scholarly journals Impaired noradrenaline-induced lipolysis in white fat of aP2-Ucp1 transgenic mice is associated with changes in G-protein levels

2002 ◽  
Vol 364 (2) ◽  
pp. 369-376 ◽  
Author(s):  
Pavel FLACHS ◽  
JiŘí NOVOTNÝ ◽  
Filip BAUMRUK ◽  
Kristina BARDOVÁ ◽  
Lenka BOUŘOVÁ ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
G Protein ◽  
Energy Status ◽  
Α Subunit ◽  
Fat Depots ◽  
Ucp1 Expression ◽  
White Fat ◽  
Stimulation Of

In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein α subunit was increased while that of the inhibitory G-protein α subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

scholarly journals Histone Carbonylation Is a Redox-Regulated Epigenomic Mark That Accumulates with Obesity and Aging

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1210
Author(s):  
Amy K. Hauck ◽  
Tong Zhou ◽  
Ambuj Upadhyay ◽  
Yuxiang Sun ◽  
Michael B. O’Connor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Disease ◽  
Adipose Tissue ◽  
Fat Depots ◽  
Michael Adducts ◽  
Lipid Aldehydes ◽  
Visceral Adipose ◽  
Fat Feeding

Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging.

scholarly journals Evaluation of Browning Agents on the White Adipogenesis of Bone Marrow Mesenchymal Stromal Cells: A Contribution to Fighting Obesity

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 403
Author(s):  
Girolamo Di Maio ◽  
Nicola Alessio ◽  
Ibrahim Halil Demirsoy ◽  
Gianfranco Peluso ◽  
Silverio Perrotta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
White Adipocyte ◽  
Drug Candidates ◽  
Fat Depots ◽  
Treatment Of Obesity ◽  
White Fat

Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as “browning” or “beiging”. These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.

scholarly journals Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo

2017 ◽  
Vol 114 (45) ◽  
pp. E9559-E9568 ◽  
Author(s):  
Qing He ◽  
Richard Bouley ◽  
Zun Liu ◽  
Marc N. Wein ◽  
Yan Zhu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
G Protein ◽  
Critical Role ◽  
Hek293 Cells ◽  
Activity Levels ◽  
Α Subunit ◽  
Proteomic Screen ◽  
Protein Levels ◽  
G Protein Α Subunit

Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by GNAS, XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it. Similarly, primary cardiomyocytes derived from XLαs knockout (XLKO) pups showed enhanced transferrin internalization. Early postnatal XLKO mice showed a significantly higher degree of cardiac iron uptake than wild-type littermates following iron dextran injection. In XLKO neonates, iron and ferritin levels were elevated in heart and skeletal muscle, where XLαs is normally expressed abundantly. XLKO heart and skeletal muscle, as well as XLKO Ocy454 cells, showed elevated SNX9 protein levels, and siRNA-mediated knockdown of SNX9 in XLKO Ocy454 cells prevented enhanced transferrin internalization. In transfected cells, XLαs also inhibited internalization of the parathyroid hormone and type 2 vasopressin receptors. Internalization of transferrin and these G protein-coupled receptors was also inhibited in cells expressing an XLαs mutant missing the Gα portion, but not Gsα or an N-terminally truncated XLαs mutant unable to interact with SNX9 or dynamin. Thus, XLαs restricts clathrin-mediated endocytosis and plays a critical role in iron/transferrin uptake in vivo.

scholarly journals Hybrid Transgenic Mice Reveal In Vivo Specificity of G Protein–Coupled Receptor Kinases in the Heart

2000 ◽  
Vol 86 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Andrea D. Eckhart ◽  
Sandra J. Duncan ◽  
Raymond B. Penn ◽  
Jeffrey L. Benovic ◽  
Robert J. Lefkowitz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Receptor Kinases ◽  
G Protein Coupled

scholarly journals Genome-Scale Analysis Reveals Sst2 as the Principal Regulator of Mating Pheromone Signaling in the Yeast Saccharomyces cerevisiae

2006 ◽  
Vol 5 (2) ◽  
pp. 330-346 ◽  
Author(s):  
Scott A. Chasse ◽  
Paul Flanary ◽  
Stephen C. Parnell ◽  
Nan Hao ◽  
Jiyoung Y. Cha ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transition State ◽  
G Protein ◽  
Common Property ◽  
Rgs Proteins ◽  
Homologous Proteins ◽  
Yeast Saccharomyces Cerevisiae ◽  
Α Subunit ◽  
Pheromone Signaling

ABSTRACT A common property of G protein-coupled receptors is that they become less responsive with prolonged stimulation. Regulators of G protein signaling (RGS proteins) are well known to accelerate G protein GTPase activity and do so by stabilizing the transition state conformation of the G protein α subunit. In the yeast Saccharomyces cerevisiae there are four RGS-homologous proteins (Sst2, Rgs2, Rax1, and Mdm1) and two Gα proteins (Gpa1 and Gpa2). We show that Sst2 is the only RGS protein that binds selectively to the transition state conformation of Gpa1. The other RGS proteins also bind Gpa1 and modulate pheromone signaling, but to a lesser extent and in a manner clearly distinct from Sst2. To identify other candidate pathway regulators, we compared pheromone responses in 4,349 gene deletion mutants representing nearly all nonessential genes in yeast. A number of mutants produced an increase (sst2, bar1, asc1, and ygl024w) or decrease (cla4) in pheromone sensitivity or resulted in pheromone-independent signaling (sst2, pbs2, gas1, and ygl024w). These findings suggest that Sst2 is the principal regulator of Gpa1-mediated signaling in vivo but that other proteins also contribute in distinct ways to pathway regulation.

scholarly journals Treatment with atrial natriuretic peptide induces adipose tissue browning and exerts thermogenic actions in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haruka Kimura ◽  
Tomohisa Nagoshi ◽  
Yuhei Oi ◽  
Akira Yoshii ◽  
Yoshiro Tanaka ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Cold Exposure ◽  
Lipid Droplets ◽  
Adipose Tissues ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Tissue Browning

AbstractIncreasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP-treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

Impaired parasympathetic heart rate control in mice with a reduction of functional G protein βγ-subunits

2002 ◽  
Vol 282 (2) ◽  
pp. H445-H456 ◽  
Author(s):  
Josef Gehrmann ◽  
Michael Meister ◽  
Colin T. Maguire ◽  
Donna C. Martins ◽  
Peter E. Hammer ◽  
...  
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Transgenic Mice ◽  
G Protein ◽  
Rate Control ◽  
Sinus Node ◽  
Physiological Role ◽  
Heart Rate Control ◽  
Electrophysiological Studies

Acetylcholine released on parasympathetic stimulation slows heart rate through activation of muscarinic receptors on the sinus nodal cells and subsequent opening of the atrial muscarinic potassium channel (KACh). KACh is directly activated by G protein βγ-subunits. To elucidate the physiological role of Gβγ for the regulation of heart rate and electrophysiological function in vivo, we created transgenic mice with a reduced amount of membrane-bound Gβ protein by overexpressing nonprenylated Gγ2-subunits in their hearts using the α-myosin heavy chain promoter. At baseline and after muscarinic stimulation with carbachol, heart rate and heart rate variability were determined with electrocardiogram telemetry in conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional Gβγ protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were observed in wild types. In addition, sinus node recovery time and inducibility of atrial arrhythmias were reduced in transgenic mice. Our data demonstrate in vivo that Gβγ plays a crucial role for parasympathetic heart rate control, sinus node automaticity, and atrial arrhythmia vulnerability.

Glycerokinase in mammalian adipose tissue: stimulation by lipogenic substances

1975 ◽  
Vol 228 (6) ◽  
pp. 1868-1874 ◽  
Author(s):  
PA Persico ◽  
M Cerchio ◽  
H Jeffay
Keyword(s):  
Adipose Tissue ◽  
Fat Metabolism ◽  
Main Function ◽  
Fat Pad ◽  
Fat Cell ◽  
Fat Depots ◽  
Anabolic Action ◽  
Brown Adipose ◽  
Gradual Accumulation

A connecting link between carbohydrate and fat metabolism in adipose tissue is theconcentration of alpha-glycerophosphate derived predominantly from the glycolysis ofglucose entering the fat cell. However, several investigators have reported the presence of a glycerol specific kinase in the epidiymal fat-pad of the rat and obob mouse.This enzyme's presence in other mammalian adipose tissue could contribute to the alpha-glycerophosphate pool and thus affect both carbohydrate and fat metabolism within the fat cell. Glycerokinase was demonstrated in isolated fat cells obtained from the subcutaneous, perirenal, epididymal, and dorsal intrascapular brown fat depots of the adultmale rat. It was found to be particularly sensitive to in vivo lipogenic stimuli in both the subcutaneous and the brown adipose tissue and concluded that insulin is involved in adipose glycerokinase stimulation. Therefore, the main function of glycerokinase in normal adipose tissue may be to augment the anabolic action of insulin. It isfurther suggested that deviation from the normal control of this lipogenic enzyme couldlead to a gradual accumulation of fat and eventual obesity.

scholarly journals Resveratrol-Induced White Adipose Tissue Browning in Obese Mice by Remodeling Fecal Microbiota

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3356 ◽  
Author(s):  
Weiyao Liao ◽  
Xiaohan Yin ◽  
Qingrong Li ◽  
Hongmin Zhang ◽  
Zihui Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gut Microbiota ◽  
White Adipose Tissue ◽  
Additional Treatment ◽  
The Body ◽  
Sirtuin 1 ◽  
Obese Mice ◽  
Positive Role ◽  
White Fat

Promoting the browning of white fat may be a potential means of combating obesity. Therefore, in this study, we investigated the effect of resveratrol (RES) on the body weight and browning of white fat in high-fat diet (HFD)-induced obese mice and the potential associated mechanism in vivo. Eight-week-old male mice were randomized to receive different treatments: (1), chow without any additional treatment (chow); (2), chow plus 0.4% resveratrol (chow-RES); (3), HFD without any additional treatment (HFD); and (4), HFD plus 0.4% resveratrol (HFD-RES). After 4 weeks of feeding, additional 8-week-old male recipient mice were randomly allocated to the following 4 treatments: (5), HFD and received feces from chow-fed mice; (6), HFD and received feces from chow-RES-fed mice; (7), HFD and received feces from HFD-fed mice; and (8), HFD and received feces from HFD-RES-fed mice. RES treatment significantly inhibited increases in fat accumulation, promoted the browning of white adipose tissue (WAT) and alleviated gut microbiota dysbiosis in HFD-fed mice. Subsequent analyses showed that the gut microbiota remodeling induced by resveratrol had a positive role in WAT browning, and sirtuin-1 (Sirt1) signaling appears to be a key component of this process. Overall, the results show that RES may serve as a potential intervention to reduce obesity by alleviating dysbiosis of the gut microbiota.

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