AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

OBJECTIVE-To determine the contribution of liver and viscera to splanchnic cortisol production in humans. RESEARCH DESIGN AND METHODS-D4cortisol was infused intravenously; arterial, portal venous, and hepatic venous blood was sampled; and liver and visceral fat were biopsied in subjects undergoing bariatric surgery.RESULTS-Ratios of arterial and portal vein D4 cortisol/cortisol total (0.06 Ϯ 0.01 vs. 0.06 Ϯ 0.01) and D4 cortisol/D3 cortisol (1.80 Ϯ 0.14 vs. 1.84 Ϯ 0.14) did not differ, indicating that no visceral cortisol production or conversion of D4 cortisol to D3 cortisol via 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) occurred. Conversely, ratios of both D4 cortisol to cortisol total (0.05 Ϯ 0.01; P Ͻ 0.05) and D4 cortisol to D3 cortisol (1.33 Ϯ 0.11; P Ͻ 0.001) were lower in the hepatic vein than in the portal vein, indicating production of both cortisol and D3 cortisol by the liver. The viscera did not produce either cortisol (Ϫ8.1 Ϯ 2.6 g/min) or D3 cortisol (Ϫ0.2 Ϯ 0.1 g/min). In contrast, the liver produced both cortisol (22.7 Ϯ 3.90 g/min) and D3 cortisol (1.9 Ϯ 0.4 g/min) and accounted for all splanchnic cortisol and D3 cortisol production. Additionally, 11␤-HSD-1 mRNA was approximately ninefold higher (P Ͻ 0.01) in liver than in visceral fat. Although 11␤-HSD-2 gene expression was very low in visceral fat, the viscera released cortisone (P Ͻ 0.001) and D3 cortisone (P Ͻ 0.01) into the portal vein. CONCLUSIONS-The liver accounts for all splanchnic cortisol production in obese nondiabetic humans. In contrast, the viscera releases cortisone into the portal vein, thereby providing substrate for intrahepatic cortisol production. Diabetes 58:39-45, 2009 A lthough it has been long known that glucocorticoids are potent regulators of glucose, fat, and protein metabolism, glucocorticoids have not been thought to cause insulin resistance in either obese or diabetic individuals because plasma concentrations do not differ from those present in lean nondiabetic subjects. However, extra-adrenal conversion of cortisone to cortisol via 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) can result in high local concentrations of cortisol. This observation focused attention on the possibility that tissue-specific synthesis of glucocorticoids may contribute to the pathogenesis of insulin resistance and other components of the so called "metabolic syndrome" (1). The enzyme 11␤-HSD-2 (which converts cortisol to cortisone) is present primarily in the kidney, whereas 11␤-HSD-1 (which converts cortisone to cortisol) is present in both liver and adipose tissue with in vitro activity being greater in omental than subcutaneous fat deposits (2-5). Inhibition (6) or knockout (7-9) of 11␤-HSD-1 in mice improves hepatic insulin action and protects against obesity and hyperglycemia. Conversely, selective overexpression of 11␤-HSD-1 in adipose tissue in mice results in development of visceral obesity, hyperglycemia, hyperlipidemia, and hypertension (7-11).Using a novel tracer infusion method, Andrew et al. (12) demonstrated...

The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirusmediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor ␥ coactivator 1␤, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice.

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