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Aug 31, 2015
Functional footprinting of regulatory DNA
Regulatory regions harbor multiple transcription factor (TF) recognition sites; however, the contribution of individual sites to regulatory function remains challenging to define. We describe an approach that exploits the error-prone nature of genome editing-induced double-strand break repair to map functional elements within regulatory DNA at nucleotide resolution.
Jul 2, 2015
Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo
SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice.
Jul 1, 2015
Hypoactivity following perturbed estrogen signaling in the medial amygdala
Activation of estrogen receptor α (ERα) in the brain prevents obesity as the result of increased energy expenditure and decreased food intake. While ERα is present on several neural populations, it is not clear how different regions of the brain mediate the weight-regulating effects of ERα activation.
Jun 22, 2015
Estrogen receptor–α in medial amygdala neurons regulates body weight
Estrogens play critical roles in the regulation of energy homeostasis. Depletion of endogenous estrogens in female rodents, via ovariectomy (OVX), causes increased body weight and hyperadiposity (1,2). 17β-estradiol replacement can prevent obesity in OVX female animals (1).
May 6, 2015
Identification of a plant isoflavonoid that causes biliary atresia
Biliary atresia (BA) is a rapidly progressive and destructive fibrotic disorder of unknown etiology affecting the extrahepatic biliary tree of neonates. Epidemiological studies suggest that an environmental factor, such as a virus or toxin, is the cause of the disease, although none have been definitively established.
Mar 5, 2015
Hypothalamic POMC neurons promote cannabinoid-induced feeding
Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons.
Feb 26, 2015
Sensory detection of food rapidly modulates arcuate feeding circuits
Hunger is controlled by specialized neural circuits that translate homeostatic needs into motivated behaviors. These circuits are under chronic control by circulating signals of nutritional state, but their rapid dynamics on the timescale of behavior remain unknown.
Jan 15, 2015
Activated type 2 innate lymphoid cells regulate beige fat biogenesis
Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined.
Jan 15, 2015
An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ
Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists.
Dec 4, 2014
Transcriptional regulation of autophagy by an FXR-CREB axis
Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown.
Dec 4, 2014
Nutrient-sensing nuclear receptors coordinate autophagy
Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not.
Nov 6, 2014
Human genetics shape the gut microbiome
Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear.
Oct 24, 2014
Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis
The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection.
Oct 9, 2014
Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects
Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice.
Aug 1, 2014
Spectrum of statin hepatotoxicity: Experience of the drug-induced liver injury network
The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins.