Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals

Abstract

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.

The adiponectin promoter activator NP-1 induces high levels of circulating TNFα and weight loss in obese (fa/fa) Zucker rats

“…When administrated acutely, NP-1 demonstrated its ability to increase adiponectin levels and to ameliorate both hepatic steatosis and insulin resistance in a rat model of diet-induced obesity. Of note too was the fact that NP-1 also reduced both food intake and body weight in this diet-induced obesity model 10 . However, an apparent limitation of NP-1 after repeated administration was the induction of pharmacologic tolerance.…”

Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

“…Liver samples embedded in paraffin were sectioned into 3 μm slices and deparaffinized in xylene followed by haematoxylin and eosin (H&E) stainning. Total fat was extracted from the liver and assessed as previously described [ 12 , 40 ].…”

Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high fat diet-induced steatosis in IL-6 deficient mice

“…Total fat was extracted from the liver as previously described ( Serrano et al, 2012 ). Briefly, total lipids were extracted from frozen liver samples according to the Bligh and Dyer method ( Bligh and Dyer, 1959 ) using chloroform-methanol (2:1, v/v) and butylated hydroxytoluene (0.025%, w/v).…”

“…Protein extraction and western blot analysis were performed as previously described ( Serrano et al, 2012 ; Vida et al, 2013 ). The samples (50 µg of total proteins each) were resolved on 4-15% Ready Gel Precast Gels (Bio-Rad Laboratories, Inc.) and subsequently blotted onto nitrocellulose membranes (Bio-Rad).…”