Fat tissues, the brite and the dark sides.

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.

Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate.

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.

Treatment of obesity-related diabetes: significance of thermogenic adipose tissue and targetable receptors.

Diabetes mellitus is mainly classified into four types according to its pathogenesis, of which type 2 diabetes mellitus (T2DM) has the highest incidence rate and is most relevant to obesity. It is characterized by high blood glucose, which is primarily due to insulin resistance in tissues that are responsible for glucose homeostasis (such as the liver, skeletal muscle, and white adipose tissue (WAT)) combined with insufficiency of insulin secretion from pancreatic ß-cells. Treatment of diabetes, especially treatment of diabetic complications (such as diabetic nephropathy), remains problematic. Obesity is one of the main causes of insulin resistance, which, however, could potentially be treated by activating thermogenic adipose tissues, like brown and beige adipose tissues, because they convert energy into heat through non-shivering thermogenesis and contribute to metabolic homeostasis. In this review, we summarize the function of certain anti-diabetic medications with known thermogenic mechanisms and focus on various receptor signaling pathways, such as previously well-known and recently discovered ones that are involved in adipose tissue-mediated thermogenesis and could be potentially targeted to combat obesity and its associated diabetes, for a better understanding of the molecular mechanisms of non-shivering thermogenesis and the development of novel therapeutic interventions for obesity-related diabetes and potentially diabetic complications.

Latest Advancements on Combating Obesity by Targeting Human Brown/Beige Adipose Tissues.

Obesity is defined as overaccumulation of white adipose tissue in the body, mainly under the skin (subcutaneous adiposity) or in the abdominal cavity (visceral adiposity). It could be the origin of various metabolic disorders including hypertension, hyperlipidemia, type 2 diabetes, cardiovascular diseases etc. Active adipose tissue was discovered in humans through 18F-fluorodeoxyglucose Positron Emission Tomography coupled with Computer Tomography (18F FDG-PET/CT), which was initially performed for tumor scanning. Since human active adipose tissue is probably composed of brown and beige adipose tissues and they burn white adipose tissue to generate heat, targeting human brown/beige adipose tissue to induce their thermogenic function is considered significant to combat obesity. In this review, we describe the latest advancements on promising therapeutic strategies to combat obesity by targeting human thermogenic adipose tissues to achieve further metabolic balance in humans.

Pitfalls of the Semi-Quantitative Analyzing 99mTc-Pyrophosphate Planar Images for Diagnosing Transthyretin Cardiac Amyloidosis: A Possible Solution.

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.

Emerging roles of Glucagon like peptide-1 in the management of autoimmune diseases and diabetes-associated comorbidities.

Currently, gastrointestinal hormone glucagon like peptide-1 (GLP-1) has received significant attention in maintaining glucose homeostasis through mechanisms involving augmentation of insulin, inhibition of glucagon secretion and regulation of gut motility. Therefore, GLP-1 receptor agonist (GLP-1RA) turns to be one of the most promising hypoglycemic agents for the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, the benefits of GLP-1 and GLP-1RAs are not limited to glucose control and weight loss. Here, we provide a concise overview of the roles of GLP-1 and GLP-1RAs in autoimmune disease, cardiovascular disease (CVD), diabetic kidney disease (DKD), diabetic foot ulcer (DFU), polycystic ovary syndrome (PCOS), and Alzheimer's disease (AD) as well as future challenges in this regard.

AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium.

BACKGROUND: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium. METHODS: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice. RESULTS: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes. CONCLUSIONS: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.

Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle.

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.

Fat biology and metabolic balance: On the significance of sex.

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.

Management of Oxidative Stress: Crosstalk Between Brown/Beige Adipose Tissues and Skeletal Muscles.

Exercise plays an important role in the physiology, often depending on its intensity, duration, and frequency. It increases the production of reactive oxygen species (ROS). Meanwhile, it also increases antioxidant enzymes involved in the oxidative damage defense. Prolonged, acute, or strenuous exercise often leads to an increased radical production and a subsequent oxidative stress in the skeletal muscles, while chronic regular or moderate exercise results in a decrease in oxidative stress. Notably, under pathological state, such as obesity, aging, etc., ROS levels could be elevated in humans, which could be attenuated by proper exercise. Significantly, exercise stimulates the development of beige adipose tissue and potentially influence the function of brown adipose tissue (BAT), which is known to be conducive to a metabolic balance through non-shivering thermogenesis (NST) and may protect from oxidative stress. Exercise-related balance of the ROS levels is associated with a healthy metabolism in humans. In this review, we summarize the integrated effects of exercise on oxidative metabolism, and especially focus on the role of brown and beige adipose tissues in this process, providing more evidence and knowledge for a better management of exercise-induced oxidative stress.

Interaction of Severe Acute Respiratory Syndrome Coronavirus 2 and Diabetes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a worldwide epidemic. It spreads very fast and hits people of all ages, especially patients with underlying diseases such as diabetes. In this review, we focus on the influences of diabetes on the outcome of SARS-CoV-2 infection and the involved mechanisms including lung dysfunction, immune disorder, abnormal expression of angiotensin-converting enzyme 2 (ACE2), overactivation of mechanistic target of rapamycin (mTOR) signaling pathway, and increased furin level. On the other hand, SARS-CoV-2 may trigger the development of diabetes. It causes the damage of pancreatic ß cells, which is probably mediated by ACE2 protein in the islets. Furthermore, SARS-CoV-2 may aggravate insulin resistance through attacking other metabolic organs. Of note, certain anti-diabetic drugs (OADs), such as peroxisome proliferator-activated receptor γ (PPARγ) activator and glucagon-like peptide 1 receptor (GLP-1R) agonist, have been shown to upregulate ACE2 in animal models, which may increase the risk of SARS-CoV-2 infection. However, Metformin, as a first-line medicine for the treatment of type 2 diabetes mellitus (T2DM), may be a potential drug benefiting diabetic patients with SARS-CoV-2 infection, probably via a suppression of mTOR signaling together with its anti-inflammatory and anti-fibrosis function in lung. Remarkably, another kind of OADs, dipeptidyl Peptidase 4 (DPP4) inhibitor, may also exert beneficial effects in this respect, probably via a prevention of SARS-CoV-2 binding to cells. Thus, it is of significant to identify appropriate OADs for the treatment of diabetes in the context of SARS-CoV-2 infections.

Metabolic Improvement via Enhancing Thermogenic Fat-Mediated Non-shivering Thermogenesis: From Rodents to Humans.

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.

Autologous Platelet-Rich Plasma for Diabetic Foot Ulcer.

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).

Combating Obesity With Thermogenic Fat: Current Challenges and Advancements.

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 ß3-adrenergic receptor (AR). Notwithstanding, administering ß3-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.

Covalent organic framework mesocrystals through dynamic modulator manipulated mesoscale self-assembly of imine macrocycle precursors.

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.

Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions.

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.

Shape and phase controlled synthesis of mesostructured carbon single crystals through mesoscale self-assembly of reactive monomicelles and their unprecedented exfoliation into single-layered carbon nanoribbons.

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.

Regulation of brown and beige fat by microRNAs.

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.

Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity.

Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. (18)F-fluorodeoxyglucose ((18)F-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 (18)F-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.