentrations of uric acid. NO production increased in a concentration-dependent manner. (<b>B</b>) Uric acid treatment of Min6 cells induced an increase in iNOS mRNA levels, as detected by RT-PCR. This effect was reversed by 50 µmol/L benzbromarone. (<b>C</b>) 5 µmol/L BAY 11–7082 also reversed the uric acid-induced increase in iNOS mRNA levels. **<i>P</i><0.01.</p

Uric acid treatment decreases glucose-stimulated insulin secretion.

<p>(<b>A</b>) Min6 cells were treated with uric acid (5 mg/dL), uric acid+benzbromarone (50 µmol/L), uric acid+BAY 11–7082 (5 µmol/L), or uric acid+L-NMMA (1 mmol/L) for 24 h. (<b>B</b>) Isolated mouse islets (eight islets per well) were treated as above. After incubation for 1 h in glucose-free KRB buffer, Min6 cells or mouse islets were treated for 1 h with KRB buffer containing low (3.3 mmol/L) or high (16.7 mmol/L) concentrations of glucose, and the supernatant fractions were collected for insulin concentration analysis. Uric acid treatment reduced glucose-stimulated insulin secretion by both Min6 cells and islets, and in both cases insulin secretion was restored by all three inhibitors. *<i>P</i><0.05, **<i>P</i><0.01.</p

Uric acid activates the NF-κB signaling pathway in pancreatic β-cells.

<p>(<b>A</b>) Treatment of Min6 cells with 5 mg/dL uric acid for 24 h upregulated NF-κB transcriptional activity, as detected by a luciferase reporter assay. The uric acid-induced increase in NF-κB transcriptional activity was reversed by benzbromarone. (<b>B</b>) IκBα phosphorylation, detected by Western blotting, increased in a time-dependent manner in Min6 cells stimulated with 5 mg/dL uric acid at 60 mins. (<b>C</b>) Benzbromarone (50 µmol/L) reversed the uric acid-induced increase in IκB phosphorylation. (<b>D</b>) Total p65 protein levels in Min6 cells, detected by Western blotting, were unaffected by treatment with different concentrations of uric acid. **<i>P</i><0.01.</p