Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals.
Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.
Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya, Instituto IBIMA-Fundación IMABIS, Málaga, Spain.
Antonia
A
Serrano
Francisco J
FJ
Pavón
Juan
J
Suarez
Patricia
P
Rivera
Margarita
M
Vida
Francisco J
FJ
Bermúdez-Silva
Mónica
M
Alonso
Ana
A
Martínez
Javier
J
López-Ogalla
Mercedes
M
Alonso-Gascón
Gema
G
Santamaría
Miguel
M
Romero-Cuevas
Vidal
V
Pérez-Valero
Elena
E
Baixeras
Fernando
F
Rodríguez de Fonseca
D052242:Adiponectin / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects*; D002460:Cell Line; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032446:Myoblasts / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013649:Taste / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D052242:Adiponectin; D004041:Dietary Fats; C572148:NP-1 compound; D013844:Thiazoles; D012313:RNA