Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity

BACKGROUND: Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity. METHODOLOGY/PRINCIPAL FINDINGS: We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007-2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = -0.47, p = 0.010), visceral fat areas (R = -0.39, p = 0.044), visceral/total fat areas (R = -0.52, p = 0.0043) and waist circumferences (R = -0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = -0.009, p = 0.009) were the two independent predictors of BAT activities. CONCLUSIONS/SIGNIFICANCE: Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity

Tissue functions mediated by β3-adrenoceptors—findings and challenges

As β3-adrenoceptor agonists metamorphose from experimental tools into therapeutic drugs, it is vital to obtain a comprehensive picture of the cell and tissue functions mediated by this receptor subtype in humans. Human tissues with proven functions and/or a high expression of β3-adrenoceptors include the urinary bladder, the gall bladder, and other parts of the gastrointestinal tract. While several other β3-adrenoceptor functions have been proposed based on results obtained in animals, their relevance to humans remains uncertain. For instance, β3-adrenoceptors perform an important role in thermogenesis and lipolysis in rodent brown and white adipose tissue, respectively, but their role in humans appears less significant. Moreover, the use of tools such as the agonist BRL 37344 and the antagonist SR59230A to demonstrate functional involvement of β3-adrenoceptors may lead in many cases to misleading conclusions as they can also interact with other β-adrenoceptor subtypes or even non-adrenoceptor targets. In conclusion, we propose that many responses attributed to β3-adrenoceptor stimulation may need re-evaluation in the light of the development of more selective tools. Moreover, findings in experimental animals need to be extended to humans in order to better understand the potential additional indications and side effects of the β3-adrenoceptor agonists that are beginning to enter clinical medicine

The limited prosocial effects of meditation: A systematic review and meta-analysis

Many individuals believe that meditation has the capacity to not only alleviate mental-illness but to improve prosociality. This article systematically reviewed and meta-analysed the effects of meditation interventions on prosociality in randomized controlled trials of healthy adults. Five types of social behaviours were identified: compassion, empathy, aggression, connectedness and prejudice. Although we found a moderate increase in prosociality following meditation, further analysis indicated that this effect was qualified by two factors: type of prosociality and methodological quality. Meditation interventions had an effect on compassion and empathy, but not on aggression, connectedness or prejudice. We further found that compassion levels only increased under two conditions: when the teacher in the meditation intervention was a co-author in the published study; and when the study employed a passive (waiting list) control group but not an active one. Contrary to popular beliefs that meditation will lead to prosocial changes, the results of this meta-analysis showed that the effects of meditation on prosociality were qualified by the type of prosociality and methodological quality of the study. We conclude by highlighting a number of biases and theoretical problems that need addressing to improve quality of research in this area

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely: 1. the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), 2. the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently 3. the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes). This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity

The African Cichlid Fish Astatotilapia burtoni Uses Acoustic Communication for Reproduction: Sound Production, Hearing, and Behavioral Significance

Sexual reproduction in all animals depends on effective communication between signalers and receivers. Many fish species, especially the African cichlids, are well known for their bright coloration and the importance of visual signaling during courtship and mate choice, but little is known about what role acoustic communication plays during mating and how it contributes to sexual selection in this phenotypically diverse group of vertebrates. Here we examined acoustic communication during reproduction in the social cichlid fish, Astatotilapia burtoni. We characterized the sounds and associated behaviors produced by dominant males during courtship, tested for differences in hearing ability associated with female reproductive state and male social status, and then tested the hypothesis that female mate preference is influenced by male sound production. We show that dominant males produce intentional courtship sounds in close proximity to females, and that sounds are spectrally similar to their hearing abilities. Females were 2–5-fold more sensitive to low frequency sounds in the spectral range of male courtship sounds when they were sexually-receptive compared to during the mouthbrooding parental phase. Hearing thresholds were also negatively correlated with circulating sex-steroid levels in females but positively correlated in males, suggesting a potential role for steroids in reproductive-state auditory plasticity. Behavioral experiments showed that receptive females preferred to affiliate with males that were associated with playback of courtship sounds compared to noise controls, indicating that acoustic information is likely important for female mate choice. These data show for the first time in a Tanganyikan cichlid that acoustic communication is important during reproduction as part of a multimodal signaling repertoire, and that perception of auditory information changes depending on the animal's internal physiological state. Our results highlight the importance of examining non-visual sensory modalities as potential substrates for sexual selection contributing to the incredible phenotypic diversity of African cichlid fishes

Boost Camp’, a universal school-based transdiagnostic prevention program targeting adolescent emotion regulation; evaluating the effectiveness by a clustered RCT : a protocol paper

Abstract Background The transition from childhood into adolescence can be considered as a critical developmental period. Moreover, adolescence is associated with a decreased use of adaptive emotion regulation strategies and an increased use of maladaptive emotion regulation strategies increasing the risk of emotional problems. Targeting emotion regulation is therefore seen as an innovative prevention approach. The present study aims to evaluate the effectiveness of Boost camp, an innovative school-based prevention program targeting ER, on adolescents’ emotion regulation skills and emotional wellbeing. Also secondary outcomes and possible moderators will be included. Methods The aim is to reach 300 adolescents (16 class groups, 6 schools) in their first year of high school. A clustered Randomized Controlled Trial (RCT) with two conditions, intervention (n = 150) and control (n = 150), will be set up. Adolescents in the intervention condition will receive 14 lessons over the course of 2 days, followed by Booster sessions, and will be compared with adolescents in a non-intervention control group. The outcomes will be measured by self-report questionnaires at baseline, immediately after Boost camp, and at three and 6 months follow-up. Discussion Data-collection is planned to be completed in May 2018. Data-analyses will be finished the end of 2018. The presented paper describes the Boost camp program and the clustered RCT design to evaluate its effectiveness. It is expected that Boost camp will have beneficial effects. If found effective, Boost camp will have the potential to increase adolescent’s ER and well-being, and reduce the risk to become adults in need. The trials is registered on the 13th of June 2017 in ISRCTN registry [ISRCTN68235634]

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways

<p>Abstract</p> <p>Background</p> <p>Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis <it>in vivo </it>unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that <it>chronic </it>HIV-<it>replication in non-endothelial cells </it>may produce novel factors that provoke angiogenic pathways.</p> <p>Methods</p> <p>Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth <it>in vitro </it>over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses.</p> <p>Results</p> <p>By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development.</p> <p>Conclusion</p> <p>Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10^-4to 10^-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has <it>suppressed </it>VEGF/VEGFR-PTK expression and promoted <it>VEGFR-independent </it>pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies <it>in vivo </it>would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel <it>VEGF-independent </it>angiogenic pathways.</p