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1.
Pediatr Endocrinol Rev ; 17(1): 4-16, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599132

RESUMO

Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes including growth and metabolism. GH promotes anabolic action in all tissues except adipose, where it catabolizes stored fat to release energy for the promotion of growth in other tissues. However, chronic stimulation of lipolysis by GH results in an increased flux of free fatty acids (FFAs) into systemic circulation. Hence, a sustained release of high levels of GH contributes significantly to the development of insulin resistance by antagonizing the anti-lipolytic action of insulin. The molecular pathways associated with the lipolytic effect of GH in adipose tissue however, remain elusive. Recent studies have provided molecular insights into GH-induced lipolysis and impairment of insulin signaling. This review discusses the physiological and metabolic actions of GH on adipose tissue as well as GH-mediated deregulation of the FSP27-PPARγ axis which alters adipose tissue homeostasis and contributes to the development of insulin resistance and Type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Hormônio do Crescimento Humano , Resistência à Insulina , Lipólise , Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/fisiopatologia , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/farmacologia , Humanos , Lipólise/efeitos dos fármacos
2.
J Drugs Dermatol ; 18(9): 870-877, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31524342

RESUMO

BACKGROUND: ATX-101 (deoxycholic acid) causes adipocytolysis when injected into subcutaneous fat. OBJECTIVE: Evaluate the long-term safety and efficacy of ATX-101 for submental fat (SMF) reduction. METHODS: Adults (N=165) with moderate-to-extreme SMF received ≤6 treatments of open-label ATX-101 (2 mg/cm2) and were evaluated up to 12 months after last treatment. Efficacy end points included improvements in SMF based on clinician or subject assessment, patient-reported outcomes, downtime (via subject questionnaire), and skin laxity. Safety was evaluated throughout the study. RESULTS: Twelve weeks after last treatment, most subjects achieved a ≥1-grade improvement in SMF based on clinician (86.8%) or subject (83.8%) evaluation; at 12 months, 90.4% and 80.7% of these responders, respectively, maintained the response. Overall, 84.9% of subjects were satisfied with the appearance of their face/chin. At 12 months, 82.9% of subjects had unchanged, and 10.1% had improved, skin laxity relative to 12 weeks after last treatment. Adverse events were mild to moderate and mainly involved the treatment area. During the 7 days after the first treatment, 13.3% of subjects missed work and 33.9% missed social/leisure activities. Following subsequent treatments, 2.4%­6.0% of subjects missed work and 10.0%­15.7% missed social/leisure activities. CONCLUSION: The safety and efficacy of ATX-101 were sustained over 12 months. ClinicalTrials.gov identifier, NCT01426373 J Drugs Dermatol. 2019;18(9):870-877.


Assuntos
Técnicas Cosméticas , Ácido Desoxicólico/administração & dosagem , Lipólise/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Adulto , Queixo , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Gordura Subcutânea/metabolismo , Resultado do Tratamento
3.
Eur J Pharm Biopharm ; 142: 258-264, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276759

RESUMO

The effect of drug load and digestion on the solubilization and absorption of fenofibrate in self-nanoemulsifying drug delivery system (SNEDDS) was assessed in a pharmacokinetic study in rats and in an in vitro lipolysis model. SNEDDS containing fenofibrate at 75% of equilibrium solubility (Seq), a super-saturated SNEDDS (super-SNEDDS) containing fenofibrate at 150% of Seq and a super-SNEDDS suspension containing fenofibrate at 100% of Seq and an additional 50% Seq fenofibrate suspended (150% of Seq in total) were used. To assess the effect of lipid digestion on fenofibrate absorption in rats and fenofibrate solubilization during in vitro lipolysis, the lipase inhibitor orlistat was added at 1% (w/w) to the SNEDDS, resulting in six different SNEDDS: SNEDDS, super-SNEDDS and super-SNEDDS suspension with and without orlistat 1% (w/w). In vivo, super-SNEDDS had a higher Cmax and AUC0-30h compared to SNEDDS and super-SNEDDS suspension, both with and without orlistat. While orlistat did not affect fenofibrate absorption in SNEDDS and super-SNEDDS, an increase of Tmax and AUC0-30h for super-SNEDDS suspension was found when orlistat was present. During in vitro lipolysis, the addition of orlistat decreased digestion and lowered drug precipitation. Super-SNEDDS showed significantly increased absorption in rats compared to SNEDDS and super-SNEDDS suspension and the inhibition of digestion resulted in prolonged and increased absorption for the super-SNEDDS suspension.


Assuntos
Fenofibrato/administração & dosagem , Fenofibrato/metabolismo , Administração Oral , Animais , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos , Suspensões/administração & dosagem , Suspensões/farmacocinética
4.
J Drugs Dermatol ; 18(7): 675-680, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31334926

RESUMO

Introduction: Injectable deoxycholic acid (DCA; Kybella; Allergan, Irvine, CA) is currently approved only for treatment of persistent submental fat (SMF). Many cosmetic surgeons use DCA off-label to treat fat tissue in other areas of the body. There is no review summarizing the off-label uses of injectable DCA. Methods: A systematic literature search was conducted through PubMed, Cochrane, CINAHL, and Web of Science databases using search terms "ATX-101 OR Kybella OR deoxycholic OR deoxycholate NOT amphotericin NOT bile" in accordance to PRISMA guidelines to identify off-label uses for injectable DCA or ATX-101. Results: Ten pertinent articles were identified for review. Anatomic areas treated include the face, brassiere line, foot, and gluteotrochanteric region. Indications include facial contouring, paradoxical adipose hyperplasia, HIV/HAART-associated buccal fat pad lipodystrophy, and reduction of lipomatous tumors. DCA is efficacious at causing lipolysis and safe with minimal side effects. Most patients treated for cosmetic indications reported high patient satisfaction. Conclusion: Off-label use of injectable DCA demonstrate a similar safety profile, effectiveness, and overall patient satisfaction compared to FDA-approved use for persistent SMF. DCA appears to be a safe and efficacious alternative to surgical reduction of unwanted adipose tissue in non-submental areas. Larger-scale studies are warranted to explore further cosmetic and potential medical applications. J Drugs Dermatol. 2019;18(7):675-680.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Técnicas Cosméticas/efeitos adversos , Ácido Desoxicólico/administração & dosagem , Uso Off-Label , Nádegas , Ácido Desoxicólico/efeitos adversos , Estética , Face , , Humanos , Injeções Subcutâneas/efeitos adversos , Lipólise/efeitos dos fármacos , Satisfação do Paciente , Resultado do Tratamento
5.
Fitoterapia ; 137: 104250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271784

RESUMO

Obesity is associated with a number of metabolic disorders. Lipolysis is the initial step in the metabolism of lipids stored in adipocytes and is therefore considered a therapeutic target for obesity. Quassinoids are unique terpenes found in plants of the Simaroubaceae family, which were recently reported to have lipolytic activity and to suppress weight gain. Brucea javanica is a plant employed in traditional medicines in Asia, which is known to contain various quassinoids. Here, we investigated the lipolytic activity of B. javanica extracts, and identified six quassinoids: brucein A, brucein B, brucein C, 3'-hydroxybrucein A, brusatol, and bruceantinol, which represent the bioactive principals. The quassinoids contained in B. javanica demonstrated lipolytic activity at nanomolar concentrations, which were an order of magnitude lower than those of the previously reported quassinoids, suggesting that they may be useful for the treatment of obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Brucea/química , Lipólise/efeitos dos fármacos , Quassinas/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Frutas/química , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Quassinas/isolamento & purificação , Sementes/química
6.
Chem Biol Interact ; 311: 108755, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31319077

RESUMO

Effective control of white adipose tissue accumulation would provide a therapeutic strategy for obesity, which poses a growing global problem. The plant chemical mangiferin stimulates adenosine monophosphate-activated protein kinase (AMPK), which inhibits adipogenesis and has therefore been considered a therapeutic target for obesity and related diseases. We previously reported the anti-inflammatory properties of 6'-O-acetyl mangiferin (OAM). In this study, we evaluated the potential of OAM as an AMPK activator in vitro in 3T3-L1 preadipocytes. OAM inhibited adipogenesis as indicated by lower intracellular lipid and triglyceride accumulation as well as reduced adipogenic gene and protein expression upon treatment. OAM-treated 3T3-L1 cells excreted more glycerol, indicating increased lipolysis, which was supported by increased expression of lipolysis-related genes, including adipose triglyceride lipase and hormone-sensitive lipase. We determined that OAM upregulates lipolysis via phosphorylation-dependent activation of AMPK. Further, OAM upregulated the ß-oxidation pathway as indicated by enhanced expression of phosphorylated acetyl-CoA-carboxylase and long-chain acyl-CoA synthetase 1. In conclusion, OAM markedly decreased intracellular lipid accumulation by enhancing lipolysis via AMPK activation and by upregulating ß-oxidation. Thus, OAM has potential as a drug for the prevention and/or improvement of obesity and related diseases and deserves further study.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Iris (Planta)/química , Lipólise/efeitos dos fármacos , Xantonas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iris (Planta)/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
7.
J Nat Med ; 73(4): 707-716, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31104252

RESUMO

Diabetes is a chronic disease associated with triglyceride metabolism disorder, being an etiological factor in fatty liver disease, hypertension, and cardiovascular diseases. Diet-based therapy including energy balance and herbal supplements is a suitable approach to ameliorate progression of the disease. Leaves of Lippia triphylla (lemon verbena) from the family Verbenaceae are a foodstuff used as a tea drink or cooking seasoning, with confirmed safety during long-term use. We report herein the regulatory effect of L. triphylla extract (LTE) and its major compound acteoside (ACT) on abnormal liver lipid metabolism. Both LTE and ACT administration significantly decreased serum and hepatic lipid content, increased the phosphorylation level of the energy metabolism moderator adenosine 5'-monophosphate-activated protein kinase (AMPK), and reduced two major markers of lipid synthesis, viz. acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), with an obvious enhancement in ACC phosphorylation. Furthermore, ACT promoted lipolysis and fatty acid oxidation by increasing messenger RNA (mRNA) expression of adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase (CPT)-1. These results provide scientific evidence for the development of functional foods containing L. triphylla extract and acteoside for treatment of diabetes-associated lipid metabolism disorder.


Assuntos
Diabetes Mellitus/dietoterapia , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lippia/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
8.
Biosci Biotechnol Biochem ; 83(9): 1782-1789, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31045477

RESUMO

Activation of the adipose lipolytic pathway during lipid metabolism is mediated by protein kinase A (PKA), which responds to ß-adrenergic stimulation, leading to increased lipolysis. Soy is well known as a functional food and it is able to affect lipolysis in adipocytes. However, the mechanism by which soy components contribute to the lipolytic pathway remains to be fully elucidated. Here, we show that hydrolyzed soy enhances isoproterenol-stimulated lipolysis and activation of PKA in 3T3-L1 adipocytes. We also found that the expression of ß-adrenergic receptors, which coordinate the activation of PKA, is elevated in adipocytes differentiated in the presence of soy hydrolysate. The activity of the soy hydrolysate towards ß-adrenergic receptor expression was detected in its hydrophilic fraction. Our results suggest that the soy hydrolysate enhances the PKA pathway through the upregulation of ß-adrenergic receptor expression and thereby, increase lipolysis in adipocytes.


Assuntos
Adipócitos/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Soja/metabolismo , Células 3T3-L1 , Animais , Cromatografia Líquida de Alta Pressão/métodos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hidrólise , Camundongos
9.
J Agric Food Chem ; 67(22): 6232-6240, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31075194

RESUMO

This study investigated the effects and molecular mechanism of a combination of capsaicin and capsiate on promoting lipid metabolism and inducing browning in 3T3-L1 white adipocytes. The combination significantly suppressed lipid accumulation in adipocytes ( p = 0.019) and robustly improved lipid metabolic profiles, including decreased triacylglycerol (0.6703 ± 0.0385 versus 0.2849 ± 0.0188 mmol/g of protein; p < 0.001), total cholesterol (0.1282 ± 0.0241 versus 0.0651 ± 0.0178 mmol/g of protein; p = 0.003), and low-density lipoprotein cholesterol (0.0021 ± 0.0017 versus 0.0005 ± 0.0002 mmol/g of protein; p = 0.024) and increased high-density lipoprotein cholesterol (0.0162 ± 0.0141 versus 0.1002 ± 0.0167 mmol/g of protein; p = 0.012). Furthermore, this combination markedly upgraded the protein levels of cluster of differentiation 36 ( p = 0.007) and adipose triglyceride lipase ( p = 0.013) and phosphorylation of hormone-sensitive lipase at Ser660, Ser565, and Ser563 ( p < 0.001, p = 0.027, and p = 0.002, respectively), indicating increases of fatty acid transport and lipolysis. The levels of lipid metabolism regulators, phosphorylation of adenosine-monophosphate-activated protein kinases α and ß ( p = 0.011, and p < 0.001, respectively), sirtuin 1 ( p = 0.004), and vanilloid transient receptor subtype I ( p = 0.014) were also increased by the combination. Moreover, the combination greatly activated the browning program in adipocytes, as demonstrated by increases in beige-specific gene and protein. Further research found that the protein levels of peroxisome proliferator-activated receptor γ (PPARγ; p = 0.001) and ß3-adrenergic receptor (ß3-AR; p = 0.026) were elevated by the combination, and most of the beige-specific markers were abolished by pretreatment of antagonists of PPARγ or ß3-AR. In conclusion, these results indicated that a combination of capsaicin and capsiate could induce browning in white adipocytes via activation of the PPARγ/ß3-AR signaling pathway, and this combination might be worth investigating as a potential cure for obesity.


Assuntos
Adipócitos Marrons/citologia , Adipócitos Brancos/efeitos dos fármacos , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR gama/metabolismo , Receptores Adrenérgicos beta/metabolismo , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Camundongos , PPAR gama/genética , Receptores Adrenérgicos beta/genética , Transdução de Sinais/efeitos dos fármacos
10.
Nutrients ; 11(3)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901932

RESUMO

In this study, two in vitro digestion models were employed to compare the rate of lipolysis in soybean oil (SBO), pomegranate oil (PGO), a physical blend (PHY, 1:1 molar ratio of SBO:PGO, w/w), and their enzymatically interesterified oil (IO). In the pH-stat digestion model (emulsified oils with bile salts), PGO emulsion containing 74.7% conjugated form of linolenic acid (CLn) showed a significantly lower release rate of free fatty acid (FFA) than the other oil emulsions (p < 0.05). In FFA release rates and oil droplet sizes between PHY and IO emulsions, no significant differences were observed (p > 0.05). In a simulated model of small intestinal digestion, the lipolysis rates of SBO, PGO, PHY, and IO after digestion for 30 min in digestion fluids were 80.4%, 66.5%, 74.8%, and 77.0%, respectively. The rate of lipolysis in PGO was significantly lower than that in SBO (p < 0.05), and the lowest lipolysis rate was observed in the conjugated form of trilinolenoyl glycerol (CLn-CLn-CLn).


Assuntos
Ácidos Graxos/farmacologia , Lipólise/efeitos dos fármacos , Óleos Vegetais/farmacologia , Punicaceae , Óleo de Soja/farmacologia , Ácidos e Sais Biliares , Digestão/efeitos dos fármacos , Emulsões/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Intestino Delgado/metabolismo , Modelos Biológicos , Ácido alfa-Linoleico
11.
J Drugs Dermatol ; 18(3): 266-272, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909331

RESUMO

Copy: The injectable adipocytolytic drug deoxycholic acid (DCA) is the first pharmacological intervention approved for the reduction of submental fat (SMF) and offers an alternative to invasive measures to improve the submental profile and the cervico-mental angle. DCA injection (ATX-101, Kybella [United States], Belkyra [Canada]; Kythera Biopharmaceuticals, Inc., Westlake Village, CA, acquired by Allergan, Inc.), are proprietary formulations of synthetically derived DCA that is FDA approved for improvement in the appearance of moderate to severe convexity or fullness associated with SMF. Aim: As none of the aforementioned are available in India, we undertook this study to study the efficacy of generic DCA for SMF reduction in Indian patients. Methods: 50 patients with confirmed Indian ethnicity and unwanted SMF were injected 3 mg/cm2 of generic DCA into their SMF, with a 12-week follow-up period. In each session, 5 ml of 30 mg /ml DCA was injected. The sessions were spaced approximately 2 months apart. All these patients with reductions in SMF were reported using Clinician Reported SMF Rating Scale (CR-SMFRS) and Patient Reported SMF Rating Scale (PR-SMFRS) using the Validated Rating Scale for improvement in the appearance of their chin, the neck, and the cervico-mental profile. Also, for objective assessment of improvement in SMF, caliper measurements were used. Results: One session was required in 2 patients, 12 patients needed 2 sessions, 32 patients needed 3 sessions, and 4 patients needed 4 sessions. Altogether, 90% patients showed at least a decrease of 1 point in (CR-SMFRS). Reduction in SMF as confirmed by caliper measurements was statistically significant. Conclusion: The findings show generic deoxycholic acid to be equally effective in the treatment for SMF in Indian patients. J Drugs Dermatol. 2019;18(3):266-272.


Assuntos
Técnicas Cosméticas , Ácido Desoxicólico/administração & dosagem , Lipólise/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Adulto , Queixo/anatomia & histologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Índia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Pescoço/anatomia & histologia , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
12.
Br J Surg ; 106(5): 616-625, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30725479

RESUMO

BACKGROUND: Visceral obesity is one of the risk factors for clinically relevant pancreatic fistula after pancreatic resection. The objective of this study was to evaluate the impact of intraperitoneal lipolysis on postoperative pancreatic fistula. METHODS: The degree of intraperitoneal lipolysis was investigated by measuring the free fatty acid concentration in drain discharge in patients after pancreatic resection. An experimental pancreatic fistula model was prepared by pancreatic transection, and the impact of intraperitoneal lipolysis was evaluated by intraperitoneal administration of triolein (triglyceride) with, or without orlistat (lipase inhibitor). RESULTS: Thirty-three patients were included in the analysis. The free fatty acid concentration in drain discharge on postoperative day 1 was significantly associated with the development of a clinically relevant pancreatic fistula (P = 0·004). A higher free fatty acid concentration in drain discharge was associated with more visceral adipose tissue (P = 0·009). In the experimental model that included 98 rats, intraperitoneal lipolysis caused an increased amount of pancreatic juice leakage and multiple organ dysfunction. Intraperitoneal administration of a lipase inhibitor reduced lipolysis and prevented deterioration of the fistula. CONCLUSION: Intraperitoneal lipolysis significantly exacerbates pancreatic fistula after pancreatic resection. Inhibition of lipolysis by intraperitoneal administration of a lipase inhibitor could be a promising therapy to reduce clinically relevant postoperative pancreatic fistula. Surgical relevance Clinically, there are two types of pancreatic fistula after pancreatic resections: harmless biochemical leak and harmful clinically relevant pancreatic fistula. Visceral obesity is one of the known risk factors for clinically relevant pancreatic fistula; however, the underlying mechanisms remained to be elucidated. Patients with clinically relevant pancreatic fistula had a higher free fatty acid concentration in the drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The experimental model of pancreatic fistula demonstrated that intraperitoneal lipolysis caused deterioration in pancreatic fistula, suggesting that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula. Intraperitoneal administration of a lipase inhibitor prevented lipolysis as well as pancreatic fistula deterioration in the experimental model, suggesting a future clinical application for lipase inhibitors in prevention of clinically relevant pancreatic fistula.


Assuntos
Gordura Intra-Abdominal/fisiopatologia , Lipólise/fisiologia , Pancreatectomia/efeitos adversos , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Idoso , Animais , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Lipase/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Obesidade Abdominal/fisiopatologia , Fístula Pancreática/prevenção & controle , Suco Pancreático/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Ratos Sprague-Dawley , Fatores de Risco
13.
Nat Commun ; 10(1): 548, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710078

RESUMO

Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; however, concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion. The mechanisms behind these alterations are unknown. Here we show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. Treatment with a loop diuretic, furosemide, under insulinopenic conditions replicates the effect of dapagliflozin and causes ketoacidosis. Furthermore, the effects of SGLT2 inhibition to promote ketoacidosis are independent from hyperglucagonemia. Taken together these data in rats identify the combination of insulinopenia and dehydration as a potential target to prevent euglycemic ketoacidosis associated with SGLT2i.


Assuntos
Desidratação/complicações , Insulina/metabolismo , Cetose/induzido quimicamente , Cetose/etiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Animais , Compostos Benzidrílicos/efeitos adversos , Desidratação/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Glucocorticoides/metabolismo , Glucose/metabolismo , Glucosídeos/efeitos adversos , Humanos , Cetose/patologia , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/metabolismo
14.
PLoS One ; 14(2): e0212459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794618

RESUMO

BACKGROUND: Patients with cystic fibrosis have to take enzymatic supplements to allow for food digestion. However, an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy (PERT) is inexistent, and lipid content of meals is used as a rough criterion. OBJECTIVE: In this study, an in vitro digestion model was set up to determine the theoretical optimal dose (TOD) of enzymatic supplement for a selection of foods, which is the dose that allows for maximum lipolysis extent. METHODS: A static in vitro digestion model was applied to simulate digestion of eight foods covering a wide range of lipid contents. First, the dose of the enzymatic supplement was fixed at 2000 lipase units per gram of fat (LU/g fat) using intestinal pH and bile salt concentration as variables. Second, intestinal pH and bile salt concentrations were fixed and the variable was the dose of the enzymatic supplement. Lipolysis extent was determined by measuring the free fatty acids released from initial triglycerides content of foods after digestion. Results in terms of percentage of lipolysis extent were fitted into a linear-mixed segmented model and the deducted equations were used to predict the TOD to reach 90% of lipolysis in every food. In addition, the effect of intestinal pH and bile salt concentration were investigated. RESULTS: The predictive equations obtained for the assessed foods showed that lipolysis was not only dependent on the dose of the enzyme supplement or the lipid content. Moreover, intestinal pH and bile salt concentration had significant effects on lipolysis. Therefore an evidence-based model can be developed taking into account these variables. CONCLUSIONS: Depending on food characteristics, a specific TOD should be assigned to achieve an optimal digestion extent. This work represents a first step towards an evidence-based method for PERT dosing, which will be applied in an in vivo setting to validate its efficacy.


Assuntos
Fibrose Cística/tratamento farmacológico , Terapia de Reposição de Enzimas/métodos , Simulação por Computador , Fibrose Cística/metabolismo , Digestão/efeitos dos fármacos , Medicina Baseada em Evidências , Análise de Alimentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Técnicas In Vitro , Lipase/uso terapêutico , Lipólise/efeitos dos fármacos , Modelos Biológicos , Pâncreas/enzimologia , Extratos Pancreáticos/uso terapêutico , Peptídeo Hidrolases/uso terapêutico
15.
Biosci Biotechnol Biochem ; 83(6): 975-985, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30773997

RESUMO

Plant materials have been widely studied for their preventive and therapeutic effects for type 2 diabetes mellitus (T2DM) and obesity. The effect of a plant material arises from its constituents, and the study of these bioactive compounds is important to achieve a deeper understanding of its effect at the molecular level. In particular, the study of the effects of such bioactive compounds on various biological processes, from digestion to cellular responses, is required to fully understand the overall effects of plant materials in these health contexts. In this review, I summarize the bioactive compounds we have recently studied in our research group that target digestive enzymes, dipeptidyl peptidase-4, myocyte glucose uptake, and lipid accumulation in adipocytes. Abbreviations: AC: adenylyl cyclase; AMPK: AMP-activated protein kinase; ßAR: ß-adrenergic receptor; CA: catecholamine; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; DPP-4: dipeptidyl peptidase-4; ERK: extracellular signal-regulated kinase; GC: guanylyl cyclase; GH: growth hormone; GLP-1: glucagon-like peptide-1; GLUT: glucose transporter; HSL: hormone-sensitive lipase; IR: insulin receptor; IRS: insulin receptor substrate; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; MG: maltase-glucoamylase; NP: natriuretic peptide; NPR: natriuretic peptide receptor; mTORC2: mechanistic target of rapamycin complex-2; PC: proanthocyanidin; PI3K: phosphoinositide 3-kinase; PKA: cAMP-dependent protein kinase; PKB (AKT): protein kinase B; PKG: cGMP-dependent protein kinase; PPARγ: peroxisome proliferator-activated receptor-γ; SGLT1: sodium-dependent glucose transporter 1; SI: sucrase-isomaltase; T2DM: type 2 diabetes mellitus; TNFα: tumor necrosis factor-α.


Assuntos
Produtos Biológicos/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Obesidade/prevenção & controle , Plantas/química , Adipócitos/efeitos dos fármacos , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Tamanho Celular/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Humanos , Lipólise/efeitos dos fármacos , Células Musculares/metabolismo , Peptídeos/uso terapêutico
16.
Exp Mol Med ; 51(1): 5, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635550

RESUMO

Vinpocetine, a phosphodiesterase (PDE) type-1 inhibitor, increases cAMP and cGMP levels and is currently used for the management of cerebrovascular disorders, such as stroke, cerebral hemorrhage, and cognitive dysfunctions. In this study, we first determined that vinpocetine effectively suppressed adipogenesis and lipid accumulation. However, we questioned which molecular mechanism is involved because the role of PDE in adipogenesis is still controversial. Vinpocetine decreased adipogenic cell signaling, including the phosphorylation of ERK, AKT, JAK2, and STAT3, and adipokine secretion, including IL-6, IL-10, and IFN-α. Interestingly, vinpocetine increased the phosphorylation of HSL, suggesting the induction of the lipolysis pathway. Moreover, vinpocetine increased UCP1 expression via increasing cAMP and PKA phosphorylation. The administration of vinpocetine with a normal-chow diet (NFD) or a high-fat diet (HFD) in mice attenuated body weight gain in mice fed both the NFD and HFD. These effects were larger in the HFD-fed mice, without a difference in food intake. Vinpocetine drastically decreased fat weight and adipocyte cell sizes in gonadal and inguinal white adipose tissues and in the liver in both diet groups. Serum triacylglycerol levels and fasting blood glucose levels were reduced by vinpocetine treatment. This study suggested that vinpocetine prevents adipocyte differentiation through the inhibition of adipogenesis-associated cell signaling in the early stages of adipogenesis. Moreover, upregulating cAMP levels leads to an increase in lipolysis and UCP1 expression and then inhibits lipid accumulation. Therefore, we suggest that vinpocetine could be an effective agent for treating obesity, as well as improving cognition and cardiovascular function in older individuals.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Alcaloides de Vinca/farmacologia , Células 3T3 , Adipócitos/citologia , Adipócitos/metabolismo , Adipocinas/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Proteína Desacopladora 1/metabolismo , Ganho de Peso/efeitos dos fármacos
17.
Phytomedicine ; 55: 255-263, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668437

RESUMO

BACKGROUND: We previously showed that 3-O-ß-D-glucopyranosyl-(3R)-hydroxybutanolide (kinsenoside), a major compound of Anoectochilus formosanus, increased lipolysis through an AMP-activated protein kinase (AMPK)-dependent pathway. PURPOSE: To extend our previous finding, we investigated the in vivo and in vitro effects of kinsenoside on lipolysis and the involvement of cyclic AMP (cAMP)-dependent protein kinase A (PKA) and AMPK in kinsenoside-mediated lipolysis. STUDY DESIGN/METHODS: Mice were fed a high-fat diet for six weeks to induce lipid deposition and then treated with 50 and 100  mg/kg kinsenoside for two weeks. The coordination of PKA and AMPK activation in lipolysis in C3H10T1/2 adipocytes was evaluated in vitro by using PKA and AMPK's corresponding inhibitors, oil-red O staining, a glycerol production assay, and Western blot analysis. RESULTS: Kinsenoside reduced body weight, fat pad mass, and hepatic lipid accumulation in obese mice, and concurrently increased the induction and activation of hormone-sensitive lipase (HSL), perilipin, adipose triglyceride lipase (ATGL), and carnitine palmitoyltransferase I (CPT1). Kinsenoside concentration-dependently increased PKA activation by increasing the phosphorylation of Ser/Thr-PKA substrates in vitro. These increases were accompanied by a reduction in fat accumulation. Using H89 and Rp-8-Br-cAMPs to inhibit PKA reduced the release of glycerol but did not alter the activation of peroxisome proliferator-activated receptor alpha or the expression of CPT1 or ATGL. By contrast, compound C, an AMPK inhibitor, inhibited CPT1 and ATGL expression in kinsenoside-treated C3H10T1/2 adipocytes. In addition, H89 caused the reactivation of AMPK downstream targets by increasing the levels of the active form of pAMPK-Thr172, suggesting that PKA negatively modulates AMPK activity. CONCLUSION: Kinsenoside increased HSL activation through PKA-mediated phosphorylation at Ser660/563 and concomitantly increased perilipin activation in lipolysis. These lipolytic effects of kinsenoside were validated using 6-Bnz-cAMPs, a PKA agonist. In this study, we demonstrated that in addition to AMPK, PKA also plays a crucial role in kinsenoside-mediated lipolysis.


Assuntos
4-Butirolactona/análogos & derivados , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Lipólise/efeitos dos fármacos , Monossacarídeos/metabolismo , Extratos Vegetais/metabolismo , Esterol Esterase/metabolismo , 4-Butirolactona/metabolismo , Animais , Masculino , Camundongos , Orchidaceae/química , Extratos Vegetais/química
18.
Biochem Biophys Res Commun ; 509(1): 306-313, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30583863

RESUMO

Erythropoietin (EPO) has been reported to exert a beneficial effect on glucose metabolism in obesity. However, the effect of EPO on lipid metabolism and non-alcoholic fatty liver disease (NAFLD) was unclear. Furthermore, the effect of long acting erythropoiesis stimulating agents (ESA) on metabolism has not been poorly understood. The objective of this study was to investigate the effect of EPO and long acting ESA on NAFLD and lipid metabolism. We administered EPO and darbepoetin alpha (DEPO), a long acting ESA, by intraperitoneally injection for 4 weeks to mice with high-fat-diet (HFD)-induced obesity. EPO and DEPO treatment reduced body weight, ameliorated glucose tolerance and insulin resistance, and prevented lipid accumulation in liver and white adipose tissue (WAT). Administration of EPO and DEPO suppressed lipid synthesis-related protein in liver, including sterol regulatory element-binding protein 1 (SREBP-1), acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS). EPO and DEPO also increased lipolysis protein in visceral WAT, including hormone-sensitive lipase (HSL), atni-adipose triglyceride lipase (ATGL). EPO and DEPO increased phosphorylation signal transducer and activator of transcription 3 (STAT3) and STAT5, transcriptional factors with crucial roles of lipid metabolism. These data suggest that EPO and DEPO ameliorated NAFLD by improving lipid metabolism via EPO/EPOR-induced STAT3 and STAT5 activation. EPO and DEPO may be a therapeutic option for NAFLD.


Assuntos
Darbepoetina alfa/uso terapêutico , Eritropoetina/uso terapêutico , Hematínicos/uso terapêutico , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores da Eritropoetina/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
J Physiol Biochem ; 75(1): 83-88, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539499

RESUMO

Kaempferol is a natural flavonoid widely found in fruits, vegetables, and tea. Kaempferol possesses beneficial biological properties such as anti-inflammatory and antioxidant activities. Positive energy balance during obesity correlates with a pro-inflammatory chronic state. In this context, we hypothesized that kaempferol might promote anti-obesity effects by modulating adipogenesis and lipolytic pathways. Adipocyte viability at 24, 48, and 72 h was measured by an ATP-based assay. Pre-adipocytes (day 0) or mature adipocytes (day 12) were treated with 60 µM kaempferol until day 21 to evaluate its potential anti-adipogenic and lipolytic effect, respectively. Total lipid accumulation was assessed using Oil Red O staining assay. Gene expression was measured by RT-qPCR to evaluate the effect of kaempferol on adipogenesis and lipolysis gene expression. Our results showed a dose-dependent effect of kaempferol treatment on cell viability promoting cell death at higher than 60 µM concentration. Pre-adipocytes stimulation by 60 µM kaempferol resulted in 62% adipogenesis inhibition whereas in mature adipocytes, it reduced 39% intracellular lipid accumulation. Also, 60 µM kaempferol treatment decreased Cebpa mRNA expression when compared to control cells. In contrast, Pnpla2 and Lipe gene expression were upregulated in 3T3-L1 cells incubated with 60 µM kaempferol. In summary, our results showed that kaempferol modulates adipogenic differentiation in 3T3-L1 cells by promoting downregulation of Cebpa gene expression and decreasing lipid accumulation in mature adipocytes by its positive effects on Pnpla2 and Lipe mRNA levels. Kaempferol might display an anti-obesity effect.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Quempferóis/farmacologia , Lipólise/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Animais , Compostos Azo , Proteínas Estimuladoras de Ligação a CCAAT/antagonistas & inibidores , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Lipase/genética , Lipase/metabolismo , Lipólise/genética , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
Mol Cell Endocrinol ; 483: 1-10, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543876

RESUMO

BACKGROUND AND AIM: Bile acids (BA) are increasingly recognized as pleiotropic and hormone-like signaling molecules with metabolic and endocrine functions. However, the role of BA in white adipocyte physiology remains somewhat obscure. It was the aim to investigate the BA receptors (FXR, TGR5) and FGFR1 (Fibroblast growth factor receptor 1) as well as Bsep (bile salt export pump) in white adipocytes and in murine and human adipose tissue (AT) and to investigate effects of different BA species in adipocyte physiology. PATIENTS, MATERIAL AND METHODS: Receptor mRNA expression was quantified by real-time PCR in mice, humans and during 3T3-L1 pre-adipocyte differentiation. Adipokines were measured by ELISA upon stimulation by several BA. Effects of BA on TNF- and LPS-induced MCP-1 secretion and lipolysis were analyzed. TNF-induced lipolysis was investigated by glycerol assay. RESULTS: The present data provide for the first time a detailed expression profile of FXR, TGR5, FGFR1, and Bsep during adipocyte differentiation and in murine and human AT. FGFR1 expression is upregulated in adipose tissue of LPS-injected animals. Several BA regulate secretion of adipokines such as adiponectin and resistin differentially. Importantly, TNF- and LPS-induced MCP-1 release from adipocytes as well as TNF-induced lipolysis can be antagonized by cholic acid (CA) and deoxycholic acid (DCA). CONCLUSIONS: The present data provide evidence of functional BA signaling pathways in adipocytes and argue for certain MCP-1 related anti-inflammatory effects of BA in TNF- and LPS-induced inflammation, whereas pro-inflammatory resistin is induced by CA and glycocholic acid (GCA). Systemic bile acids might represent a hormonal network regulating white adipocyte physiology including lipolysis.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adipócitos Brancos/citologia , Ácidos e Sais Biliares/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores Citoplasmáticos e Nucleares/genética , Receptores Acoplados a Proteínas-G/genética , Células 3T3-L1 , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Adipocinas/metabolismo , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipólise/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
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