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Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism.

Author(s): Anila K. Madiraju [sup.1] [sup.2] [sup.3] , Yang Qiu [sup.1] [sup.4] , Rachel J. Perry [sup.1] , Yasmeen Rahimi [sup.1] , Xian-Man Zhang [sup.1] , Dongyan Zhang [sup.1] , [...], In the version of this article originally published, the V.sub.PC and V.sub.CS flux data shown in Fig. 6e,f were inadvertently duplicated from Fig. 5j,k. The correct data are now shown in Fig. 6e,f. In these corrected data, V.sub.PC flux in response to chronic oral metformin treatment was still significantly decreased (Fig. 6e), and there was still no impact of metformin on V.sub.CS flux (Fig. 6f). Therefore, the text describing these data remains the same and this correction does not change the conclusion of this study.

Author(s): Alexander S. Banks [sup.1] , Fiona E. McAllister [sup.2] , João Paulo G. Camporez [sup.3] , Peter-James H. Zushin [sup.1] , Michael J. Jurczak [sup.3] , Dina Laznik-Bogoslavski [sup.4] [...], Blocking ERK/MAP kinases improves insulin sensitivity thorough a mechanism similar to the actions of the anti-diabetic thiazolidinediones drugs on PPAR[gamma]. Role of MEK/ERK pathway in glucose metabolism The nuclear receptor PPAR[gamma] is required for glucose metabolism and is a drug target in diabetes. Earlier work has suggested that PPAR[gamma] phosphorylation has an adverse effect on insulin sensitivity and that the kinase Cdk5 is the main kinase responsible for phosphorylation at this site. Now Bruce Spiegelman and colleagues report the paradoxical observation that insulin resistance is worsened in mice lacking Cdk5 in adipose tissue. The authors further show that Cdk5 suppresses the MEK/ERK signalling pathway that is central to the regulation of cell growth and proliferation, and that ERK directly phosphorylates PPAR[gamma]. MEK/ERK inhibitors can improve insulin resistance in obese wild-type and ob/ob mice. This work suggests that MEK/ERK inhibitors -- already approved for cancer treatment -- might also be effective against diabetes. Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPAR[gamma] (peroxisome proliferator-activated receptor [gamma]) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues.sup.1. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPAR[gamma], such as the thiazolidinediones and PPAR[gamma] partial agonists or non-agonists.sup.2. For a better understanding of the importance of this obesity-linked PPAR[gamma] phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPAR[gamma] phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPAR[gamma] in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPAR[gamma] function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.

Exposure to the toxins methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG) of unripe ackee and litchi fruit can lead to hypoglycemia and death; however, the molecular mechanisms by which MCPA and MCPG cause hypoglycemia have not been established in vivo. To determine the in vivo mechanisms of action of these toxins, we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic acyl-CoA and hepatic acetyl-CoA content, and hepatocellular energy charge. MCPG suppressed rates of hepatic ß-oxidation as reflected by reductions in hepatic ketogenesis, reducing both short- and medium-chain hepatic acyl-CoA concentrations. Hepatic acetyl-CoA content decreased, and hepatic glucose production was inhibited. MCPA also suppressed ß-oxidation of short-chain acyl-CoAs, rapidly inhibiting hepatic ketogenesis and hepatic glucose production, depleting hepatic acetyl-CoA content and ATP content, while increasing other short-chain acyl- CoAs. Utilizing a recently developed positional isotopomer NMR tracer analysis method, we demonstrated that MCPA-induced reductions in hepatic acetyl-CoA content were associated with a marked reduction of hepatic pyruvate carboxylase (PC) flux. Taken together, these data reveal the in vivo mechanisms of action of MCPA and MCPG: the hypoglycemia associated with ingestion of these toxins can be ascribed mostly to MCPA- or MCPG-induced reductions in hepatic PC flux due to inhibition of ß-oxidation of short-chain acyl-CoAs by MCPA or inhibition of both short- and medium-chain acyl- CoAs by MCPG with resultant reductions in hepatic acetyl-CoA content, with an additional contribution to hypoglycemia through reduced hepatic ATP stores by MCPA. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a great problem of world public health. Its prevalence come epidemic proportion and diabetes type 2 reaches more than 90% of the cases. This disease has as etiologic characteristic the peripheral insulin resistance, characteristic as an abnormal response to an amount of this hormone, that is related a many pathogeneses such as obesity, hypertension and polycystic ovarian. A constant strain to develop methods of prevention and control of diabetes has been goal of many researches at last years. So, the exercise is indicated as an efficient alternative to prevention and control of diabetes and associate disease. Regular practice of physical exercise leads to an improvement on peripheral insulin resistance, altering the function of proteins and enzymes engaged in transduction signal from insulin. In this regard, exercise reduces the state of reduced action of this hormone. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a great problem of world public health. Its prevalence come epidemic proportion and diabetes type 2 reaches more than 90% of the cases. This disease has as etiologic characteristic the peripheral insulin resistance, characteristic as an abnormal response to an amount of this hormone, that is related a many pathogeneses such as obesity, hypertension and polycystic ovarian. A constant strain to develop methods of prevention and control of diabetes has been goal of many researches at last years. So, the exercise is indicated as an efficient alternative to prevention and control of diabetes and associate disease. Regular practice of physical exercise leads to an improvement on peripheral insulin resistance, altering the function of proteins and enzymes engaged in transduction signal from insulin. In this regard, exercise reduces the state of reduced action of this hormone. [ABSTRACT FROM AUTHOR]