The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2–4-h intervals of culture over 24–48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2–4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamicpituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.[Keywords: JNK1; obesity; insulin resistance; thyroid hormone] Supplemental material is available at http://www.genesdev.org. Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of insulin resistance, hyperglycemia, and metabolic syndrome that can lead to b-cell dysfunction and type 2 diabetes (Kahn et al. 2006). It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity, because this knowledge represents a basis for the design of potential therapeutic interventions.The cJun N-terminal kinase 1 (JNK1) represents one signaling pathway that has been implicated in dietinduced obesity (Weston and Davis 2007). JNK1 is activated when mice are fed a high-fat diet (HFD) (Hirosumi et al. 2002). Moreover, Jnk1 À/À mice are protected against HFD-induced weight gain (Hirosumi et al. 2002). The mechanism that accounts for the effect of germline JNK1 deficiency to control body weight is unclear. Tissue-specific deficiency of JNK1 in fat, muscle, liver, and myeloid cells does not affect HFD-induced weight gain (Sabio et al. 2008(Sabio et al. , 2009(Sabio et al. , 2010. A different organ must therefore play a major role in the diet-induced regulation of body weight by JNK1. The brain represents a possible site of JNK1 function because the hypothalamus and pituitary gland are known to regulate metabolism, including feeding behavior, physical activity, and energy expenditure (Lenard and Berthoud 2008).The purpose of this study was to investigate the role of JNK1 in the brain. Our approach was to examine the effect of selective ablation of the Jnk1 gene in the mouse nervous system. We found that HFD-fed control (N WT ) mice gained substantially greater body weight than JNK1-deficient (N KO ) mice. The decreased weight gain by N KO mice was accounted for by decreased food intake, increased physical activity, and increased energy expenditure. These changes were associated with increased amounts of thyroid hormone in the blood and increased expression of thyroid hormone-responsive genes in target tissues. Importantly, pharmacological inhibition of thyroid hormone markedly attenuated N KO phenotypes. These data demonstrate that the hypothalamic-pituitary-thyroid axis is a major target of the JNK1 signaling pathway that regulates metabolis...

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The c-Jun NH2-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of ␤ cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4 ؉ T cells from JNK2-deficient nonobese diabetic mice produced less IFN-␥ but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1͞Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.insulitis ͉ T cell differentiation ͉ nonobese diabetic mouse ͉ stress-activated protein kinase