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Obesity and its related metabolic disorders are caused by an imbalance between homeostatic energy consumption and expenditure. Brown and beige adipose tissues have been shown to be protective against these diseases due to their critical roles in non-shivering thermogenesis; additionally, adrenergic innervation of these cells promotes lipolysis and fatty acid oxidation1. A key enzyme promoting fatty acid oxidation in adipose tissues, particularly in response to cold-stimulus, is mitochondrial acyl-CoA synthetase long-chain family member 1(ACSL1)2 However, the regulatory mechanism of the subcellular localization of ACSL1 in adipocytes remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that facilitates the translocation of ACSL1 from mitochondria to lysosome for further degradation. In brown and beige adipose tissues, sortilin is downregulated upon adrenergic stimulation but its levels are restored to baseline after the stimulus is withdrawn. Depletion of Sort1 in adipocytes results in an increase in whole body energy expenditure. Moreover, mice with adipose-specific Sort1 depletion are resistant to high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings identify sortilin as a promising therapeutic target that negatively regulates non-shivering thermogenesis in adipocytes by promoting the translocation of ACSL1 from the mitochondria to lysosome.

Application of autologous platelet-rich plasma (PRP), especially leukocyte- and platelet-rich fibrin (L-PRF), has emerged as a promising adjuvant therapy for the treatment of diabetic foot ulcers (DFUs). Conflicting results of PRP efficacy can be attributed to the lack of standardization in the PRP preparation process in addition to a paucity of well-designed randomized clinic trials (RCTs).

Background: Two different approaches, 1-h heart-to-contralateral (H/CL) ratio and 3-h visual grading scale relative to ribs (VGSr), have been established to interpret 99mTc-PYP planar images for the detection of amyloid transthyretin cardiac amyloidosis (ATTR-CA). Since they are prone to pitfalls, this pilot study aimed to explore the diagnostic practicality of the 3-h visual grading scale relative to the upper segment of sternum (VGSs) approach for interpreting 99mTc-PYP planar images. Methods: A total of 42 patients were enrolled in this retrospective study. SPECT/CT approach and planar approaches including H/CL ratio, VGSr, and VGSs were utilized to interpret the 99mTc-PYP images obtained at both 1 and 3 h. The classification criteria of the latest expert consensus recommendations were considered as the gold standard. The concordance between the interpretation of each approach and the gold standard was investigated. Results: In addition to 1- and 3-h SPECT/CT approaches, the interpretation of planar images using the 3-h VGSs approach was also applicable, which turns identical to the gold standard (κ = 1.000; p < 0.001). Conclusions: For the interpretation of 99mTc-PYP planar images, the 3-h VGSs approach should be the optimal method, particularly in the case without available or feasible tomography imaging. Only one imaging session (planar and SPECT/CT) at 3 h would be sufficient for the detection of ATTR-CA, and favorable for patient satisfaction.

Here, through the synergism between kinetic dynamic imine-exchange control and thermodynamic control, rarely observed compressible, porous, crystalline covalent organic framework (COF) aerogels were synthesized, the mechanism behind which is a framework crystallization induced self-assembly (FCISA) process. The prepared COF aerogel possessed extremely high BET surface over 2000 m2·g−1 and high maximum equilibrium adsorption capacity toward bisphenol-A of 699 mg·g−1 in aqueous solution.

Brown and beige adipose tissues play a large role in non-shivering thermogenesis (NST) in mammals, and subsequently have been studied for decades as potential therapeutic targets to treat obesity and its related metabolic diseases. However, the mechanistic regulation of brown/beige adipose tissue induction and maintenance in humans is very limited due to the ethical reasons. In fact, metabolic signaling has primarily been investigated using rodent models. A better understanding of non-shivering thermogenesis in humans is thus vital and urgent in order to treat obesity by targeting human brown adipose tissue (BAT). In this review, we summarize the anatomical and physiological differences between rodent and human BAT, current useful and mostly non-invasive methods in studying human BAT, as well as recent advancements targeting thermogenic adipocytes as a means to combat metabolic diseases in humans. Furthermore, we also discuss several novel relevant strategies of therapeutic interventions, which has been attempted in rodent experiments, and possible future investigations in humans in this field.

Brown fat and beige fat are known as thermogenic fat due to their contribution to non-shivering thermogenesis in mammals following cold stimulation. Beige fat is unique due to its origin and its development in white fat. Subsequently, both brown fat and beige fat have become viable targets to combat obesity. Over the last few decades, most therapeutic strategies have been focused on the canonical pathway of thermogenic fat activation via the β3-adrenergic receptor (AR). Notwithstanding, administering β3-AR agonists often leads to side effects including hypertension and particularly cardiovascular disease. It is thus imperative to search for alternative therapeutic approaches to combat obesity. In this review, we discuss the current challenges in the field with respect to stimulating brown/beige fat thermogenesis. Additionally, we include a summary of other newly discovered pathways, including non-AR signaling- and non-UCP1-dependent mechanisms, which could be potential targets for the treatment of obesity and its related metabolic diseases.

Framework crystallization is an unresolved challenge in the chemistry of covalent organic frameworks (COFs) due to the poorly controlled simultaneous polymerization and crystallization processes. Here, we report the first morphogenesis of COF mesocrystals with two-dimensional hexagonal p6m symmetry through the combination of alkyl amine as a dynamic modulator and 2,4,6- triformylresorcinol imine as an asymmetrical building block. The amine modulator depresses the lateral growth of 2D sheets, and the slow kinetics combined with the asymmetrical conformation of 2,4,6-triformylresorcinol imine lead to the formation of transient imine macrocycles, which further undergo mesoscale self-assembly into nanotubular structures. The nanotubular structures tend to join together into rod-like bundles with ordered hexagonal rods, which finally grow into uniform hexagonal COF mesocrystals. The present strategy opens a nonclassical nucleation and crystal growth approach to create COFs with unexplored mesocrystal structures, which further extends the scope of crystalline framework materials and provides a new strategy for crystal morphogenesis.

The formation of mesostructured polymer and carbon single-crystals is very difficult due to increased complexity of the energy hypersurface and the role of slowed-down kinetics. Here we reported the synthesis of ordered mesostructured phloroglucinol-formaldehyde single crystals through mesoscale self-assembly of reactive monomicelles under acidic conditions which were traditionally thought very difficult to control the morphology because of the rapid polymerization rate. Polymeric and carbon single crystals from unusual curved hexagonal rods and spindles with two-dimensional hexagonal mesostructures, to previously unreported lozenge single-crystal sheets with lamellar mesostructures were obtained. Contrary to the literature reports, the lamellar mesostructured lozenge single-crystal sheets were successfully transformed to graphene-like layered carbons after calcination under 800 °C, and they can be further exfoliated into unprecedented high-quality single-layered carbon nanoribbons. These results unambiguously expanded our understanding about mesocrystals, and opened up new avenues for the efficient production of single-layered carbon nanoribbons which possess promising applications in electrochemical devices.

Obesity and its related metabolic disorders have become prevalent and fatal, which are faced by the entire human beings since decades. An energy equilibrium is urgently important for human metabolic health, which requires the participation of multiple organs, such as adipose tissues, liver and skeletal muscles. It seems that both sex and age play a role in the above processes. In this review, we focus on the sexual dimorphism in energy metabolism mediated by adipose tissues, including white and thermogenic (brown/beige) adipose tissues. Remarkably, past investigations have focused on targeting brown/beige adipose tissues to combat obesity because of their contributions to non-shivering thermogenesis. However, sex differences in the regulation of adipose tissue metabolism are likely overlooked. Particularly, increasing data show that males display more visceral fat than females, and females show increased visceral fat after menopause. Visceral adiposity is more deleterious and closely related to metabolic disorders, such as cardiovascular diseases. In this review, we discuss current findings on sexual dimorphism in WAT and BAT biology for a better metabolic balance in humans.

The hydrogen evolution reaction (HER) is the crucial step in electrochemical water splitting. To succeed in real applications, one of the major challenges faced by HER is the development of robust and efficiency electrocatalysts. Herein, robust highly crystalline aromatic imide-based two-dimensional covalent organic frameworks (COFs) were prepared through a high temperature solvothermal process, taking advantage of the uniform pore size and specialized pore environment, efficient HER catalyst Cryst-2D-PMPI-Ru were synthesized in which ruthenium (Ru) nanoclusters are uniform dispersed with small particle size (less than 2 nm). In alkaline media, Cryst-2D-PMPI-Ru requires overpotential of only 35.1 mV to afford a current density of 10 mA/cm2, which outperforms the benchmark 20% Pt/C catalyst (37.3 mV). The excellent performance of was presumably attributed to the uniform and ultrasmall Ru nanoclusters with a satisfied dispersion, which provides the massive active sites for HER. In acid solution, the overpotential of Cryst-2D-PMPI-Ru (55.3 mV) is close to Pt/C (40.3 mV). The Tafel slope of PMDA/MA-Ru-180-800 is 36.5 mV/dec and the mechanism of the reaction is of the Volmer-Heyrovsky type. Besides, compared with their counterpart with low degree of crystllinity, the Cryst-2D-PMPI-Ru electrocatalyst also exhibits superior performance stability due to the stability of COF. The results provide important evidence that high crystallinity and robust aromatic structure of the polymeric frameworks precursors can substantially enhance their electrocatalytic performance and stability.

MicroRNAs (miRNAs) are small non-coding RNA molecules consisting of approximately 20 to 22 nucleotides. They play a very important role in the regulation of gene expression. miRNAs can be found in different species and a variety of organs and tissues including adipose tissue. There are two types of adipose tissue in mammals: White adipose tissue (WAT) is the largest energy storage, whereas brown adipose tissue (BAT) dissipates energy to maintain body temperature. BAT was first identified in hibernating animals and newborns as a defense against cold. Later on, it was also discovered in human adults, suggesting its potential role in energy balance and metabolism. Moreover, "brown-like" adipocytes present in WAT depots, so called beige or brite (brown-in-white) cells, were discovered by several groups. In recent years, miRNAs were found to have important regulatory function during brown fat differentiation, brown fat activation and white fat "browning". In this review, we focus on the regulation of brown and beige fat by miRNAs including the role in their differentiation and function, providing evidence for their therapeutic potential in metabolic diseases.

Fat tissue is well known for its capacity to store energy and its detrimental role in obesity and metaflammation. However, humans possess different types of fat that have different functions in physiology and metabolic diseases. Apart from white adipose tissue (WAT), the body’s main energy storage, there is also brown adipose tissue (BAT) that dissipates energy as a defense against cold and maintains energy balance for the whole body. BAT is present not only in newborns but also in adult humans and its mass correlates with leanness. Moreover, “brown-like” adipocytes have been detected in human WAT. These “brown-in-white” (brite) or beige cells can be induced by cold and a broad spectrum of pharmacological substances and, therefore, they are also known as “inducible brown adipocytes.” Activation of brown and/or brite adipocytes reduces metabolic diseases, at least in murine models of obesity. Thus, brown/brite adipocytes represent the “brite” side of fat and are potential targets for novel therapeutic approaches for treatment of obesity and obesity-associated diseases.

Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4is) are oral anti-diabetic drugs (OADs) for the treatment of type 2 diabetes mellitus (T2DM) through inhibiting the degradation of incretin peptides. Numerous investigations have been focused on the effects of DPP4is on glucose homeostasis. However, there are limited evidences demonstrating their Potential modulatory functions in the immune system. DPP4, originally known as the lymphocyte cell surface protein CD26, is widely expressed in many types of immune cells including CD4(+) and CD8(+) T cells, B cells, NK cells, dendritic cells, and macrophages; and regulate the functions of these cells. In addition, DPP4 is capable of modulating plenty of cytokines, chemokines and peptide hormones. Accordingly, DPP4/CD26 is speculated to be involved in various immune/inflammatory diseases and DPP4is may become a new drug class applied in these diseases. This review focuses on the regulatory effects of DPP4is on immune functions and their possible underlying mechanisms. Further clinical studies will be necessitated to fully evaluate the administration of DPP4is in diabetic patients with or without immune diseases.

Background Obesity is associated with an increased incidence of left ventricular hypertrophy, diastolic dysfunction, heart failure, and premature cardiac aging. In the heart, intrinsic activation of the AMP-dependent protein kinase (AMPK) plays a pivotal role in the stress response to ischemia and hypertrophy. Furthermore, AMPK is an important regulator of cardiac mitochondrial biogenesis. The purpose of the present study was to investigate the influence of obesity and aging on the AMPK signaling pathway in human cardiac tissue. Methods 60 male cardiac surgery patients were included in the study and divided into 4 groups (old normal weight: ON; old obese: OO; young normal weight: YN, young obese: YO) according to their body mass index (18.5–25: normal weight or 30–35: obese) and age ( 70: old) with 15 patients each. Right atrial tissue (RA) was analyzed for the expression of the AMPK upstream kinases CAMKK and LKB1, activation of AMPK as well as phosphorylation of the AMPK downstream targets ACC, eEF2, mTOR and eNOS. Epicardial adipose tissue was analyzed for the expression of the endogenous AMPK activator adiponectin. The metabolic state of all patients was further characterized in fasting blood samples. Results Old patients (ON, OO) and young obese (YO) subjects displayed higher fasting glucose, insulin and leptin serum levels compared to the young, normal weight group, although HbA1c was below the threshold required for the diagnosis of type 2 diabetes. Serum adiponectin as well as total adiponectin protein expression in epicardial adipose tissue was decreased in these three groups. Analyses of adiponectin isoforms by native gel electrophoresis revealed significant differences in the high molecular weight (HMW) isoforms between the groups. Despite the low total serum adiponectin and HMW adiponectin, AMPK activation was high in the RA of obese patients (YO, OO). Among the AMPK upstream kinases, LKB1 expression showed a strong positive correlation with AMPK activation. While the phosphorylation of the AMPK downstream targets mTOR, eEF-2 and ACC was not altered, phospho-eNOS was significantly lower in old patients (ON, OO). Despite strong AMPK activation, mitochondrial biogenesis and respiration were impaired in old (ON, OO) and young obese (YO) subjects. Conclusion These data indicate that obesity and aging result in significant changes although many direct parameters in the AMPK signaling pathway are not changed in the same direction. LKB1 may represent a stronger activator of the AMPK pathway than adiponectin or the CAMKKs in human right atrial tissue.

Posttranslational modifications of the transcriptional coactivator PGC-1α by the deacetylase SIRT1 and the kinase AMPK are involved in exercise-induced mitochondrial biogenesis in skeletal muscle. However, similar investigations have not been performed in the left ventricle (LV). Here, we tested whether treadmill training (12 weeks) modifies PGC-1α and mitochondrial biogenesis in gastrocnemius muscle and LV of C57BL/6 J wild-type mice and IL-6-deficient mice with a reported impairment in muscular AMPK activation similarly. Physical activity lowered the plasma insulin and glucose in both mouse strains, suggesting improved insulin sensitivity. The gastrocnemius muscle of IL-6-deficient mice showed reduced mitochondrial respiration and enzyme activity, which was partially normalized after training. Chronic exercise enhanced the mitochondrial biogenesis in gastrocnemius muscle as indicated by increased mRNA or protein expression of primary mitochondrial transcripts, higher mtDNA content and increased citrate synthase activity. Parallel to these changes, we observed AMPK activation, SIRT1 induction and PGC-1α deacetylation. Chronic treadmill training resulted in a mild cardiac hypertrophy in both mouse strains. However, none of these changes observed in skeletal muscle were detected in the LV (both mouse strains) with the exception of AMPK activation and a mildly increased succinate-dependent respiration. Thus, chronic endurance training induces a sustained mitochondrial biogenic response in mouse gastrocnemius muscle but not in the LV. Although AMPK activation occurs in both muscular organs, the absence of SIRT1-dependent PGC-1α deacetylation may be responsible for this significant difference. AMPK activation by IL-6 appears to be dispensable for the mitochondrial biogenic responses to chronic treadmill exercise.

OBJECTIVE Transcriptional peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α–independent mechanisms without mtDNA replication.

Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography coupled with computer tomography (PET/CT) is still the standard for measuring BAT activity, but exposes subjects to ionizing radiation. To study BAT function in large human cohorts, novel diagnostic tools are needed. Here we show that brown adipocytes release exosomes and that BAT activation increases exosome release. Profiling miRNAs in exosomes released from brown adipocytes, and in exosomes isolated from mouse serum, we show that levels of miRNAs change after BAT activation in vitro and in vivo. One of these exosomal miRNAs, miR-92a, is also present in human serum exosomes. Importantly, serum concentrations of exosomal miR-92a inversely correlate with human BAT activity measured by 18F-FDG PET/CT in two unique and independent cohorts comprising 41 healthy individuals. Thus, exosomal miR-92a represents a potential serum biomarker for BAT activity in mice and humans.

Obesity-associated heart disease results in myocardial lipid accumulation leading to lipotoxicity. However, recent studies are suggestive of protective effects of high-fat diets (HFD). To determine whether age results in differential changes in diet-induced obesity, we fed young and old (3 and 18 months) male C57Bl/6 mice control diet, low-fat diet (both 10 kcal% fat) or HFD (45 kcal% fat) for 16 weeks, after which we analyzed LV function, mitochondrial changes, and potential modifiers of myocardial structure. HFD or age did not change LV systolic function, although a mildly increased BNP was observed in all old mice. This was associated with increased myocardial collagen, triglyceride, diacylglycerol, and ceramide content as well as higher caspase 3 activation in old mice with highest levels in old HFD mice. Pyruvate-dependent respiration and mitochondrial biogenesis were reduced in all old mice and in young HFD mice. Activation of AMPK, a strong inducer of mitochondrial biogenesis, was reduced in both HFD groups and in old control or LFD mice. Cardiomyocytes from old rats demonstrated significantly reduced AMPK activation, impaired mitochondrial biogenesis, higher ceramide content, and reduced viability after palmitate (C16:0) in vitro, while no major deleterious effects were observed in young cardiomyocytes. Aged but not young cardiomyocytes were unable to respond to higher palmitate with increased fatty acid oxidation. Thus, HFD results in cardiac structural alterations and accumulation of lipid intermediates predominantly in old mice, possibly due to the inability of old cardiomyocytes to adapt to high-fatty acid load.

OBJECTIVE Transcriptional peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α–independent mechanisms without mtDNA replication.