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Increasing evidence indicates that brown adipose tissue (BAT) transplantation enhances whole-body energy metabolism in a mouse model of diet-induced obesity. However, it remains unclear whether BAT also has such beneficial effects on genetically obese mice. To address this issue, we transplanted BAT from C57/BL6 mice into the dorsal subcutaneous region of age- and sex-matched leptin deficient Ob/Ob mice. Interestingly, BAT transplantation led to a significant reduction of body weight gain with increased oxygen consumption and decreased total body fat mass, resulting in improvement of insulin resistance and liver steatosis. In addition, BAT transplantation increased the level of circulating adiponectin, whereas it reduced the levels of circulating free T3 and T4, which regulate thyroid hormone sensitivity in peripheral tissues. BAT transplantation also increased β3-adrenergic receptor and fatty acid oxidation related gene expression in subcutaneous and epididymal (EP) white adipose tissue. Accordingly, BAT transplantation increased whole-body thermogenesis. Taken together our results demonstrate that BAT transplantation may reduce obesity and its related diseases by activating endogenous BAT.
RNF20, an E3 ligase critical for monoubiquitination of histone H2B at lysine 120 (H2Bub), has been implicated in the regulation of various cellar processes; however, its physiological roles in adipocytes remain poorly characterized. Here, we report that the adipocyte-specific knockout of Rnf20 (ASKO) in mice led to progressive fat loss, organomegaly and hyperinsulinemia. Despite signs of hyperinsulinemia, normal insulin sensitivity and improved glucose tolerance were observed in the young and aged CD-fed ASKO mice. In addition, high-fat diet-fed ASKO mice developed severe liver steatosis. Moreover, we observed that the ASKO mice were extremely sensitive to a cold environment due to decreased expression levels of brown adipose tissue (BAT) selective genes, including uncoupling protein 1 (Ucp1), and impaired mitochondrial functions. Significantly decreased levels of peroxisome proliferator-activated receptor gamma (Pparγ) were observed in the gonadal white adipose tissues (gWAT) from the ASKO mice, suggesting that Rnf20 regulates adipogenesis, at least in part, through Pparγ. Rosiglitazone-treated ASKO mice exhibited increased fat mass compared to that of the non-treated ASKO mice. Collectively, our results illustrate the critical role of RNF20 in control of white and brown adipose tissue development and physiological function.
TGFβ1 signaling pathway is associated with many diseases, which can induce the activation of hepatic stellate cells (HSCs) and induce liver fibrosis. Studies have shown that 20S-protopanaxadiol (PPD) has a therapeutic effect on liver fibrosis, but the target is unknown. In this study, we confirmed that PPD reduced the mRNA expression of downstream genes of the TGFβ1 pathway, which suggesting PPD is associated with the TGFβ1 pathway. The protein dissociation temperature and dissociation constant (Kd) of PPD on TGFβR1 and TGFβR2 were determined, which showed that PPD combined with TGFβR1 (Kd = 1.54 μM). The docking and simulation methods were used to find their binding sites. Site mutations, protein expression and in vitro binding experiments were performed to demonstrated these sites. In particular, these sites of TGFβR1 were also the active sites of TGFβR2. Therefore, we speculated that PPD blocked the combination of TGFβR1 and TGFβR2 by binding to the D57, R58, P59, and N78 of the TGFβR1 extracellular domain. Thus, PPD could block the transmission of TGFβ1 pathway and inhibit the activation of HSCs, and treating fibrosis. Our studies showed that PPD has the potential to treat diseases related to the TGFβ1 pathway and broadens its clinical application.
We have solved the x-ray crystal structures of the RabGAP domains of human TBC1D1 and human TBC1D4 (AS160), at 2.2 and 3.5 Å resolution, respectively. Like the yeast Gyp1p RabGAP domain, whose structure was solved previously in complex with mouse Rab33B, the human TBC1D1 and TBC1D4 domains both have 16 α-helices and no β-sheet elements. We expected the yeast Gyp1p RabGAP/mouse Rab33B structure to predict the corresponding interfaces between cognate mammalian RabGAPs and Rabs, but found that residues were poorly conserved. We further tested the relevance of this model by Ala-scanning mutagenesis, but only one of five substitutions within the inferred binding site of the TBC1D1 RabGAP significantly perturbed catalytic efficiency. In addition, substitution of TBC1D1 residues with corresponding residues from Gyp1p did not enhance catalytic efficiency. We hypothesized that biologically relevant RabGAP/Rab partners utilize additional contacts not described in the yeast Gyp1p/mouse Rab33B structure, which we predicted using our two new human TBC1D1 and TBC1D4 structures. Ala substitution of TBC1D1 Met(930), corresponding to a residue outside of the Gyp1p/Rab33B contact, substantially reduced catalytic activity. GLUT4 translocation assays confirmed the biological relevance of our findings. Substitutions with lowest RabGAP activity, including catalytically dead RK and Met(930) and Leu(1019) predicted to perturb Rab binding, confirmed that biological activity requires contacts between cognate RabGAPs and Rabs beyond those in the yeast Gyp1p RabGAP/mouse Rab33B structure.
Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH(+)) of T2D; and family history-negative control individuals (FH(–)). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH(+) groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH(+) and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.
Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer's disease.
The relation between gut microbiota and the host has been suggested to benefit metabolic homeostasis. Brown adipose tissue (BAT) and beige adipocytes facilitate thermogenesis to maintain host core body temperature during cold exposure. However, the potential impact of gut microbiota on the thermogenic process is confused. Here, we evaluated how BAT and white adipose tissue (WAT) responded to temperature challenges in mice lacking gut microbiota. We found that microbiota depletion via treatment with different cocktails of antibiotics (ABX) or in germ-free (GF) mice impaired the thermogenic capacity of BAT by blunting the increase in the expression of uncoupling protein 1 (UCP1) and reducing the browning process of WAT. Gavage of the bacterial metabolite butyrate increased the thermogenic capacity of ABX-treated mice, reversing the deficit. Our results indicate that gut microbiota contributes to upregulated thermogenesis in the cold environment and that this may be partially mediated via butyrate.
Cold-activated thermogenesis of brown adipose tissues (BAT) is vital for the survival of animals under cold stress and also inhibits the development of tumours. The development of small-molecule tools that target thermogenesis pathways could lead to novel therapies against cold, obesity, and even cancer. Here, we identify a chemical signal that is produced in beetles in the winter to activate fat thermogenesis. This hormone elevates the basal body temperature by increasing cellular mitochondrial density and uncoupling in order to promote beetle survival. We demonstrate that this hormone activates UCP4-mediated uncoupled respiration through adipokinetic hormone receptor (AKHR). This signal serves as a novel fat-burning activator that utilizes a conserved mechanism to promote thermogenesis not only in beetles, nematode and flies, but also in mice, protecting the mice against cold and tumor growth. This hormone represents a new strategy to manipulate fat thermogenesis.
The prevention of diseases through health control is essential at zoos. Here, we investigated the gut microbiota formation during infancy in an Asian elephant and compared the composition between infant and mother. Besides, we analyzed the components of breast milk and examined the correlation with the infant gut microbiota. Analysis revealed the gut microbiota of the infant contained high amount of Lactobacillales and its diversity was relatively low compared to that of the mother. We found several milk components, showed a positive correlation with the change of Lactobacillales. The present study revealed the mechanism of gut microbiota formation during infancy in an Asian elephant and provides important insights into the health control of Asian elephants in zoos.
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