Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have ...specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IRlox/lox/IGF1Rlox/lox mice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.
Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut ...microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential.
Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is ...unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.
Abstract
The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related ...to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921–1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094–8.977,
P
= 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index.
Abstract
We present a multiple emission line study of ∼1300 H
α
emitters (HAEs) at
z
∼ 2.3 in the ZFOURGE survey. In contrast to the traditional spectroscopic method, our sample is selected based on ...the flux excess in the ZFOURGE
K
s
broadband data relative to the best-fit stellar continuum. Using the same method, we also extract the strong diagnostic emission lines for these individual HAEs: O
iii
λ
λ
4959, 5007 and O
ii
λ
λ
3726, 3729. Our measurements demonstrate good consistency with those obtained from spectroscopic surveys. We investigate the relationship between the equivalent widths (EWs) of these emission lines and various galaxy properties, including stellar mass, stellar age, star formation rate, specific star formation rate, and ionization state (O32). We have identified a discrepancy between HAEs at
z
∼ 2.3 and typical local star-forming galaxies observed in the Sloan Digital Sky Survey, suggesting the evolution of lower gas-phase metallicity (
Z
) and higher ionization parameters (
U
) with redshift. Notably, we have observed a significant number of low-mass HAEs exhibiting exceptionally high EW
O
iii
. Their galaxy properties are comparable to those of extreme objects, such as extreme O3 emitters and Ly
α
emitters at
z
≃ 2–3. Considering that these characteristics may indicate potential strong Lyman continuum leakage, higher-redshift analogs of the low-mass HAEs could be significant contributors to the cosmic reionization. Further investigations of this particular population are required to gain a clearer understanding of galaxy evolution and cosmic reionization.
The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. ...Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na
and K
channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.
Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under ...euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.
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•Physiological insulin regulates a broad transcriptional network in muscle and liver•In addition to mRNA of coding genes, insulin regulates mRNA splicing and lncRNAs•Insulin-regulated gene expression involves multiple transcriptional regulators•The insulin-suppressed lncRNA Gm15441 regulates fatty acid oxidation in hepatocytes
Batista et al. demonstrate potent transcriptional remodeling by physiological insulin action in skeletal muscle and liver, involving interrelated networks of protein-coding genes, transcription factors, and long non-coding RNAs (lncRNAs). From an array of metabolically sensitive lncRNAs, Gm15441 is identified as a regulator of fatty acid oxidation in hepatocytes.
Deep vein thrombosis （DVT） is a frequent complication of total knee arthroplasty （TKA）, which may cause pulmonary embolism （PE） among other serious conditions. Therefore, the prevention of DVT is ...crucial. Recent reports indicate that the risk of DVT can be reduced by introducing early physical therapy following surgery; however, in Japanese medical literature, such reports are limited. Since 2017, Showa University Fujigaoka Hospital has implemented early physical therapy starting from the day of surgery to prevent DVT and PE. This study aimed to examine the effectiveness of initiating physical therapy on the day of TKA for DVT prevention. The study included 319 patients who underwent TKA at Showa University Fujigaoka Hospital from 2017 to 2019. We extracted data, including patient background, surgery details, presence or absence of physiotherapy on the day of surgery, and postoperative presence or absence of lower extremity DVT via ultrasound imaging, from the patients’ charts. The incidence of DVT was compared between the physiotherapy intervention and nonintervention groups. Furthermore, factors contributing to DVT development were investigated. The incidence of DVT following unilateral and bilateral TKA was significantly lower in the intervention group than in the nonintervention group. Logistic regression analysis revealed that the presence or absence of physiotherapy on the day of surgery and sex were associated with DVT development. DVT commonly occurs either immediately postsurgery or on the subsequent day. Thus, it is conceivable that physiotherapy during this period of immobility could improve blood flow and prevent thrombus formation.
We investigate the molecular gas in and star formation properties of the host galaxy (CGCG 137-068) of a mysterious transient, AT2018cow, at kpc and larger scales, using archival band-3 data from the ...Atacama Large Millimeter/submillimeter Array (ALMA). AT2018cow is the nearest fast-evolving luminous transient (FELT); this is the first study unveiling molecular-gas properties of FELT hosts. The achieved rms and beam size are 0.21 mJy beam−1 at a velocity resolution of 40 km s−1 and 3 66 × 2 71 (1.1 kpc × 0.8 kpc), respectively. CO(J = 1-0) emission is successfully detected. The total molecular gas mass inferred from the CO data is (1.85 0.04) × 108 M with the Milky Way CO-to-H2 conversion factor. The H2 column density at the AT2018cow site is estimated to be 8.6 × 1020 cm−2. The ALMA data reveal that (1) CGCG 137-068 is a normal star-forming (SF) dwarf galaxy in terms of its molecular gas and star formation properties, and (2) that AT2018cow is located between a CO peak and a blue star cluster. These properties suggest ongoing star formation and favor the explosion of a massive star as the progenitor of AT2018cow. We also find that CGCG 137-068 has a solar or super-solar metallicity. If the metallicity of the other FELT hosts is not higher than average, then some properties of SF dwarf galaxies other than metallicity may be related to FELTs.
Abstract
Using a prototype of the Tomo-e Gozen wide-field CMOS mosaic camera, we acquire wide-field optical images at a cadence of $2\:$Hz and search them for transient sources of duration 1.5 to ...$11.5\:$s. Over the course of eight nights, our survey encompasses the equivalent of roughly two days on one square degree, to a fluence equivalent to a limiting magnitude of about $V = 15.6$ in a 1-s exposure. After examining by-eye the candidates identified by a software pipeline, we find no sources which meet all our criteria. We compute upper limits to the rate of optical transients consistent with our survey, and compare those to the rates expected and observed for representative sources of ephemeral optical light.
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