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1.
PLoS Biol ; 20(4): e3001619, 2022 04.
Article in English | MEDLINE | ID: mdl-35476671

ABSTRACT

Skeletal muscle regeneration is essential for maintaining muscle function in injury and muscular disease. Myogenesis plays key roles in forming new myofibers during the process. Here, through bioinformatic screen for the potential regulators of myogenesis from 5 independent microarray datasets, we identify an overlapping differentially expressed gene (DEG) optineurin (OPTN). Optn knockdown (KD) delays muscle regeneration in mice and impairs C2C12 myoblast differentiation without affecting their proliferation. Conversely, Optn overexpression (OE) promotes myoblast differentiation. Mechanistically, OPTN increases nuclear levels of ß-catenin and enhances the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription activity, suggesting activation of Wnt signaling pathway. The activation is accompanied by decreased protein levels of glycogen synthase kinase 3ß (GSK3ß), a negative regulator of the pathway. We further show that OPTN physically interacts with and targets GSK3ß for autophagic degradation. Pharmacological inhibition of GSK3ß rescues the impaired myogenesis induced by Optn KD during muscle regeneration and myoblast differentiation, corroborating that GSK3ß is the downstream effector of OPTN-mediated myogenesis. Together, our study delineates the novel role of OPTN as a potential regulator of myogenesis and may open innovative therapeutic perspectives for muscle regeneration.


Subject(s)
Autophagy , Cell Cycle Proteins , Glycogen Synthase Kinase 3 beta , Membrane Transport Proteins , Muscle Development , Wnt Signaling Pathway , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Differentiation/genetics , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice , Muscle Development/genetics , Muscle, Skeletal/metabolism , Wnt Signaling Pathway/genetics
2.
PLoS Biol ; 20(2): e3001517, 2022 02.
Article in English | MEDLINE | ID: mdl-35202387

ABSTRACT

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.


Subject(s)
Camptothecin/pharmacology , Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics , Growth Differentiation Factor 15/genetics , Obesity/prevention & control , Animals , Body Weight/drug effects , Body Weight/genetics , Camptothecin/pharmacokinetics , Cell Line , Cell Line, Tumor , Diet, High-Fat/adverse effects , Eating/drug effects , Eating/genetics , Gene Expression Regulation/drug effects , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Growth Differentiation Factor 15/metabolism , HEK293 Cells , HL-60 Cells , Humans , MCF-7 Cells , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Obesity/etiology , Obesity/genetics , PC-3 Cells
3.
PLoS Biol ; 18(3): e3000688, 2020 03.
Article in English | MEDLINE | ID: mdl-32218572

ABSTRACT

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.


Subject(s)
Adipose Tissue, Brown/metabolism , Anti-Obesity Agents/therapeutic use , Coumarins/therapeutic use , Obesity/prevention & control , Adipocytes, Brown/drug effects , Adipocytes, Brown/metabolism , Adipocytes, White/drug effects , Adipocytes, White/metabolism , Adipose Tissue, White/metabolism , Animals , Diet, High-Fat/adverse effects , Energy Metabolism/drug effects , Fatty Liver/prevention & control , Glucose Intolerance/prevention & control , Insulin Resistance , Maillard Reaction , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/metabolism , Propylthiouracil/toxicity , Thermogenesis , Triiodothyronine/antagonists & inhibitors , Triiodothyronine/metabolism , Weight Gain/drug effects
4.
FASEB J ; 34(5): 6688-6702, 2020 05.
Article in English | MEDLINE | ID: mdl-32212192

ABSTRACT

Mitochondrial aconitase (Aco2) catalyzes the conversion of citrate to isocitrate in the TCA cycle, which produces NADH and FADH2, driving synthesis of ATP through OXPHOS. In this study, to explore the relationship between adipogenesis and mitochondrial energy metabolism, we hypothesize that Aco2 may play a key role in the lipid synthesis. Here, we show that overexpression of Aco2 in 3T3-L1 cells significantly increased lipogenesis and adipogenesis, accompanied by elevated mitochondrial biogenesis and ATP production. However, when ATP is depleted by rotenone, an inhibitor of the respiratory chain, the promotive role of Aco2 in adipogenesis is abolished. In contrast to Aco2 overexpression, deficiency of Aco2 markedly reduced lipogenesis and adipogenesis, along with the decreased mitochondrial biogenesis and ATP production. Supplementation of isocitrate efficiently rescued the inhibitory effect of Aco2 deficiency. Similarly, the restorative effect of isocitrate was abolished in the presence of rotenone. Together, these results show that Aco2 sustains normal adipogenesis through mediating ATP production, revealing a potential mechanistic link between TCA cycle enzyme and lipid synthesis. Our work suggest that regulation of adipose tissue mitochondria function may be a potential way for combating abnormal adipogenesis related diseases such as obesity and lipodystrophy.


Subject(s)
Aconitate Hydratase/metabolism , Adenosine Triphosphate/metabolism , Adipogenesis , Adipose Tissue/cytology , Mitochondria/enzymology , 3T3-L1 Cells , Aconitate Hydratase/genetics , Adipose Tissue/metabolism , Animals , Male , Mice , Mice, Inbred C57BL
5.
Cells ; 9(2)2020 01 31.
Article in English | MEDLINE | ID: mdl-32023857

ABSTRACT

The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 µM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.


Subject(s)
Adipogenesis/drug effects , Dietary Supplements , Down-Regulation/drug effects , Janus Kinase 2/metabolism , Lactones/pharmacology , Mitosis/drug effects , Phorbols/pharmacology , STAT3 Transcription Factor/metabolism , Sesquiterpenes/pharmacology , Signal Transduction , 3T3-L1 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Adipogenesis/genetics , Animals , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Clone Cells , Diet, High-Fat , Down-Regulation/genetics , Gene Expression Regulation/drug effects , Hyperglycemia/genetics , Hyperglycemia/pathology , Lactones/chemistry , Male , Mice , Mice, Inbred C57BL , Obesity/genetics , Obesity/pathology , Phorbols/chemistry , Sesquiterpenes/chemistry , Signal Transduction/drug effects , Triglycerides/biosynthesis
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