Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-dependent transcription factor highly expressed in adipocytes, is a master regulator of adipogenesis and lipid storage, a central player ...in thermogenesis and an active modulator of lipid metabolism and insulin sensitivity. As a nuclear receptor governing numerous target genes, its specific signaling transduction relies on elegant transcriptional and post-translational regulations. Notably, in response to different metabolic stimuli, PPARγ recruits various cofactors and forms distinct transcriptional complexes that change dynamically in components and epigenetic modification to ensure specific signal transduction. Clinically, PPARγ activation via its full agonists, thiazolidinediones, has been shown to improve insulin sensitivity and induce browning of white fat, while undesirably induce weight gain, visceral obesity and other adverse effects. Thus, deciphering the combinatorial interactions between PPARγ and its transcriptional partners and their preferential regulatory network in the processes of development, function and senescence of adipocytes would provide us the molecular basis for developing novel partial agonists that promote benefits of PPARγ signaling without detrimental side effects. In this review, we discuss the dynamic components and precise regulatory mechanisms of the PPARγ-cofactors complexes in adipocytes, as well as perspectives in treating metabolic diseases via specific PPARγ signaling.
Panic buying is a common phenomenon that occurs during public emergencies and has a significant undesirable impact on society. This research explored the effect of scarcity on panic buying and the ...role of perceived control and panic in this effect through big data, an online survey and behavior experiments in a real public emergency (i.e., COVID-19) and simulative public emergencies. The findings showed that scarcity aggravates panic buying (Studies 1-3), and this aggravation effect is serially mediated by perceived control and panic (Studies 2-3). Moreover, this serial mediation model is more suitable for public health emergencies (Study 3). These findings enrich the understanding of panic buying and provide important enlightenment for guiding rational public behavior and managing public opinion during public emergencies.
Beige fat plays key roles in the regulation of systemic energy homeostasis; however, detailed mechanisms and safe strategy for its activation remain elusive. In this study, we discovered that local ...hyperthermia therapy (LHT) targeting beige fat promoted its activation in humans and mice. LHT achieved using a hydrogel-based photothermal therapy activated beige fat, preventing and treating obesity in mice without adverse effects. HSF1 is required for the effects since HSF1 deficiency blunted the metabolic benefits of LHT. HSF1 regulates Hnrnpa2b1 (A2b1) transcription, leading to increased mRNA stability of key metabolic genes. Importantly, analysis of human association studies followed by functional analysis revealed that the HSF1 gain-of-function variant p.P365T is associated with improved metabolic performance in humans and increased A2b1 transcription in mice and cells. Overall, we demonstrate that LHT offers a promising strategy against obesity by inducing beige fat activation via HSF1-A2B1 transcriptional axis.
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•Local hyperthermia therapy (LHT) induces thermogenesis in mouse and human adipocytes•HSF1 is indispensable for the effects of chronic LHT against obesity in mice•HNRNPA2B1 acts downstream of HSF1 to enhance stability of metabolic gene transcripts•A human HSF1 variant improves HNRNPA2B1 expression and measures of beige fat function
Local application of heat leads to the activation of beige fat in mice and humans, suggesting a novel approach to counter obesity.
Abstract
The kagome lattice provides a fertile platform to explore novel symmetry-breaking states. Charge-density wave (CDW) instabilities have been recently discovered in a new kagome metal family, ...commonly considered to arise from Fermi-surface instabilities. Here we report the observation of Raman-active CDW amplitude modes in CsV
3
Sb
5
, which are collective excitations typically thought to emerge out of frozen soft phonons, although phonon softening is elusive experimentally. The amplitude modes strongly hybridize with other superlattice modes, imparting them with clear temperature-dependent frequency shift and broadening, rarely seen in other known CDW materials. Both the mode mixing and the large amplitude mode frequencies suggest that the CDW exhibits the character of strong electron-phonon coupling, a regime in which phonon softening can cease to exist. Our work highlights the importance of the lattice degree of freedom in the CDW formation and points to the complex nature of the mechanism.
Significance This paper reports that the transcription factor forkhead box protein A3 (Foxa3) is directly involved in the development of age-associated obesity and insulin resistance. Mice that lack ...the Foxa3 gene remodel their fat tissues, store less fat, and burn more energy as they age. These mice also live significantly longer. We show that Foxa3 suppresses a key metabolic cofactor, PGC1α, which is involved in the gene programs that turn on energy expenditure in adipose tissues. Overall, these findings suggest that Foxa3 contributes to the increased adiposity observed during aging, and that it can be a possible target for the treatment of metabolic disorders.
Aging is associated with increased adiposity and diminished thermogenesis, but the critical transcription factors influencing these metabolic changes late in life are poorly understood. We recently demonstrated that the winged helix factor forkhead box protein A3 (Foxa3) regulates the expansion of visceral adipose tissue in high-fat diet regimens; however, whether Foxa3 also contributes to the increase in adiposity and the decrease in brown fat activity observed during the normal aging process is currently unknown. Here we report that during aging, levels of Foxa3 are significantly and selectively up-regulated in brown and inguinal white fat depots, and that midage Foxa3-null mice have increased white fat browning and thermogenic capacity, decreased adipose tissue expansion, improved insulin sensitivity, and increased longevity. Foxa3 gain-of-function and loss-of-function studies in inguinal adipose depots demonstrated a cell-autonomous function for Foxa3 in white fat tissue browning. Furthermore, our analysis revealed that the mechanisms of Foxa3 modulation of brown fat gene programs involve the suppression of peroxisome proliferator activated receptor γ coactivtor 1 α (PGC1α) levels through interference with cAMP responsive element binding protein 1-mediated transcriptional regulation of the PGC1α promoter. Overall, our data demonstrate a role for Foxa3 in energy expenditure and in age-associated metabolic disorders.
Calorie restriction (CR) and fasting are common approaches to weight reduction, but the maintenance is difficult after resuming food consumption. Meanwhile, the gut microbiome associated with energy ...harvest alters dramatically in response to nutrient deprivation. Here, we reported that CR and high-fat diet (HFD) both remodeled the gut microbiota with similar microbial composition, Parabacteroides distasonis was most significantly decreased after CR or HFD. CR altered microbiota and reprogramed metabolism, resulting in a distinct serum bile acid profile characterized by depleting the proportion of non-12α-hydroxylated bile acids, ursodeoxycholic acid and lithocholic acid. Downregulation of UCP1 expression in brown adipose tissue and decreased serum GLP-1 were observed in the weight-rebound mice. Moreover, treatment with Parabacteroides distasonis or non-12α-hydroxylated bile acids ameliorated weight regain via increased thermogenesis. Our results highlighted the gut microbiota-bile acid crosstalk in rebound weight gain and Parabacteroides distasonis as a potential probiotic to prevent rapid post-CR weight gain.
Periaxins (encoded by
) play an important role in the stabilization of peripheral nerve myelin. Mutations in
can lead to Charcot-Marie-Tooth disease type 4F (CMT4F).
In this study, we screened for
...mutations using next-generation sequencing and whole-exome sequencing in a large Chinese CMT cohort consisting of 465 unrelated index patients and 650 healthy controls. Sanger sequencing was used for the validation of all identified variants. We also reviewed all previously reported
-related CMT cases and summarized the clinical manifestations and genetic features of
-related CMTs.
The hit rate for biallelic
variants in our cohort of Chinese CMT patients was 0.43% (2/465). One patient carried a previously unreported splice-site mutation (c.25_27 + 9del) compound heterozygous with a known nonsense variant. Compiling data on CMT4F cases and
variants from the medical literature confirmed that early-onset (95.2%), distal amyotrophy or weakness (94.0%), feet deformity (75.0%), sensory impairment or sensory ataxia (65.5%), delayed motor milestones (60.7%), and spinal deformity (59.5%) are typical features for CMT4F. Less frequent features were auditory impairments, respiratory symptoms, late onset, dysarthria or hoarseness, ophthalmic problems, and central nervous system involvement. The two cases with biallelic missense mutations have later onset age than those with nonsense or frameshift mutations. We did not note clear correlations between the type and site of mutations and clinical severity or distinct constellations of symptoms.
Consistent with observations in other countries and ethnic groups,
-related CMT is rare in China. The clinical spectrum is wider than previously anticipated.
Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown ...that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.
Background
Age‐associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied ...with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain‐containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age‐associated sarcopenia and metabolic dysfunction.
Methods
The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2‐ and 24‐month‐old mice or human subjects were analysed using qRT‐PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14‐month‐old) for 4 months or in aged mice (22‐month‐old) for 1 month to systematically investigate irisin's effects on age‐associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver.
Results
We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (−3.23%, P < 0.05), muscle weights (quadriceps femoris QU: −20.05%; gastrocnemius GAS: −17.91%; tibialis anterior TA: −19.51%, all P < 0.05), fibre size (QU: P < 0.01) and worse molecular phenotypes compared with wild‐type mice. We then delivered recombinant irisin protein intraperitoneally into ageing or aged mice and found that it could improve sarcopenia with grip strength (+18.42%, P < 0.01 or +13.88%, P < 0.01), muscle weights (QU: +9.02%, P < 0.01 or +16.39%, P < 0.05), fibre size (QU: both P < 0.05) and molecular phenotypes and alleviated age‐associated fat tissues expansion, insulin resistance and hepatic steatosis (all P < 0.05), accompanied with altered gene signatures.
Conclusions
Together, this study revealed the importance of irisin in the maintenance of muscle physiology and systematic energy homeostasis during ageing and suggested a potent therapeutic strategy against age‐associated metabolic diseases via irisin administration.
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•A novelty interfacial structure of Al/Al2O3/Sn was performed by reactive air soldering, with remarkable increase in strength of joints.•An amorphous Al2O3 transient layer with ...γ-Al2O3 nanocrystallines formed between Al and Sn can strengthen the interface.•The doping route of oxygen atoms was dominated by the triple junction of the liquid-gas-solid interface.
The joining of aluminum using a metal of pure Sn as an interlayer or solder was investigated by reactive air soldering and vacuum diffusion bonding. The interfacial structure and mechanical property of the joints were examined. A nanometer-scale interlayer of amorphous Al2O3 dotted with nanocrystalline γ-Al2O3 was observed and identified at the Al/Sn interface by reactive air soldering. The shear strength of the joints (∼40 MPa) by reactive air soldering was higher than that (∼20 MPa) by vacuum diffusion bonding. The reaction and diffusion behaviors of oxygen dopants at the Al/Sn interface were studied through geometry optimization and a transition state search, respectively. The work of separation values of these two interfaces between Al/O-terminated or Sn/O-terminated was 6.46 and 2.83 J/m2, respectively, which were both larger than that of a Al/Sn interface (1.06 J/m2). The results indicated that oxygen atoms could strengthen the interfacial adhesion of Al/Sn. In addition, the interfacial reaction of Al and O and the formation process of Al2O3 were discussed. It has the potential to be used to realize a high-strength joint in other weak bonding systems such as solder/ceramics, through O doping in air.
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