A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications.

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

Skeletal muscles and gut microbiota-derived metabolites: novel modulators of adipocyte thermogenesis.

Obesity occurs when overall energy intake surpasses energy expenditure. White adipose tissue is an energy storage site, whereas brown and beige adipose tissues catabolize stored energy to generate heat, which protects against obesity and obesity-associated metabolic disorders. Metabolites are substrates in metabolic reactions that act as signaling molecules, mediating communication between metabolic sites (i.e., adipose tissue, skeletal muscle, and gut microbiota). Although the effects of metabolites from peripheral organs on adipose tissue have been extensively studied, their role in regulating adipocyte thermogenesis requires further investigation. Skeletal muscles and intestinal microorganisms are important metabolic sites in the body, and their metabolites play an important role in obesity. In this review, we consolidated the latest research on skeletal muscles and gut microbiota-derived metabolites that potentially promote adipocyte thermogenesis. Skeletal muscles can release lactate, kynurenic acid, inosine, and ß-aminoisobutyric acid, whereas the gut secretes bile acids, butyrate, succinate, cinnabarinic acid, urolithin A, and asparagine. These metabolites function as signaling molecules by interacting with membrane receptors or controlling intracellular enzyme activity. The mechanisms underlying the reciprocal exchange of metabolites between the adipose tissue and other metabolic organs will be a focal point in future studies on obesity. Furthermore, understanding how metabolites regulate adipocyte thermogenesis will provide a basis for establishing new therapeutic targets for obesity.

New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.

Bone marrow stromal cell-derived exosome combinate with fibrin on tantalum coating titanium implant accelerates osseointegration.

This study aims to present a sustainably releasing system of exosomes-fibrin combinate loaded on tantalum-coating titanium implants. We hope to investigate potential effects of the system on osseointegration between tantalum coating titanium implants and its surrounding bone tissue. Exosomes derived from rabbit bone marrow stromal cells (rBMSCs) and fibrin were deposited onto the micro-nanostructure tantalum coating surface (Ta + exo + FI) and compared to control groups, including tantalum coating (Ta), tantalum coating loaded exosomes (Ta + exo) and tantalum coating loaded fibrin (Ta + FI). The optimal concentration of loading exosomes, exosomes uptake capacity by BMSCs, and the effect of controlled-release by fibrin were assessed by laser scanning confocal microscope (LCSM) and microplate reader. The optimal concentration of exosomes was 1 µg/µL. Adhesion, proliferation, and osteogenic differentiation ability of BMSCs on different materials were assessed in vitro. Finally, osseointegrative capacity of Ta, Ta + exo, Ta + FI, Ta + exo + FI implants in rabbit tibia were respectively evaluated with histology and bone-implant contact ratio (BIC%). It was demonstrated that exosome sustained-release system with fibrin loading on the tantalum coating was successfully established. Fibrin contribute to exosomes release extension from 2d to 6d. Furthermore, Ta + exo + FI significantly promoted adhesion, proliferation, and osteogenic differentiation of BMSCs. In vivo, the implants in Ta + exo + FI group displayed the highest osseointegrative capability than those in other groups. It is concluded that this exosome delivery system on the implants may be an effective way for tantalum coating titanium implants to promote osseointegration between implant and its surrounding bone tissue.

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes.

Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.

Synchrotron Infrared Microspectroscopy for Stem Cell Research.

Stem cells have shown great potential functions for tissue regeneration and repair because of their unlimited self-renewal and differentiation. Stem cells reside in their niches, making them a hotspot for the development and diagnosis of diseases. Complex interactions between niches and stem cells create the balance between differentiation, self-renewal, maturation, and proliferation. However, the multi-facet applications of stem cells have been challenged since the complicated responses of stem cells to biological processes were explored along with the limitations of current systems or methods. Emerging evidence highlights that synchrotron infrared microspectroscopy, known as synchrotron radiation-based Fourier transform infrared microspectroscopy, has been investigated as a potentially attractive technology with its non-invasive and non-biological probes in stem cell research. With their unique vibration bands, the quantitative mapping of the content and distribution of biomolecules can be detected and characterized in cells or tissues. In this review, we focus on the potential applications of synchrotron infrared microspectroscopy for investigating the differentiation and fate determination of stem cells.

Paracrine Regulation of Adipose Tissue Macrophages by Their Neighbors in the Microenvironment of Obese Adipose Tissue.

Obesity has recently been defined as a chronic low-grade inflammatory disease. Obesity-induced inflammation of adipose tissue (AT) is an essential trigger for insulin resistance (IR) and related metabolic diseases. Although the underlying molecular basis of this inflammation has not been fully identified, there is consensus that the recruited and activated macrophages in AT are the most important culprits of AT chronic inflammation. Adipose tissue macrophages (ATMs) are highly plastic and could be polarized from an anti-inflammatory M2 to proinflammatory M1 phenotypes on stimulation by microenvironmental signals from obese AT. Many efforts have been made to elucidate the molecular signaling pathways of macrophage polarization; however, the upstream drivers governing and activating macrophage polarization have rarely been summarized, particularly regulatory messages from the AT microenvironment. In addition to adipocytes, the AT bed also contains a variety of immune cells, stem cells, as well as vascular, neural, and lymphatic tissues throughout, which together orchestrate the AT microenvironment. Here, we summarize how the aforesaid neighbors of ATMs in the AT microenvironment send messages to ATMs and thus regulate its phenotype during obesity. Deciphering the biology and polarization of ATMs in the obese environment is expected to provide a precise immunotherapy for adipose inflammation and obesity-related metabolic diseases.

Organokines and Exosomes: Integrators of Adipose Tissue Macrophage Polarization and Recruitment in Obesity.

The prevalence of obesity is escalating and has become a worldwide health challenge coinciding with the development of metabolic diseases. Emerging evidence has shown that obesity is accompanied by the infiltration of macrophages into adipose tissue, contributing to a state of low-grade chronic inflammation and dysregulated metabolism. Moreover, in the state of obesity, the phenotype of adipose tissue macrophages switches from the M2 polarized state to the M1 state, thereby contributing to chronic inflammation. Notably, multiple metabolic organs (adipose tissue, gut, skeletal muscle, and the liver) communicate with adipose tissue macrophages via secreting organokines or exosomes. In this review, we systematically summarize how the organokines (adipokines, gut microbiota and its metabolites, gut cytokines, myokines, and hepatokines) and exosomes (adipocyte-, skeletal muscle-, and hepatocyte-derived exosomes) act as important triggers for macrophage recruitment in adipose tissue and adipose tissue macrophage polarization, thus providing further insight into obesity treatment. In addition, we also highlight the complex interaction of organokines with organokines and organokines with exosomes, revealing new paths in understanding adipose tissue macrophage recruitment and polarization.

Adipose endothelial cells mastering adipose tissues metabolic fate.

Dynamic communication within adipose tissue depends on highly vascularized structural characteristics to maintain systemic metabolic homoeostasis. Recently, it has been noted that adipose endothelial cells (AdECs) act as essential bridges for biological information transmission between adipose-resident cells. Hence, paracrine regulators that mediate crosstalk between AdECs and adipose stromal cells were summarized. We also highlight the importance of AdECs to maintain adipocytes metabolic homoeostasis by regulating insulin sensitivity, lipid turnover and plasticity. The differential regulation of AdECs in adipose plasticity often depends on vascular density and metabolic states. Although choosing pro-angiogenic or anti-angiogenic therapies for obesity is still a matter of debate in clinical settings, the growing numbers of drugs have been confirmed to play an anti-obesity effect by affecting vascularization. Pharmacologic angiogenesis intervention has great potential as therapeutic strategies for obesity.

High Serum Asprosin Levels Are Associated with Presence of Metabolic Syndrome.

OBJECTIVE: Asprosin, a new adipocytokine, has reportedly been associated with glucose release, dyslipidemia, and insulin resistance (IR). However, the relationship of asprosin with metabolic syndrome (MetS) remains unknown. This study aimed to investigate serum asprosin levels in MetS as well as their association with various metabolic parameters in humans. METHODS: A total of 131 consecutive patients with MetS, and 162 age-matched, healthy subjects were recruited for this study. Serum asprosin concentrations were determined using the enzyme-linked immunosorbent assay. Lipid profile, glucose, insulin, and inflammatory markers were also measured. RESULTS: Serum asprosin levels were higher in subjects with MetS (23.52 [16.70, 32.05] ng/mL) than in controls (16.70 [12.87, 22.38] ng/mL; P < 0.01), and they showed an increasing trend with increasing numbers of metabolic components (P for trend < 0.01). In all studied subjects, serum asprosin levels were positively correlated with body mass index, waist circumference, triglycerides, fasting plasma glucose, 2-hour plasma glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, interleukin-6, and monocyte chemoattractant protein-1 and negatively correlated with high-density lipoprotein cholesterol (P < 0.05). In multiple linear regression, asprosin was independently and positively correlated with triglyceride and HOMA-IR (P < 0.05). Binary logistic regression revealed that asprosin was independently and positively correlated with the occurrence of MetS and IR, even after controlling for anthropometric variables, lipid profiles, and inflammatory markers. CONCLUSION: Asprosin is a potential metabolic-related adipokine and may be related to IR and MetS. This trial was registered with ChiCTR, ChiCTR1800018347.

Dosimetric evaluation of helical tomotherapy and volumetric-modulated arc therapy for malignant pleural mesothelioma: a planning study for dose escalation.

BACKGROUND: To compare the dosimetric differences between helical tomotherapy (HT) and volumetric-modulated arc therapy (VMAT) treatment plans for inoperable malignant pleural mesothelioma (MPM). METHODS: Ten patients with inoperable MPM were retrospectively planned with the HT and VMAT techniques, and the dose-volume histogram (DVH)-based parameters of the planning target volume (PTV) and organs at risk (OARs) were compared. RESULTS: Compared with the VMAT plans, the target homogeneity index (HI) and conformity index (CI) of the HT plans were significantly better (HI: 1.04±0.01 vs. 1.11±0.03, CI: 0.80±0.07 vs. 0.71±0.12, respectively) (P<0.001, P=0.013, respectively). Regarding the OARs, including the ipsilateral lung, contralateral lung, heart, and spinal cord, the differences among the V30 (Vx: fraction of volume receiving >5, 10, 20, and 30 Gy, respectively) of the ipsilateral lung and V5, V10, and V20 of the contralateral lung were statistically significant (P=0.031, P=0.030, P=0.021, P=0.003, respectively). However, there was no significant differences between HT plans and VMAT plans, regarding the V5, V10 and V20 of the ipsilateral lung, V3 of the contralateral lung, V5 and Dmean of the heart, and Dmax of the cord. The treatment delivery time of the VMAT was significantly shorter than that of the HT (mean delivery time: 3.27±1.65 vs. 11.11±3.75 min, respectively) (P<0.001). CONCLUSIONS: Compared to the VMAT plans, the HT plans not only demonstrated more optimal target coverage and conformity but also considerably reduced the dose-volume parameters of the OARs in both low-dose areas in contralateral lung and high-dose areas in ipsilateral lung and contralateral lung, which is correlated to radiation injury. However, the treatment delivery time of the HT plans was longer.

Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes.

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

Exogenous Hydrogen Sulfide Alleviates-Induced Intracellular Inflammation in HepG2 Cells.

Fatty acids induced hepatic inflammation plays an important role in nonalcoholic fatty liver disease (NAFLD) pathogenesis. Hydrogen sulfide (H2S), an endogenous gasotransmitter, has been established to possess potent anti-inflammation in various human organs. However, the anti-inflammation property of H2S in the fatty liver is still needed to further elucidate. Hence, this study aimed to investigate whether exogenous H2S can protect hepatocytes against inflammation induced by palmitic acid (PA). HepG2 hepatocytes were exposed to PA for 24 h to induce free fatty acids-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to PA. Cell viability, inflammatory cytokines (TNF-α, IL-6 and IL-1ß), NLRP3 inflammasome and NF-κB were measured by a combination of MTT assay, ELISA, Western blot and Immunofluorescence. Here, we found that exogenous H2S dose-dependently inhibited the expression of pro-inflammatory cytokines, NLRP3 inflammasome and activation of NF-κB signaling in PA-induced HepG2 cells. Thus, H2S might be a candidate therapeutic agent against NAFLD.

Serum CCN3 levels are increased in type 2 diabetes mellitus and associated with obesity, insulin resistance and inflammation.

BACKGROUD: CCN3 is a novel adipokine and has emerged as a potential metabolic regulator. However, information regarding the role of CCN3 in type 2 diabetes mellitus (T2DM) remains unclear. This study measured for the first time serum CCN3 levels in T2DM and explored the correlations between its serum levels and various metabolic parameters in humans. METHODS: A total of 219 newly diagnosed T2DM (nT2DM) patients and 205 healthy control subjects, matched for age and sex ratio, were enrolled. Circulating CCN3 and TNF-α, IL-6 and MCP-1 were measured by ELISA. The anthropometric assessment and biochemical evaluation were done in all subjects. OGTT were performed in 34 healthy individuals to investigate the association of CCN3 with glucose. RESULTS: Serum CCN3 levels were significantly higher in nT2DM patients compared to those of the healthy controls (6.71[4.88, 8.56] vs. 4.51[3.55, 5.99] ng/ml, P < 0.01). Serum CCN3 positively correlated with BMI, WC, FAT%, TG, FPG, 2 h-PG, HbA1c, FIns, HOMA-IR, hs-CRP and TNF-α, IL-6 and MCP-1, but negatively with HOMA-ß in all individuals (P < 0.05). Multiple linear regression analysis indicated that BMI, HOMA-IR, TNF-α and MCP-1 were independently associated with CCN3. Multivariate logistic regression analysis demonstrated that CCN3 was correlated with nT2DM. Finally, area under ROC curve of CCN3 (gender and age adjusted) for predicting the presence of nT2DM was 0.725(95% CI: 0.676-0.773). After an oral glucose challenge, there was no obvious change in the circulating levels of CCN3 as compared to 0 min (P > 0.05). CONCLUSIONS: Elevation of CCN3 in nT2DM supports the hypothesis that CCN3 may serve as a risk factor associated with the pathogenesis of T2DM.

JAZF1, a relevant metabolic regulator in type 2 diabetes.

Excessive adiposity and metabolic inflammation are the key risk factors of type 2 diabetes mellitus (T2DM). Juxtaposed with another zinc finger gene 1 (JAZF1) has been identified as a novel transcriptional cofactor, with function of regulating glucose and lipid homeostasis and inflammation. JAZF1 is involved in metabolic process of T2DM via interaction with several nuclear receptors and protein kinases. Additionally, increasing evidence from genome-wide association studies (GWAS) has shown that JAZF1 polymorphisms are closely associated with T2DM. In this review, we have updated the latest research advances on JAZF1 and discussed its regulatory network in T2DM. The association between JAZF1 polymorphisms and T2DM is discussed as well. The information provided is of importance for guiding future studies as well as for the design of JAZF1-based T2DM therapy.

Serum zinc-α2-glycoprotein levels are elevated and correlated with thyroid hormone in newly diagnosed hyperthyroidism.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.

Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis.

BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.