The cJun NH2-terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated in this process. To test the role of JNK, we established mice with selective JNK-deficiency in macrophages. We report that feeding a high fat diet to control and JNK-deficient mice caused similar obesity, but only mice with JNK-deficient macrophages remained insulin sensitive. The protection of mice with macrophage-specific JNK-deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotyping demonstrated that JNK was required for pro-inflammatory macrophage polarization. These studies demonstrate that JNK in macrophages is required for the establishment of obesity-induced insulin resistance and inflammation.

The recessive resistance genes pot-1 and pvr2 in Lycopersicon hirsutum and Capsicum annuum, respectively, control Potato virus Y (PVY) accumulation in the inoculated leaves. Infectious cDNA molecules from two PVY isolates differing in their virulence toward these resistances were obtained using two different strategies. Chimeras constructed with these cDNA clones showed that a single nucleotide change corresponding to an amino acid substitution (Arg119His) in the central part of the viral protein genome-linked (VPg) was involved in virulence toward the pot-1 resistance. On the other hand, 15 nucleotide changes corresponding to five putative amino acid differences in the same region of the VPg affected virulence toward the pvr2(1) and pvr2(2) resistances. Substitution models identified six and five codons within the central and C terminal parts of the VPg for PVY and for the related potyvirus Potato virus A, respectively, which undergo positive selection. This suggests that the role of the VPg-encoding region is determined by the protein and not by the viral RNA apart from its protein-encoding capacity.

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...

Mcl-1 is a member of theMcl-1 is an antiapoptotic member of the Bcl2 family. Gene knockout studies of mice demonstrate that Mcl-1 is essential for embryonic development and for the survival of hematopoietic cells (28)(29)(30). Studies of the stress response have demonstrated that Mcl-1 plays an important role in the sensitization of cells to apoptotic signals (1,11,25). Thus, exposure to UV radiation causes the rapid degradation of Mcl-1 and the release of proapoptotic partner proteins from Mcl-1 complexes (e.g., Bim). The mechanism of rapid Mcl-1 destruction is mediated by the combined actions of two different pathways. First, the exposure to stress causes phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2␣) on the inhibitory site Ser-51 that prevents translation of Mcl-1 mRNA (1,11,25). Second, Mcl-1 is rapidly degraded by the ubiquitin-dependent proteasome pathway (27). Together, these pathways cause a rapid reduction in Mcl-1 expression. This loss of Mcl-1 may be a required initial response for the apoptosis of cells exposed to stress (25).The E3 ubiquitin protein ligase Mule/ARF-BP1 contains a BH3 domain that interacts with Mcl-1 and can initiate ubiquitin-dependent degradation of . Recent studies have demonstrated that rapid stress-induced degradation of Mcl-1 is mediated by an alternative pathway involving the E3 ubiquitin protein ligase ␤-TrCP, which binds a stress-induced phosphodegron created by the phosphorylation of Mcl-1 by glycogen synthase kinase 3 (GSK3) (7,21). How the exposure to stress causes GSK3-mediated phosphorylation of Mcl-1 is unclear, but GSK3 has been shown to directly phosphorylate Mcl-1 (7, 21). Mcl-1 phosphorylation and degradation may therefore be controlled by the prosurvival AKT pathway, which can negatively regulate GSK3 (7, 21).Mcl-1 is critically involved in the regulation of cell survival and is therefore subject to regulation by multiple mechanisms (26 Noxa, and Bak (18). Phosphorylation on Ser-121 and Thr-163 may inhibit the antiapoptotic activity of hMcl-1 (15), and phosphorylation on Thr-163 may increase hMcl-1 protein stability (9). The conserved GSK3 phosphorylation site Ser-159 (and possibly Ser-155) can initiate rapid proteasomal degradation of hMcl-1 (7, 21). Together, these findings suggest that the function of Mcl-1 is very tightly regulated.The results of previous studies have implicated the c-Jun N-terminal protein kinase (JNK) in the regulation of 18). The purpose of this study was to test whether Mcl-1 is a target of signal transduction by JNK. We demonstrate that a key function of JNK is to prime Mcl-1 for phosphorylation by GSK3. JNK is required for GSK3-mediated degradation of Mcl-1 in response to stress. Coordinated regulation of the stress-activated JNK pathway and the AKT-inhibited GSK3 pathway is therefore required for stress-induced Mcl-1 degradation. MATERIALS AND METHODSReagents. The proteasome inhibitor MG132, the JNK inhibitor TAT-JBD, and 1NM-PP1 were purchased from Calbiochem. Active recombinant GSK3␤ was obtained from...