Try a new search

Format these results:

Searched for:



Total Results:


Adipose Tissue Specific Temporal Deletion of Ager Induces Weight Loss in Diet Induced Obese Mice and Improves Glucose Homeostasis [Meeting Abstract]

Wilson, Robin; Arivazhagan, Lakshmi; Ruiz, Henry; Pendse, Jay; Frye, Laura; Mangar, Kaamashri; Ramasamy, Ravichandran; Schmidt, Ann Marie
ISSN: 0009-7322
CID: 4903182

A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis

Hurtado Del Pozo, Carmen; Ruiz, Henry H; Arivazhagan, Lakshmi; Aranda, Juan Francisco; Shim, Cynthia; Daya, Peter; Derk, Julia; MacLean, Michael; He, Meilun; Frye, Laura; Friedline, Randall H; Noh, Hye Lim; Kim, Jason K; Friedman, Richard A; Ramasamy, Ravichandran; Schmidt, Ann Marie
Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation-processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.
PMID: 31315054
ISSN: 2211-1247
CID: 3977942

Metabolism, Obesity, and Diabetes Mellitus

Ruiz, Henry H; López Díez, Raquel; Arivazahagan, Lakshmi; Ramasamy, Ravichandran; Schmidt, Ann Marie
PMID: 31242034
ISSN: 1524-4636
CID: 3963712

The Receptor for Advanced Glycation End Products (RAGE) and DIAPH1: Implications for vascular and neuroinflammatory dysfunction in disorders of the central nervous system

MacLean, Michael; Derk, Julia; Ruiz, Henry H; Juranek, Judyta K; Ramasamy, Ravichandran; Schmidt, Ann Marie
The Receptor for Advanced Glycation End Products (RAGE) is expressed by multiple cell types in the brain and spinal cord that are linked to the pathogenesis of neurovascular and neurodegenerative disorders, including neurons, glia (microglia and astrocytes) and vascular cells (endothelial cells, smooth muscle cells and pericytes). Mounting structural and functional evidence implicates the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous1 (DIAPH1), as the key cytoplasmic hub for RAGE ligand-mediated activation of cellular signaling. In aging and diabetes, the ligands of the receptor abound, both in the central nervous system (CNS) and in the periphery. Such accumulation of RAGE ligands triggers multiple downstream events, including upregulation of RAGE itself. Once set in motion, cell intrinsic and cell-cell communication mechanisms, at least in part via RAGE, trigger dysfunction in the CNS. A key outcome of endothelial dysfunction is reduction in cerebral blood flow and increased permeability of the blood brain barrier, conditions that facilitate entry of activated leukocytes into the CNS, thereby amplifying primary nodes of CNS cellular stress. This contribution details a review of the ligands of RAGE, the mechanisms and consequences of RAGE signal transduction, and cites multiple examples of published work in which RAGE contributes to the pathogenesis of neurovascular perturbation. Insights into potential therapeutic modalities targeting the RAGE signal transduction axis for disorders of CNS vascular dysfunction and neurodegeneration are also discussed.
PMID: 30902646
ISSN: 1872-9754
CID: 3778662

Adipocyte-Specific Deletion of Ager Mice With Established Obesity Induces Weight Loss and Induces Adaptive Thermogenesis in Adipose Tissue [Meeting Abstract]

Arivazhagan, Lakshmi; Ruiz, Henry H.; Pendse, Jay; Frye, Laura; Mangar, Kaamashri; Schmidt, Ann Marie
ISSN: 0009-7322
CID: 4903192

Probing the impact of high fat feeding on cellular senescence markers in heart [Meeting Abstract]

Rabbani, R.; Ruiz, H.; Ramasamy, R.
ISSN: 0002-8614
CID: 4903202

Pharmacological inhibition of NPY receptors illustrates dissociable features of experimental colitis in the mouse DSS model: Implications for preclinical evaluation of efficacy in an inflammatory bowel disease model

Ruiz, Henry H; Becker, Stephanie; Bai, Yu; Cortes-Burgos, Luz A; Eckersdorff, Melissa M; Macdonald, Lynn E; Croll, Susan D
Administration of dextran sodium sulfate (DSS) to rodents at varying concentrations and exposure times is commonly used to model human inflammatory bowel disease (IBD). Currently, the criteria used to assess IBD-like pathology seldom include surrogate measures of visceral pain. Thus, we sought to standardize the model and then identify surrogate measures to assess effects on visceral pain. We used various 4% DSS protocols and evaluated effects on weight loss, colon pathology, biochemistry, RNA signature, and open field behavior. We then tested the therapeutic potential of NPY Y1 and/or Y2 receptor inhibition for the treatment of IBD pathology using this expanded panel of outcome measures. DSS caused weight loss and colon shrinkage, increased colon NPY and inflammatory cytokine expression, altered behaviors in the open field and induced a distinct gene metasignature that significantly overlapped with that of human IBD patients. Inhibition of Y1 and/or Y2 receptors failed to improve gross colon pathology. Y1 antagonism significantly attenuated colon inflammatory cytokine expression without altering pain-associated behaviors while Y2 antagonism significantly inhibited pain-associated behaviors in spite of a limited effect on inflammatory markers. A protocol using 7 days of 4% DSS most closely modeled human IBD pathology. In this model, rearing behavior potentially represents a tool for evaluating visceral pain/discomfort that may be pharmacologically dissociable from other features of pathology. The finding that two different NPY receptor antagonists exhibited different efficacy profiles highlights the benefit of including a variety of outcome measures in IBD efficacy studies to most fully evaluate the therapeutic potential of experimental treatments.
PMID: 31369588
ISSN: 1932-6203
CID: 4903132

Nicotine Acutely Induces Hyperglycemia and Hepatic Steatosis by Altering the Sympathetic Outflow [Meeting Abstract]

Ruiz, Henry H.; Peddibhotla, Swetha; Ramalingam, Latha; Moustaid-Moussa, Naima; Shin, Andrew C.
ISSN: 0892-6638
CID: 4903212

Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis

Fischer, Katrin; Ruiz, Henry H; Jhun, Kevin; Finan, Brian; Oberlin, Douglas J; van der Heide, Verena; Kalinovich, Anastasia V; Petrovic, Natasa; Wolf, Yochai; Clemmensen, Christoffer; Shin, Andrew C; Divanovic, Senad; Brombacher, Frank; Glasmacher, Elke; Keipert, Susanne; Jastroch, Martin; Nagler, Joachim; Schramm, Karl-Werner; Medrikova, Dasa; Collden, Gustav; Woods, Stephen C; Herzig, Stephan; Homann, Dirk; Jung, Steffen; Nedergaard, Jan; Cannon, Barbara; Tschöp, Matthias H; Müller, Timo D; Buettner, Christoph
Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1-/- and interleukin-4 receptor-α double-negative (Il4ra-/-) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.
PMID: 28414329
ISSN: 1546-170x
CID: 4903122

Proinflammatory cytokines remain elevated despite long-term remission in Cushing's disease: a prospective study

Shah, Nirali; Ruiz, Henry H; Zafar, Usman; Post, Kalmon D; Buettner, Christoph; Geer, Eliza B
CONTEXT/BACKGROUND:Inflammation contributes to the development of metabolic and cardiovascular disease. Cushing's disease (CD), a state of chronic glucocorticoid (GC) excess characterized by visceral obesity and insulin resistance, may be associated with increased systemic inflammation. Cardiovascular mortality in CD remains elevated even after successful remission. It is unclear whether a chronic low-grade inflammatory state persists even after remission of CD, which may account for the increased CVD mortality. PURPOSE/OBJECTIVE:(1) To assess circulating proinflammatory cytokines in patients with active CD and BMI-matched controls; (2) to prospectively follow plasma cytokine concentrations in patients with CD before and after surgical remission; and (3) to assess whether plasma cytokine concentrations correlate with adipose tissue distribution and ectopic lipid content in liver and muscle. METHODS:Plasma cytokines from prospectively enrolled patients with CD (N = 31) were quantified during active disease (v1) vs controls (N = 18) and 19·5 ± 12·9 months after surgical remission (v2). Fasting plasma IL-6, IL-1β, TNF-α, IL-8, IL-17 and IL-10 were quantified using a multiplex assay. Total and regional fat masses were measured by whole-body MRI. RESULTS:Circulating IL-6 and IL-1β were elevated in patients with active CD vs controls (P < 0·05) and remained elevated in CD after surgical remission, despite decreases in BMI (P < 0·001), HOMA-IR (P < 0·001), and visceral, hepatic and intermuscular fat (P < 0·001, <0·001 and 0·03, respectively). CONCLUSIONS:Despite long-term remission and improvements in fat distribution and insulin sensitivity, patients with CD may suffer from a state of chronic low-grade inflammation, which could contribute to increased cardiovascular mortality.
PMID: 27630017
ISSN: 1365-2265
CID: 4030242