Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Abstract

Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetesprone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents

“…This premise is based on the demonstration in two rodent models of obesity associated with T2DM, the ZDF rat, and db/db mouse, 20 that TG accumulate in the pancreatic islets at least 2 weeks before b-cell apoptosis becomes apparent and hyperglycemia appears. Prevention of this islet steatosis, whether by caloric restriction, 21 AICAR, 22 metformin 23 or thiazolidinedione administration, 23,24 will prevent the apoptosis, the loss of b-cells, the decline in insulin and the hyperglycemia.…”

Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

“…Recently, polyphenols have been reported to reduce hyperlipidemia and hyperglycemia, and their effects on lipogenesis have been suggested to be mediated via activation of the AMP-activated protein kinase (AMPK) [9][10][11] . In this relation, AMPK has emerged as an important regulator of lipid metabolism at the cellular and systemic levels, and dysfunction of hepatic AMPK represents a key mechanism for hepatic lipid accumulation and hyperlipidemia with hepatic steatosis in genetically obese rodents [12,13] and in high-fat-fed mice [13] and rats [9,14] . Consistent with this observation, transgenic mice expressing constitutively active Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet 1506 www.nature.com/aps Guo HX et al Acta Pharmacologica Sinica npg (CA)-AMPKα 1 in liver had reduced levels of white fat and were resistant to high-fat diet-induced obesity [15] .…”

The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells

“…Chronic treatment of obese rodents with AICAR has been shown to improve insulin sensitivity, reduce blood pressure, improve lipid profiles, and prevent the development of diabetes (Buhl et al, 2002;Pold et al, 2005;Yu et al, 2004). Thus, stimulation of the AMPK by AICAR seems to ameliorate several of the clinical features of the metabolic syndrome.…”