Chung et al. show that the myomitokine GDF15 can act to modulate oxidative and lipolytic function in a non–cell-autonomous manner, thereby regulating systemic energy homeostasis in skeletal muscle-specific Crif1-deficient mice. This pathway may be a potential therapeutic target for preventing the onset of obesity and insulin resistance.

SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

Although substantial progress has been made in understanding the mechanisms underlying the expression of mtDNA-encoded polypeptides, the regulatory factors involved in mitoribosome-mediated synthesis and simultaneous insertion of mitochondrial oxidative phosphorylation (OXPHOS) polypeptides into the inner membrane of mitochondria are still unclear. In the present study, disruption of the mouse Crif1 gene, which encodes a mitochondrial protein, resulted in a profound deficiency in OXPHOS caused by the disappearance of OXPHOS subunits and complexes in vivo. CRIF1 was associated with large mitoribosomal subunits that were located close to the polypeptide exit tunnel, and the elimination of CRIF1 led to both aberrant synthesis and defective insertion of mtDNA-encoded nascent OXPHOS polypeptides into the inner membrane. CRIF1 interacted with nascent OXPHOS polypeptides and molecular chaperones, e.g., Tid1. Taken together, these results suggest that CRIF1 plays a critical role in the integration of OXPHOS polypeptides into the mitochondrial membrane in mammals.

The abbreviations used are: Prx, Peroxiredoxin; MMI, methimazole; TUNEL, terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling; TSH, thyrotropin; PCR, polymerase chain reaction.

Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and systemic insulin resistance with adipose inflammation. Macrophage GDF15 expression is reduced in mice with impaired oxidative function, but induced upon stimulation with rosiglitazone and IL-4. GDF15 upregulates the oxidative function of macrophages, leading to M2-like polarization, and reverses insulin resistance in ob/ob mice and HFD-fed mice with myeloid-specific deletion of Crif1. Thus, reduced macrophage oxidative function controls systemic insulin resistance and adipose inflammation, which can be reversed with GDF15 and leads to improved oxidative function of macrophages.

The Gadd45 family of proteins includes Gadd45␣, MyD118/Gadd45␤, and CR6/OIG37/Gadd45␥. These proteins play important roles in maintaining genomic stability and in regulating the cell cycle. This study reports the cloning of a novel protein called CR6-interacting factor 1 (CRIF1) which interacts with Gadd45␣, MyD118/Gadd45␤, and CR6/OIG37/Gadd45␥. CRIF1 binds specifically to the Gadd45 family proteins, as determined by an in vitro glutathione Stransferase pull-down assay and an in vivo mammalian cell two-hybrid assay along with coimmunoprecipitation assays. CRIF1 mRNA is highly expressed in the thyroid gland, heart, lymph nodes, trachea, and adrenal tissues. CRIF1 localizes exclusively to the nucleus and colocalizes with Gadd45␥. Recombinant CRIF1 inhibits the histone H1 kinase activity of immunoprecipitated Cdc2-cyclin B1 and Cdk2-cyclin E, and the inhibitory effects were additive with Gadd45 proteins. Overexpression of CRIF1 increases the percentage of cells in G 1 , decreases the percentage of cells in S phase, and suppresses growth in NIH3T3 cells. The downregulation of endogenous CRIF1 by the transfection of the small interfering RNA duplexes resulted in the inactivation of Rb by phosphorylation and decreased the G 1 phase cell populations. Expression of CRIF1 is barely detectable in adrenal adenoma and papillary thyroid cancer and much lower than in adjacent normal tissue. The results presented here suggest that CRIF1 is a novel nuclear protein that interacts with Gadd45 and may play a role in negative regulation of cell cycle progression and cell growth.

Growth differentiation factor 15 (GDF15) has recently been shown to have an important role in the regulation of mitochondrial function and in the pathogenesis of complex human diseases. Nevertheless, the role of GDF15 in alcohol-induced or fibrotic liver diseases has yet to be determined. In this study, we demonstrate that alcohol- or carbon tetrachloride (CCl4)-mediated hepatic GDF15 production ameliorates liver inflammation and fibrosis. Alcohol directly enhanced GDF15 expression in primary hepatocytes, which led to increased oxygen consumption. Moreover, GDF15 reduced the expression of pro-inflammatory cytokines in liver-resident macrophages, leading to an improvement in inflammation and fibrosis in the liver. GDF15 knockout (KO) mice had more TNF-α-producing T cells and more activated CD4+ and CD8+ T cells in the liver than wild-type mice. Liver-infiltrating monocytes and neutrophils were also increased in the GDF15 KO mice during liver fibrogenesis. These changes in hepatic immune cells were associated with increased tissue inflammation and fibrosis. Finally, recombinant GDF15 decreased the expression of pro-inflammatory cytokines and fibrotic mediators and prevented the activation of T cells in the livers of mice with CCl4-induced liver fibrosis. These results suggest that GDF15 could be a potential therapeutic target for the treatment of alcohol-induced and fibrotic liver diseases.

Toll-like receptors (TLRs) associate with adaptor molecules (MyD88, Mal/TIRAP, TRAM, and TRIF) to mediate signaling of host-microbial interaction. For instance, TLR4 utilizes the combination of both Mal/TIRAP-MyD88 (MyD88-dependent pathway) and TRAM-TRIF (MyD88-independent pathway). However, TLR5, the specific receptor for flagellin, is known to utilize only MyD88 to elicit inflammatory responses, and an involvement of other adaptor molecules has not been suggested in TLR5-dependent signaling. Here, we found that TRIF is involved in mediating TLR5-induced nuclear factor B (NFB) and mitogen-activated protein kinases ( Pattern-recognition receptors mediate recognition of microbes in multicellular organisms, leading to activation of innate and adaptive immune and inflammatory responses.