OBJECTIVE: To investigate whether astragalus polysaccharides (APS) combined with berberine (BBR) can reduce high-fat diet (HFD)-induced obesity in mice. METHODS: Except for normal mice, 32 HFD-induced obese mice were randomized into HFD, APS (1,000 mg/kg APS), BBR (200 mg/kg BBR), and APS plus BBR (1,000 mg/kg APS plus 200 mg/kg BBR) groups, respectively. After 6-week treatment (once daily by gavage), the obesity phenotype and pharmacodynamic effects were evaluated by histopathological examination of epididymal fat, liver, and colon using hematoxylin-eosin staining and serum biochemical analyses by an automated chemistry analyzer. The feces were collected at the 12 th week, and taxonomic and functional profiles of gut microbiota were analyzed by 16S ribosomal ribonucleic acid (16S rRNA) sequencing. RESULTS: Compared with HFD group, the average body weight of APS plus BBR group was decreased (P<0.01), accompanied with the reduced fat accumulation, enhanced colonic integrity, insulin sensitivity and glucose homeostasis (P<0.05 or P<0.01). Importantly, APS combined with BBR treatment was more effective than APS or BBR alone in improving HFD-induced insulin resistance (P<0.05 or P<0.01). 16S rRNA sequence-based analysis of fecal samples demonstrated that APS combined with BBR treatment exhibited a better impact on HFD-induced gut microbiota dysbiosis, exclusively via the enriched abundances of Bacteroides, which corresponded to the large increase of predicted bacterial genes involved in carbohydrate metabolism. CONCLUSION APS combined with BBR may synergistically reduce obesity and modulate the gut microbiota in HFD-fed mice.
Mice ; Animals ; Diet, High-Fat ; Berberine/therapeutic use* ; Mice, Obese ; RNA, Ribosomal, 16S/genetics* ; Gastrointestinal Microbiome ; Obesity/drug therapy* ; Insulin Resistance ; Mice, Inbred C57BL

Obesity has been identified as a chronic low-grade systemic inflammation and a key risk factor for diseases such as diabetes, hypertension, and malignancies, and has become an urgent global health burden. Adipose tissue macrophages play a significant role in adipose immune homeostasis and inflammatory responses. Under different conditions, they can be polarized into pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype. In obese individuals, there is abnormal polarization of macrophages in adipose tissue, leading to an imbalance in the M1/M2 phenotype dynamic equilibrium and the development of pathological inflammation. Therefore, restoring the balance of M1/M2 macrophage polarization is an important potential target for the treatment of chronic inflammation in obesity. Studies have shown that traditional Chinese medicine(TCM) can positively modulate macrophage polarization and produce beneficial effects on obesity. Based on existing evidence, this paper systematically reviewed the potential mechanisms of TCM in improving chronic inflammation in obesity from the perspective of macrophage polarization, in order to provide evidence for the clinical diagnosis and treatment of chronic inflammation in obesity with TCM and offer new insights for related research design and the development of new TCM.
Humans ; Animals ; Mice ; Medicine, Chinese Traditional ; Obesity/drug therapy* ; Adipose Tissue/pathology* ; Inflammation/drug therapy* ; Macrophages ; Mice, Inbred C57BL

Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ⩾ 24 kg/m²; lean, BMI < 24 kg/m²). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (-0.19 (1.47) versus 0.08 (1.99), P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.
Humans ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Overweight/drug therapy* ; Insulin Resistance ; Obesity/drug therapy* ; China ; DNA/therapeutic use*

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Mice ; Animals ; Glucagon-Like Peptide 1/metabolism* ; Receptors, Glucagon/therapeutic use* ; Xenopus laevis/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Glycopeptides/therapeutic use* ; Obesity/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Peptides/pharmacology*

OBJECTIVE: To investigate the protective effects of modified Linggui Zhugan Decoction (, MLZD), a traditional Chinese medicine formula, on obese type 2 diabetes mellitus (T2DM) rats. METHODS: Fifty Sprague-Dawley rats were randomly divided into 5 groups by a random number table, including normal, obese T2DM (ob-T2DM), MLZD low-dose [MLDZ-L, 4.625 g/(kg·d)], MLZD middle-dose [MLD-M, 9.25 g/(kg·d) ] and MLZD high-dose [MLD-H, 18.5 g/(kg·d)] groups, 10 rats in each group. After 4-week intervention, blood samples and liver, pancreas, muscle tissues were collected to assess the insulin resistance (IR), blood lipid, adipokines and inflammation cytokines. The alteration of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or Akt)/the mammalian target of rapamycin (mTOR)-ribosome protein subunit 6 kinase 1 (S6K1 )/AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 α) pathways were also studied. RESULTS: MLZD dose-dependently reduced fasting blood glucose, fasting insulin, homeostasis model of assessment for IR index and increased insulin sensitive index compared with ob-T2DM rats (P<0.05). Similarly, total cholesterol, triglyceride, low-density lipoprotein cholesterol and free fatty acids were also decreased compared with ob-T2DM rats after 4-week treatment (P<0.05 or P<0.01). Improvements in adipokines and inflammatory cytokines were observed with a raised level of adiponectin and a reduced level of leptin, resistin, tumor necrosis factor-α and interleukin-6 (P<0.05 or P<0.01). MLZD regulated the PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α pathways and restored the tissue structure of liver and pancreas (P<0.05 or P<0.01). CONCLUSIONS MLZD ameliorated glycolipid metabolism and inflammation, which may be attributed to the regulation of PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α pathways.
AMP-Activated Protein Kinases/metabolism* ; Animals ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 2/drug therapy* ; Glycolipids ; Inflammation ; Obesity/drug therapy* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism*

Type 2 diabetes mellitus is a progressive process. With the course of the disease progress, microvascular and macrovascular complications always happen. Thrombotic events caused by macrovascular complications, including coronary heart diseases and cerebrovascular diseases, are the main fatal factor for the patients with type 2 diabetes. Endothelial dysfunction, coagulative activation, impaired fibrinolysis, together with hyper-reactive platelets contribute to the diabetic prothrombotic state, which is strongly related to the macrovascular complications. In particular, the hyper-reactive platelets play a fundamental role among them. Type 2 diabetes is characterized by several metabolic dysfunctions such as hyperglycemia, insulin resistance and shortage, oxidative stress, systemic inflammation, obesity, and dyslipidemia. These metabolic dysfunctions work together to promote the formation of hyper-reactive platelets, which are distinctive in type 2 diabetes. The regular antiplatelet drugs, like aspirin, show limited inhibitory effect on them. Hence, studying the mechanism behind the hyper-reactive platelets could provide a brand-new view on the prevention of macrovascular complications and cardiovascular events in type 2 diabetes.
Blood Platelets ; Diabetes Mellitus, Type 2/drug therapy* ; Humans ; Hyperglycemia/complications* ; Insulin Resistance ; Obesity/complications*

Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.
Diabetes Mellitus, Type 2/drug therapy* ; Glucagon-Like Peptide-1 Receptor/therapeutic use* ; Glucagon-Like Peptides ; Humans ; Hypoglycemic Agents/therapeutic use* ; Motivation ; Obesity/drug therapy*

BACKGROUND: Obesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS. METHODS: Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein. RESULTS: Forty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P < 0.050). Mild and moderate gastrointestinal reactions were the most common adverse events in both groups. CONCLUSIONS: COM therapy was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects. TRIAL REGISTRATION ClinicalTrials.gov, NCT04029272. https://clinicaltrials.gov/ct2/show/NCT04029272.
Exenatide/therapeutic use* ; Female ; Humans ; Metformin/therapeutic use* ; Obesity/drug therapy* ; Overweight ; Polycystic Ovary Syndrome/drug therapy*

OBJECTIVE: We aimed to explore how fermented barley extracts with Lactobacillus plantarum dy-1 (LFBE) affected the browning in adipocytes and obese rats. METHODS: In vitro, 3T3-L1 cells were induced by LFBE, raw barley extraction (RBE) and polyphenol compounds (PC) from LFBE to evaluate the adipocyte differentiation. In vivo, obese SD rats induced by high fat diet (HFD) were randomly divided into three groups treated with oral gavage: (a) normal control diet with distilled water, (b) HFD with distilled water, (c) HFD with 800 mg LFBE/kg body weight (bw). RESULTS: In vitro, LFBE and the PC in the extraction significantly inhibited adipogenesis and potentiated browning of 3T3-L1 preadipocytes, rather than RBE. In vivo, we observed remarkable decreases in the body weight, serum lipid levels, white adipose tissue (WAT) weights and cell sizes of brown adipose tissues (BAT) in the LFBE group after 10 weeks. LFBE group could gain more mass of interscapular BAT (IBAT) and promote the dehydrogenase activity in the mitochondria. And LFBE may potentiate process of the IBAT thermogenesis and epididymis adipose tissue (EAT) browning via activating the uncoupling protein 1 (UCP1)-dependent mechanism to suppress the obesity. CONCLUSION These results demonstrated that LFBE decreased obesity partly by increasing the BAT mass and the energy expenditure by activating BAT thermogenesis and WAT browning in a UCP1-dependent mechanism.
3T3 Cells ; Adipocytes ; drug effects ; physiology ; Adipose Tissue, Brown ; drug effects ; physiology ; Adipose Tissue, White ; drug effects ; physiology ; Animal Feed ; analysis ; Animals ; Anti-Obesity Agents ; administration & dosage ; metabolism ; Cell Differentiation ; drug effects ; Diet ; Fermentation ; Hordeum ; chemistry ; Lactobacillus plantarum ; chemistry ; Male ; Mice ; Obesity ; drug therapy ; genetics ; Plant Extracts ; chemistry ; Probiotics ; administration & dosage ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Uncoupling Protein 1 ; genetics ; metabolism

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.
Antiviral Agents ; Apoptosis ; Carcinoma, Hepatocellular ; Cytokines ; Diet ; Drug Therapy ; Dyslipidemias ; Fibrosis ; Hepatitis B ; Humans ; Insulin Resistance ; Korea ; Liver Cirrhosis ; Liver Diseases ; Liver Transplantation ; Non-alcoholic Fatty Liver Disease ; Obesity ; United States ; Weight Loss