Synthesis and Characterization of Dimeric Artesunate Glycerol Monocaprylate Conjugate and Formulation of Nanoemulsion Preconcentrate.

Malaria is one of the major life-threatening health problems worldwide. Artesunate is the most potent antimalarial drug to combat severe malaria. However, development of drug resistance, short plasma half-life, and poor bioavailability limit the efficacy of this drug. Here, we applied the dimerization concept to synthesize dimeric artesunate glycerol monocaprylate conjugate (D-AS-GC) by conjugating artesunate (AS) with glycerol monocaprylate (GC) via esterification reaction. D-AS-GC conjugate, AS, and GC were well characterized by 1H NMR, attached proton test (APT) 13C NMR and 2D NMR spectroscopy. D-AS-GC conjugate was further analyzed by ESI-TOF MS. Finally, a series of nanoemulsion preconcentrate (F1-F6) of D-AS-GC was prepared by mixing different ratios of oil and surfactant/cosurfactant and evaluated after dilution with an aqueous phase. The optimized formulation (F6) exhibits a clear nanoemulsion and the hydrodynamic diameter of the dispersed phase was determined by DLS and DOSY NMR spectroscopy. The morphology of the nanoemulsion droplets of F6 was investigated by AFM, which revealed the formation of tiny nanoemulsion droplets on a hydrophilic mica substrate. Moreover, using a less polar silicon wafer led to the formation of larger droplets with a spherical core shell-like structure. Overall, the rational design of the dimeric artesunate-based nanoemulsion preconcentrate could potentially be used in more efficient drug delivery systems.

Chronic Treatment with Metformin Has No Disrupting Effect on the Hepatic Circadian Clock in Mice.

Background and Objectives: The antidiabetic agent metformin is known to activate AMP-activated protein kinase (AMPK) in various tissues. Because AMPK can modulate intracellular circadian clocks through regulating the stability of clock components, a single dose of metformin has been reported to affect circadian clocks in the peripheral tissues. In this study, therefore, we investigated whether chronic treatment with metformin causes the impairment of circadian clocks, especially if given at an inappropriate time. Materials and Methods: Non-diabetic C57BL/6J mice were allowed access to food only during 4 h at the beginning of the dark period, and repeatedly i.p. injected with a nearly maximum non-toxic dose of metformin, once daily either at 4 h after the beginning of the dark period or at the beginning of the light period. Diabetic ob/ob mice were given free access to food and treated with metformin in drinking water. Results: Under the controlled feeding regimen, 8-day treatment with metformin did not alter the mRNA expression rhythms of clock genes in both liver and adipose tissue of C57BL/6J mice, regardless of dosing time. In addition, chronic treatment with metformin for 2 weeks affected hepatic AMPK activation rhythm but did not disrupt the circadian clocks in the liver and adipose tissues of the ob/ob mice. Conclusions: These results mitigate concerns that treatment with metformin impairs peripheral circadian clocks, although confirmation is needed in humans.

Formation of Surface Wrinkles in Collapsed Langmuir Films of a Polyhedral Oligomeric Silsesquioxane Containing Diblock Copolymer.

Surface pressure versus mean molecular area isotherms of Langmuir films of a hybrid diblock copolymer of poly(ethylene glycol) (PEG) and poly(methacrylo polyhedral oligomeric silsesquioxane) P(MA-POSS) together with Brewster angle microscopy reveal details of the phase transitions. The formation of a periodic wrinkling pattern in collapsed films is observed by epifluorescence microscopy after applying several compression-expansion cycles above the surface pressure of ≈18 mN/m. The wrinkle formation is reversible upon compression and expansion of the Langmuir films. Two distinct orientations of POSS molecules are assumed in Langmuir films upon compression, vertically for chains close to the water surface and horizontally orientated upper layers with significant amounts of PEG in between them. Thus, the wrinkling forms mainly in the top stiffer MA-POSS blocks above a certain compressional stress. The wrinkles disappear during the Langmuir-Blodgett (LB) transfer. Nevertheless, atomic force microscopy and grazing incidence wide-angle X-ray scattering experiments reveal the formation of highly ordered POSS molecules in LB films.

Comparing C2=O and C2=S Barbiturates: Different Hydrogen-Bonding Patterns of Thiobarbiturates in Solution and the Solid State.

Carbonyl-centered hydrogen bonds with various strength and geometries are often exploited in materials to embed dynamic and adaptive properties, with the use of thiocarbonyl groups as hydrogen-bonding acceptors remaining only scarcely investigated. We herein report a comparative study of C2=O and C2=S barbiturates in view of their differing hydrogen bonds, using the 5,5-disubstituted barbiturate B and the thiobarbiturate TB as model compounds. Owing to the different hydrogen-bonding strength and geometries of C2=O vs. C2=S, we postulate the formation of different hydrogen-bonding patterns in C2=S in comparison to the C2=O in conventional barbiturates. To study differences in their association in solution, we conducted concentration- and temperature-dependent NMR experiments to compare their association constants, Gibbs free energy of association ∆Gassn., and the coalescence behavior of the N-H‧‧‧S=C bonded assemblies. In Langmuir films, the introduction of C2=S suppressed 2D crystallization when comparing B and TB using Brewster angle microscopy, also revealing a significant deviation in morphology. When embedded into a hydrophobic polymer such as polyisobutylene, a largely different rheological behavior was observed for the barbiturate-bearing PB compared to the thiobarbiturate-bearing PTB polymers, indicative of a stronger hydrogen bonding in the thioanalogue PTB. We therefore prove that H-bonds, when affixed to a polymer, here the thiobarbiturate moieties in PTB, can reinforce the nonpolar PIB matrix even better, thus indicating the formation of stronger H-bonds among the thiobarbiturates in polymers in contrast to the effects observed in solution.

Assessing the Impact of a Vi-polysaccharide Conjugate Vaccine in Preventing Typhoid Infection Among Bangladeshi Children: A Protocol for a Phase IIIb Trial.

BACKGROUND: Typhoid fever illnesses are responsible for more than 100 000 deaths worldwide each year. In Bangladesh, typhoid fever is endemic, with incidence rates between 292-395 per 100 000 people annually. While considerable effort has been made to improve access to clean water and sanitation services in the country, there is still a significant annual typhoid burden, which particularly affects children. A typhoid conjugate vaccine (Vi-TCV) was recently prequalified by the World Health Organization and recommended for use, and offers the potential to greatly reduce the typhoid burden in Bangladesh. METHODS: This study is a double-blind, cluster-randomized, controlled trial of Vi-TCV in a geographically defined area in Dhaka, Bangladesh. At least 32 500 children from 9 months to <16 years of age will be vaccinated and followed for 2 years to assess the effectiveness and safety of Vi-TCV in a real-world setting. All cluster residents will also be followed to measure the indirect effect of Vi-TCV in this community. ETHICS AND DISSEMINATION: This protocol has been approved by the International Centre for Diarrhoeal Disease Research, Bangladesh; a University of Oxford research review; and both ethical review committees. Informed written consent and assent will be obtained before enrollment. Vi-TCV has been shown to be safe and effective in previous, smaller-scale studies. The results of this study will be shared through a series of peer-reviewed journal articles. The findings will also be disseminated to the local government, stakeholders within the community, and the population within which the study was conducted. CONCLUSIONS: This trial is the largest and only cluster-randomized control trial of Vi-TCV ever conducted, and will describe the effectiveness of Vi-TCV in an endemic population. The results of this trial may provide important evidence to support the introduction of TCVs in countries with a high burden of typhoid. CLINICAL TRIALS REGISTRATION: ISRCTN11643110.

Crystallization of Poly(ethylene oxide) on the Surface of Aqueous Salt Solutions Studied by Grazing Incidence Wide-Angle X-ray Scattering.

We report the thin layer crystallization of high-molar mass poly(ethylene oxide) (PEO) on a liquid support using a 4 M K2CO3 aqueous solution as a subphase. Because of the Hofmeister effect, PEO does not dissolve and remains at the surface during compression on a Langmuir trough. The transition from the flat pancake conformation upon compression of the spread polymer film to an entangled monolayer results in a plateau region of the Langmuir isotherm. Using grazing incidence wide-angle X-ray scattering, the final crystallization of PEO was observed, and the crystal orientation was determined. The fold surface was (209̅), that is, the helix axis has a tilt angle of 2.9° to the normal vector of the water surface.

Tunable-focus lens for adaptive eyeglasses.

We demonstrate the implementation of a compact tunable-focus liquid lens suitable for adaptive eyeglass application. The lens has an aperture diameter of 32 mm, optical power range of 5.6 diopter, and electrical power consumption less than 20 mW. The lens inclusive of its piezoelectric actuation mechanism is 8.4 mm thick and weighs 14.4 gm. The measured lens RMS wavefront aberration error was between 0.73 µm and 0.956 µm.

Large aperture tunable-focus liquid lens using shape memory alloy spring.

A tunable-focus large aperture liquid lens is constructed using shape memory alloy (SMA) springs as actuators. The lens mainly consists of a shallow liquid-filled cylindrical cavity bound by a thin compressible annular rim and encapsulated by a flexible circular membrane on the top of the rim and a rigid circular plate at the rim bottom. The lens optical power is adjusted by a controlled compression of the annular rim via actuation of the three shape-memory alloy (SMA) springs. Since the volume of the cavity liquid is constant, the rim compression bulges the flexible membrane outward thus reducing its radius of curvature and the lens focal length. The fabricated tunable lens demonstrated an optical power range of 0-4 diopters utilizing a driving voltage less than 3V. Lens optical wavefront profiling was done using a Shack-Hartmann sensor displaying a RMS wave front error of 0.77 µm and 1.68 µm at 0 D and + 4 D. The aperture diameter and thickness of the fabricated lens are 34 mm and 9 mm, respectively, while weighing 16.7 g.

Selective biotic stressors' action on seed germination: A review.

In the realm of plant biology and agriculture, seed germination serves as a fundamental process with far-reaching implications for crop production and environmental health. This comprehensive review seeks to unravel the intricate web of interactions between some biotic stressors and seed germination, addressing the pertinent issue of how these stressors influence seed germination. Different chemicals produced by interacting plants (different parts), fungi, bacteria, or insects can either promote or inhibit seed germination. Releasing chemicals that modulate signaling pathways and cellular processes significantly disrupt essential cellular functions. This disruption leads to diverse germination outcomes, introducing additional layers of complexity to this regulatory landscape. The chemicals perturb enzyme activity and membrane integrity, imposing unique challenges on the germination process. Understanding the mechanisms- how allelochemicals, mycotoxins, or bacterial toxins affect seed germination or the modes of action holds promise for more sustainable agricultural practices, enhanced pest control, and improved environmental outcomes. In sum, this review contributes to a fundamental exposition of the pivotal role of biotic stressors in shaping the germination of seeds.

Degradation kinetics of lycopene from red amaranth & preparation of winter melon jelly using this lycopene and comparison with commercial jelly.

This study was conducted to observe the storage conditions, such as solvent and temperature, of lycopene content and degradation kinetics from red amaranth (Amaranthus gangeticus). Jelly was prepared using the extracted lycopene, the physicochemical properties and lycopene content. The extract with the maximum amount of lycopene was obtained by extraction with hexane, acetone and ethanol (2:1:1),50 ± 9 mg/kg. Higher lycopene degradation was observed at refrigerated temperature as compared to ambient temperature in hexane acetone (6:4) solvent throughout the storage periods. In this period, the initial lycopene concentration was measured to be 17 ± 8 mg/kg, whereas at the end of the storage time, it was found to be 3.0 ± 0.8 mg/kg. Hence, the results indicate that the hexane, acetone, and ethanol (in a ratio of 2:1:1) solvent method is viable for extracting and purifying lycopene from red amaranth at refrigerated temperature. This lycopene can serve as both a natural colorant and a value-added product. However, it is worth noting that lycopene can also be extracted and purified using recrystallization, column chromatography, and thin-layer chromatography (TLC) methods. The Winter melon jelly using lycopene from red amaranth contained moisture 29.6 %, ash 0.67 %, acidity 0.35 %, reducing sugar 26.8 %, non-reducing sugar 35.4 %, total soluble solid 66°brix and lycopene content 26.04 mg/kg. Proper utilization of lycopene extracted from red amaranth during the preparation of bakery, confectionary, baby food etc., may help and encourage the development of small-scale industries in the country.

Molecular characterization of Satsuma mandarin (Citrus unshiu Marc.) VASCULAR PLANT ONE-ZINC FINGER2 (CuVOZ2) interacting with CuFT1 and CuFT3.

Shortening the juvenility is a burning issue in breeding fruit trees such as Satsuma mandarin (Citrus unshiu Marc.). Decreasing the breeding period requires a comprehensive understanding of the flowering process in woody plants. Throughout the Arabidopsis flowering system, FLOWERING LOCUS T (FT) interacts with other transcription factors (TFs) and functions as a transmissible floral inducer. In a previous study, a VASCULAR PLANT ONE-ZINC FINGER1 (VOZ1)-like TF from the Satsuma mandarin, CuVOZ1, showed protein-protein interaction with two citrus FTs in a yeast two-hybrid (Y2H) system and precocious flowering in Arabidopsis. In this study, another VOZ, CuVOZ2, was isolated from the Satsuma mandarin 'Aoshima' and protein-protein interaction was confirmed between CuVOZ2 and CuFTs. No apical meristem (NAM) and zinc coordination motifs were identified within the N-terminal of CuVOZ2. Docking simulation predicted that interactions between CuVOZ2 and CuFTs might occur in domain B of CuVOZ2, which contains a zinc finger motif. According to docking predictions, the distances between the amino acid residues involved ranged from 1.09 to 4.37 Å, indicating weak Van der Waals forces in the interaction. Cys216, Cys221, Cys235, and His239 in CuVOZ2 were suggested to bond with a Zn2+ in the Zn coordination motif. Ectopic expression of 35SΩ:CuVOZ2 in Arabidopsis affected the flowering time, length of inflorescence and internode, and number of siliques, suggesting that CuVOZ2 might regulate both vegetative and reproductive development, act as a trigger for early flowering, and be involved in the elongation of inflorescence possibly in a slightly different way than CuVOZ1.

Enhancement of IL-6 Production Induced by SARS-CoV-2 Nucleocapsid Protein and Bangladeshi COVID-19 Patients' Sera.

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 that can have detrimental effects on multiple organs and accelerate patient mortality. This study, which encompassed 130 confirmed COVID-19 patients who were assessed at three different time points (i.e., 3, 7, and 12 days) after the onset of symptoms, investigated interleukin-6 (IL-6) enhancement induced by a viral nucleocapsid (N) protein from a myeloid cell line. Disease severity was categorized as mild, moderate, or severe. The severe cases were characterized as having significant elevations in serum IL-6, C-reactive protein, D-dimer, ferritin, creatinine, leukocytes, and neutrophil-to-lymphocyte ratio and decreased hemoglobin, hematocrit, and albumin levels compared with mild and moderate cases. To evaluate IL-6-inducing activity, heat-inactivated sera from these patients were incubated with and without the N protein. The findings showed a progressive increase in IL-6 production in severe cases upon N protein stimulation. There was a strong correlation between anti-N antibodies and levels of IL-6 secreted by myeloid cells in the presence of N protein and sera, indicating the crucial role that the anti-N antibody plays in inducing IL-6 production. Uncontrolled IL-6 production played a pivotal role in disease pathogenesis, exacerbating both disease severity and mortality. Efficiently targeting the N protein could potentially be employed as a therapeutic strategy for regulating the immune response and alleviating inflammation in severe cases.

Genetic Analysis of Dengue Virus in Severe and Non-Severe Cases in Dhaka, Bangladesh, in 2018-2022.

Dengue virus (DENV) infections have unpredictable clinical outcomes, ranging from asymptomatic or minor febrile illness to severe and fatal disease. The severity of dengue infection is at least partly related to the replacement of circulating DENV serotypes and/or genotypes. To describe clinical profiles of patients and the viral sequence diversity corresponding to non-severe and severe cases, we collected patient samples from 2018 to 2022 at Evercare Hospital Dhaka, Bangladesh. Serotyping of 495 cases and sequencing of 179 cases showed that the dominant serotype of DENV shifted from DENV2 in 2017 and 2018 to DENV3 in 2019. DENV3 persisted as the only representative serotype until 2022. Co-circulation of clades B and C of the DENV2 cosmopolitan genotype in 2017 was replaced by circulation of clade C alone in 2018 with all clones disappearing thereafter. DENV3 genotype I was first detected in 2017 and was the only genotype in circulation until 2022. We observed a high incidence of severe cases in 2019 when the DENV3 genotype I became the only virus in circulation. Phylogenetic analysis revealed clusters of severe cases in several different subclades of DENV3 genotype I. Thus, these serotype and genotype changes in DENV may explain the large dengue outbreaks and increased severity of the disease in 2019.

Structural, elastic and optoelectronic properties of inorganic cubic FrBX3 (B = Ge, Sn; X = Cl, Br, I) perovskite: the density functional theory approach.

Inorganic metal-halide cubic perovskite semiconductors have become more popular in industrial applications of photovoltaic and optoelectronic devices. Among various perovskites, lead-free materials are currently most explored due to their non-toxic effect on the environment. In this study, the structural, electronic, optical, and mechanical properties of lead-free cubic perovskite materials FrBX3 (B = Ge, Sn; X = Cl, Br, I) are investigated through first-principles density-functional theory (DFT) calculations. These materials are found to exhibit semiconducting behavior with direct bandgap energy and mechanical phase stability. The observed variation in the bandgap is explained based on the substitutions of cations and anions sitting over B and X-sites of the FrBX3 compounds. The high absorption coefficient, low reflectivity, and high optical conductivity make these materials suitable for photovoltaic and other optoelectronic device applications. It is observed that the material containing Ge (germanium) in the B-site has higher optical absorption and conductivity than Sn containing materials. A systematic analysis of the electronic, optical, and mechanical properties suggests that among all the perovskite materials, FrGeI3 would be a potential candidate for optoelectronic applications. The radioactive element Fr-containing perovskite FrGeI3 may have applications in nuclear medicine and diagnosis such as X-ray imaging technology.

Lenvatinib causes reduced expression of carnitine/organic cation transporter 2 and carnitine deficiency in the skeletal muscle of rats.

Lenvatinib, an oral tyrosine kinase inhibitor, is widely used to treat several types of advanced cancers but often causes muscular adverse reactions. Although carnitine supplementation may prevent these effects, the mechanism underlying lenvatinib-induced skeletal muscle impairment remains poorly understood. To this end, we aimed to investigate the impact of lenvatinib on carnitine disposition in rats. Once-daily administration of lenvatinib repeated for two weeks did not affect urinary excretion or serum concentration of carnitines throughout the treatment period but ultimately decreased the L-carnitine content in the skeletal muscle. The treatment decreased the expression of carnitine/organic cation transporter (OCTN) 2, a key transporter of carnitine, in skeletal muscle at the protein level but not at the mRNA level. In cultured C2C12 myocytes, lenvatinib inhibited OCTN2 expression in a dose-dependent manner at the protein level. Furthermore, lenvatinib dose-dependently decreased the protein levels of carnitine-related genes, adenosine triphosphate content, mitochondrial membrane potential, and markers of mitochondrial function in vitro. These results reveal the deleterious effects of lenvatinib on OCTN2 expression, carnitine content, and mitochondrial function in skeletal muscle that may be associated with muscle toxicity.

Correcting Presbyopia With Autofocusing Liquid-Lens Eyeglasses.

OBJECTIVE: Presbyopia, an age-related ocular disorder, is characterized by the loss in the accommodative abilities of the human eye. Conventional methods of correcting presbyopia divide the field of view, thereby resulting in significant vision impairment. We demonstrate the design, assembly and evaluation of autofocusing eyeglasses for restoration of accommodation without dividing the field of view. METHODS: The adaptive optics eyeglasses comprise of two variable-focus liquid lenses, a time-of-flight range sensor and low-power, dual microprocessor control electronics, housed within an ergonomic frame. Subject-specific accommodation deficiency models were utilized to demonstrate high-fidelity accommodative correction. The abilities of this system to reduce accommodation deficiency, its power consumption, response time, optical performance and MTF were evaluated. RESULTS: Average corrected accommodation deficiencies for 5 subjects ranged from -0.021 D to 0.016 D. Each accommodation correction calculation was performed in ∼67 ms which consumed 4.86 mJ of energy. The optical resolution of the system was 10.5 cycles/degree, and featured a restorative accommodative range of 4.3 D. This system was capable of running for up to 19 hours between charge cycles and weighed ∼132 g. CONCLUSION: The design, assembly and performance of an autofocusing eyeglasses system to restore accommodation in presbyopes has been demonstrated. SIGNIFICANCE: The new autofocusing eyeglasses system presented in this article has the potential to restore pre-presbyopic levels of accommodation in subjects diagnosed with presbyopia.

Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice.

Background and aim: Circadian clocks in most peripheral tissues are entrained mainly by feeding. Therefore, this study aimed to investigate whether the daily rhythm of core body temperature (CBT), including the effect of diet-induced thermogenesis, varies according to habitual feeding time. Methods: Wild-type and uncoupling protein 1 (UCP1) knockout mice were fed only during the first 4 h (Breakfast group) or the last 4 h of the dark period (Dinner group) for 17 days. On day 18, both groups were fed twice for 2 h, at the same starting times. Locomotor activity and CBT were measured continuously during the experiment. Results: On day 18, CBT increased at the beginning of each feeding period, regardless of the group and strain. However, the CBT increase induced by the first meal decreased sharply in the Breakfast group and mildly in the Dinner group; the opposite was observed after the second meal. In UCP1 knockout, but not wild-type, mice, the total amount of CBT was significantly lower in the Dinner group than in the Breakfast group. These effects were mostly independent of the locomotor activity and food intake. Conclusion: These results reveal that the effect of habitual feeding time on the daily rhythm of CBT is sustained at least until the following day. These effects may be mediated by both UCP1-dependent and -independent mechanisms.

Computational and structural based approach to identify malignant nonsynonymous single nucleotide polymorphisms associated with CDK4 gene.

Cycline-dependent kinase 4 (CDK4), an enzyme of the cycline dependent or Ser/Thr protein kinase family, plays a role in cell cycle progression (G1 phase) by phosphorylating a tumor suppressor protein called pRB. Alteration of this enzyme due to missense mutation/ nonsynonymous single nucleotide polymorphisms (nsSNPs) are responsible for various types of cancer progression, e.g. melanoma, lung cancer, and breast cancer. Hence, this study is designed to identify the malignant missense mutation of CDK4 from the single nucleotide polymorphism database (dbSNP) by incorporating computational algorithms. Out of 239 nsSNPs; G15S, D140Y and D140H were predicted to be highly malignant variants which may have a devastating impact on protein structure or function. We also found defective binding motif of these three mutants with the CDK4 inhibitor ribociclib and ATP. However, by incorporating molecular dynamic simulation, our study concludes that the superiority of G15S than the other two mutants (D140Y and D140H) in destabilizing proteins nature.

Risk factors of nonalcoholic fatty liver disease in lean body mass population: A systematic review and meta-analysis.

The pathophysiology and risk factors of nonalcoholic fatty liver disease (NAFLD) among lean patients is poorly understood and therefore investigated. We performed a meta-analysis of observational studies. Of 1175 articles found through searching from Medline/PubMed, Banglajol, and Google Scholar by two independent investigators, 22 were selected. Data from lean (n = 6768) and obese (n = 9253) patients with NAFLD were analyzed; lean (n = 43 398) and obese (n = 9619) subjects without NAFLD served as controls. Age, body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure (DBP) had significantly higher estimates in lean NAFLD patients than in lean non-NAFLD controls. Fasting blood sugar [MD(mean difference) 5.17 mg/dl, 95% CI(confidence interval) 4.14-6.16], HbA1c [MD 0.29%, 95% CI 0.11-0.48], and insulin resistance [HOMA-IR] [MD 0.49 U, 95% CI 0.29-0.68]) were higher in lean NAFLD patients than in lean non-NAFLD controls. All components of the lipid profile were raised significantly in the former group except high-density lipoprotein. An increased uric acid (UA) level was found to be associated with the presence of NAFLD among lean. Cardio-metabolic profiles of nonlean NAFLD patients significantly differs from the counter group. However, the magnitude of the difference of lipid and glycemic profile barely reached statistical significance when subjects were grouped according to lean and nonlean NAFLD. But DBP (slope: 0.19, P < 0.037), HOMA-IR (slope: 0.58, P < 0.001), and UA (slope: 0.36, P = 0.022) were significantly higher if NAFLD was present compared to that of non-NAFLD group. Lean and nonlean NAFLD patients are metabolically similar and share common risk factors.

Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice.

OBJECTIVE: Impaired circadian clocks can cause obesity, but their pathophysiological role in brown adipose tissue (BAT), a major tissue regulating energy metabolism, remains unclear. To address this issue, we investigated the effects of complete disruption of the BAT clock on thermogenesis and energy expenditure. METHODS: Mice with brown adipocyte-specific knockout of the core clock gene Bmal1 (BA-Bmal1 KO) were generated and analyzed. RESULTS: The BA-Bmal1 KO mice maintained normal core body temperatures by increasing shivering and locomotor activity despite the elevated expression of thermogenic uncoupling protein 1 in BAT. BA-Bmal1 KO disrupted 24 h rhythmicity of fatty acid utilization in BAT and mildly reduced both BAT thermogenesis and whole-body energy expenditure. The impact of BA-Bmal1 KO on the development of obesity became obvious when the mice were fed a high-fat diet. CONCLUSIONS: These results reveal the importance of the BAT clock for maintaining energy homeostasis and preventing obesity.