A5042873368- Pancreatic function and diabetes
- Circadian rhythm and melatonin
- Adipose Tissue and Metabolism
- Diabetes and associated disorders
- Dietary Effects on Health
- Hippo pathway signaling and YAP/TAZ
- Genetics, Aging, and Longevity in Model Organisms
- Diabetes Management and Research
- Metabolism, Diabetes, and Cancer
- Lipid metabolism and biosynthesis
- Diet, Metabolism, and Disease
- Adipokines, Inflammation, and Metabolic Diseases
- Mitochondrial Function and Pathology
- Atherosclerosis and Cardiovascular Diseases
- Diabetes Treatment and Management
- Protein Degradation and Inhibitors
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Liver Disease Diagnosis and Treatment
- Muscle Physiology and Disorders
- Cholesterol and Lipid Metabolism
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Genetics and Neurodevelopmental Disorders
- Receptor Mechanisms and Signaling
University of Pittsburgh
2018-2024
United States Department of Veterans Affairs
2024
Baylor College of Medicine
2011-2024
Pittsburg State University
2024
University of Pittsburgh Medical Center
2024
Discovery Institute
2022
City of Hope
2021
VA Pittsburgh Healthcare System
2020
Children's Hospital of Pittsburgh
2020
Diabetes Australia
2011-2017
Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there no in vivo evidence that CRP proatherogenic.We studied the effect human transgene (tg) expression, under basal and turpentine-stimulated conditions, on atherosclerosis apolipoprotein (apo) E-/- mice. Aortic atherosclerotic lesions 29-week-old male mice were 48% larger (P<0.02) turpentine-treated 34% (P<0.05) untreated CRPtg+/0/apoE-/- Turpentine treatment per se did not affect...
Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in β-cell dysfunction and diabetes. However, it is unknown if this due to loss cell-autonomous function Bmal1 β cells. To address this, we generated mice with by deleting cells (β-Bmal1(-/-)). β-Bmal1(-/-) develop diabetes glucose-stimulated insulin secretion (GSIS). This GSIS the accumulation reactive oxygen species (ROS) consequent mitochondrial uncoupling, as fully rescued...
Foam cells are a hallmark of atherosclerosis. However, it is unclear whether foam cell formation per se protects against atherosclerosis or fuels it. In this study, we investigated the role adipose differentiation-related protein (ADFP), major lipid droplet (LDP), in regulation and We show that ADFP expression facilitates induced by modified lipoproteins mouse macrophages vitro. further Adfp gene inactivation apolipoprotein E-deficient (ApoE(-/-)) mice reduces number droplets atherosclerotic...
Mutations in BSCL2 underlie human congenital generalized lipodystrophy. We inactivated Bscl2 mice to examine the mechanisms whereby absence of leads adipose tissue loss and metabolic disorders. Bscl2(-/-) develop severe lipodystrophy white (WAT), dyslipidemia, insulin resistance, hepatic steatosis. In vitro differentiation both murine embryonic fibroblasts (MEFs) stromal vascular cells (SVCs) reveals normal early-phase adipocyte but a striking failure terminal due unbridled cyclic AMP...
Circadian clocks in adipose tissue are known to regulate adipocyte biology. Although circadian dysregulation is associated with development of obesity, the underlying mechanism has not been established. Here we report that disruption clock gene, brain and muscle Arnt-like 1 (Bmal1), mice led increased adipogenesis, hypertrophy, compared wild-type (WT) mice. This due its cell-autonomous effect, as Bmal1 deficiency embryonic fibroblasts, well stable shRNA knockdown (KD) 3T3-L1 preadipocyte...
Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating the established number cardiomyocytes.
Abstract Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has been increasingly implicated a mechanism responsible for metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, mechanisms which modulate pancreatic hormone release not completely understood. We show human mouse α- β-cells express biosynthetic...
Metabolic abnormalities underlying diabetes are primarily the result of lack adequate insulin action and associated changes in protein phosphorylation gene expression. To define full set alterations expression skeletal muscle caused by loss action, we have used Affymetrix oligonucleotide microarrays streptozotocin-diabetic mice. Of genes studied, 235 were identified as changed diabetes, with 129 up-regulated 106 down-regulated. Analysis revealed a coordinated regulation at key steps glucose...
Abstract Mutations in the Berardinelli-Seip congenital lipodystrophy 2 gene (BSCL2) are underlying defect patients with generalized type 2. BSCL2 encodes a protein called seipin, whose function is largely unknown. In this study, we investigated role of Bscl2 regulation adipocyte differentiation. mRNA highly up-regulated during standard hormone-induced adipogenesis 3T3-L1 cells vitro. However, up-regulation does not occur mesenchymal stem cell (C3H10T1/2 cells) commitment to preadipocyte...
The circadian clock has been shown to regulate metabolic homeostasis. Mice with a deletion of Bmal1, key component the core molecular clock, develop hyperglycemia and hypoinsulinemia suggesting β-cell dysfunction. However, underlying mechanisms are not fully known. In this study, we investigated regulation function by Bmal1. We studied in global Bmal1-/- mice, vivo isolated islets ex vivo, as well rat insulinoma cell lines shRNA-mediated Bmal1 knockdown. Global mice diabetes secondary...
The circadian clock network is an evolutionarily conserved mechanism that imparts temporal regulation to diverse biological processes. Brain and muscle Arnt-like 1 (Bmal1), essential transcriptional activator of the clock, highly expressed in skeletal muscle. However, whether this key component impacts myogenesis, a temporally regulated event requires sequential activation myogenic regulatory factors, not known. Here we report novel function Bmal1 controlling differentiation through direct...
The molecular clock is intimately linked with metabolic regulation and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic machinery participates adipocyte development unknown. Here we show that Bmal1, essential transcription activator, inhibits adipogenesis to adversely impact fat formation thermogenic capacity. Global ablation of Bmal1 mice increases mass cold tolerance, while adipocyte-selective inactivation recapitulates these effects...
TEAD1 and the mammalian Hippo pathway regulate cellular proliferation function, though their regulatory function in β cells remains poorly characterized. In this study, we demonstrate that while cell-specific deletion results a cell-autonomous increase of cell proliferation, its canonical coactivators, YAP TAZ, does not affect suggesting involvement other cofactors. Using an improved split-GFP system yeast two-hybrid platform, identify VGLL4 MENIN as corepressors cells. We show bind to...
Diabetes mellitus is a complex metabolic disorder accompanied by alterations in cellular physiology, metabolism, and gene expression. These can be primary (due to loss of direct insulin action) or secondary the perturbations associated with disease). To dissect quantitate these two separate effects, we compared skeletal muscle gene-expression profiles receptor knockout (MIRKO) mice their Lox controls basal, streptozotocin-induced diabetic, insulin-treated diabetic states. Pure deficiency...
Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, requirement Tead1, transcriptional effector this pathway, adult heart unknown. Here, we show tamoxifen-inducible CM-specific Tead1 ablation led lethal acute-onset dilated cardiomyopathy,...
Abstract The Hippo-TEAD pathway regulates cellular proliferation and function. existing paradigm is that TEAD co-activators, YAP TAZ, co-repressor, VGLL4, bind to the pocket region of TEAD1 enable transcriptional activation or repressive Here we demonstrate a pocket-independent transcription repression mechanism whereby controls cell in both non-malignant mature differentiated cells malignant models. overexpression can repress tumor distinct cancer lines. In pancreatic β cells, conditional...
BACKGROUND: TEAD1, the mammalian Hippo pathway regulated transcription factor, plays a critical and non-redundant role in maintaining cardiomyocyte (CM) homeostasis. However, specific cellular pathways by TEAD1 CMs remain poorly defined. We hypothesized that has an essential, cell autonomous CM oxidative stress response directly regulating of NRF2, master regulator response. METHODS AND RESULTS: Tamoxifen induced conditional CM-specific deletion adult mice leads to acute heart failure (HF)...
Mixed background SHP(-/-) mice are resistant to diet-induced obesity due increased energy expenditure caused by enhanced PGC-1α expression in brown adipocytes. However, congenic on the C57BL/6 showed normal of and other genes involved adipose tissue thermogenesis. Thus, we reinvestigated impact small heterodimer partner (SHP) deletion insulin resistance using mice. Compared with their wild-type counterparts, subjected a 6 month challenge Western diet (WestD) were leaner but more glucose...
Brown adipose tissue is a major thermogenic organ that plays key role in maintenance of body temperature and whole-body energy homeostasis. Rev-erbα, ligand-dependent nuclear receptor transcription repressor the molecular clock, has been implicated regulation adipogenesis. However, whether Rev-erbα participates brown fat formation not known. Here we show regulator development by promoting Genetic ablation mice severely impairs embryonic neonatal accompanied loss identity. This defect due to...
Altered insulin secretion contributes to the pathogenesis of type 2 diabetes. This alteration is correlated with altered intracellular Ca2+-handling in pancreatic β cells. Insulin triggered by elevation cytoplasmic Ca2+ concentration ([Ca2+]cyt) [Ca2+]cyt leads activation Ca2+/calmodulin-dependent protein kinase II (CAMKII), which, turn, controls multiple aspects secretion. CaMKII known phosphorylate ryanodine receptor (RyR2), an Ca2+-release channel implicated Ca2+-dependent steps Our data...
Abstract Rev-erbα is a ligand-dependent nuclear receptor and key repressor of the molecular clock transcription network. Accumulating evidence indicate that circadian machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair mass maintenance. The physiological function myogenic regulation remains largely unknown. Here we show exerts cell-autonomous inhibitory effects on proliferation differentiation precursor cells, these actions concertedly inhibit...