scholarly journals Activin A Plays a Critical Role in Adipose Tissue Wasting in the Progression of Cancer Cachexia

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A40-A40
Author(s):  
Yi Luan ◽  
Mikyoung You ◽  
Pauline C Xu ◽  
Tom Thompson ◽  
So-Youn Kim
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Cancer Progression ◽  
Cancer Cachexia ◽  
Critical Role ◽  
Activin A ◽  
Adipose Tissues ◽  
Female Mice ◽  
Brown Adipose

Abstract Background: Nearly 50% of cancer patients suffer from cancer cachexia, a wasting syndrome with atrophy of white adipose tissue (WAT) and skeletal muscle. Cachexia leads to negative energy balance, limits cancer therapies, and reduces survival rate. It is characterized by body weight loss due to negative nutrients and energy balance from involuntary reduced food intake and abnormal metabolic conditions such as insulin resistance and hypertriglyceridemia. Cancer-driven factors such as activin A and IL-6 (interlukein-6) contribute to the occurrence of cachexia symptoms during cancer progression. While the importance of muscle atrophy has been emphasized in cachexia research, the underlying mechanism of adipose tissue wasting remains unclear. One proposed theory is that WAT switches to brown adipose tissue (BAT), characterized by the high expression level of UCP1 (uncoupling protein 1). Hypothesis: We hypothesize that activin A plays a critical role in adipose tissue wasting during cancer cachexia progression. Experiment: GDF9-iCre+; PIK3CA* female mice which shows cachexia symptoms in cancer progression were sacrificed before and after cachexia development. In addition, we injected FST288, an antagonist to activin A, for two weeks during cancer cachexia development. We harvested and analyzed multi-sites adipose tissues (gonadal, subcutaneous, interscapular and perirenal), muscle and liver. Serum activin A and IL-6 were measured using ELISA kits. DEXA and calorimetry analyses were performed, as well as immunohistochemistry, qPCR and western blotting assay. Results:GDF9-iCre+; PIK3CA* female mice started to display bilateral ovarian tumors around postnatal day (PD) 60, lose body weight around PD70 and became cachexia condition around PD80 with an increased level of serum activin A. Along with that, other body organs including liver, pancreas, muscle, and adipose tissues became dramatically small in mass. Our data proved that cachexia progression is correlated with the level of activin A rather than IL-6 in serum of GDF9-iCre+; PIK3CA* female mice. As serum activin A increased, adipocytes lost lipids and had distinct browning phenotypes in some adipocytes within WAT. Interestingly, calorimetry analysis did not display an increase in energy expenditure in cachectic mice although browning was evident in WAT. However, treatment with FST288 during cancer progression kept body weight and WAT in GDF9-iCre+; PIK3CA* female mice. Most of all, FST288 protected the size and lipid droplets of adipose tissues against WAT wasting during cachexia development. Conclusion: The progression of cancer cachexia impacts adipose tissues. Injection of FST288 supports the key role of activin A in the progress of cachexia. FST288 prevented adipose tissue wasting and cachexia development, revealing another evidence of the efficacy of activin A antagonist in preventing cancer cachexia development.

scholarly journals Nicotine Improves Obesity and Hepatic Steatosis and ER Stress in Diet-Induced Obese Male Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1679-1689 ◽  
Author(s):  
Patricia Seoane-Collazo ◽  
Pablo B. Martínez de Morentin ◽  
Johan Fernø ◽  
Carlos Diéguez ◽  
Rubén Nogueiras ◽  
...  
Keyword(s):  
Nervous System ◽  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Protein Kinase ◽  
Brown Adipose Tissue ◽  
Male Rats ◽  
Brown Adipose ◽  
Brown Adipose Tissue Thermogenesis ◽  
Amp Activated Protein Kinase

Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.

scholarly journals Gsα deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

2015 ◽  
Vol 113 (2) ◽  
pp. 446-451 ◽  
Author(s):  
Yong-Qi Li ◽  
Yogendra B. Shrestha ◽  
Min Chen ◽  
Tatyana Chanturiya ◽  
Oksana Gavrilova ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Energy Balance ◽  
Glucose Metabolism ◽  
Lipid Synthesis ◽  
Whole Body ◽  
Standard Diet ◽  
Fatty Acid Binding ◽  
Brown Adipose

Gsα, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with Gsα deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. Gsα signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight.

Abstract 605: Bone Morphogenetic Protein Inhibitors Play Important Roles in Brown and White Adipogenesis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Ana M Blazquez-Medela ◽  
Medet Jumabay ◽  
Kristina I Bostrom
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Body Fat ◽  
Lipid Accumulation ◽  
Adipogenic Differentiation ◽  
Critical Role ◽  
Matrix Gla Protein ◽  
Brown Adipocyte ◽  
Brown Adipose ◽  
Time Point

Adipose tissue is intimately connected to the development of metabolic syndrome, type 2 diabetes and cardiovascular disease. The near pandemic increase in incidence and prevalence of obesity makes it necessary to understand adipose regulation in order to develop strategies against obesity and its comorbidities. Adipose tissue performs a variety of functions. White adipose tissue (WAT) is responsible for energy storage, hormone production and organ protection, whereas brown adipose tissue (BAT) has a key role in thermogenesis. Previous studies have shown the importance of Bone Morphogenetic Proteins (BMPs) in the differentiation of brown and white adipocytes. BMP4 has been linked to both brown and white adipogenesis and BMP7 is essential for brown adipogenesis. Nevertheless, the role of the BMP inhibitors, which modulate the actions of BMPs, has not yet been elucidated. Our hypothesis is that the BMP inhibitors play important roles in the adipogenic process. Using two different mice models -Matrix Gla Protein (Mgp) KO and Noggin fat-specific KO- we found that the absence of Mgp resulted in dramatic adipose changes, suggesting a critical role in the separation of white and brown adipocytes. Adipocyte-specific deletion of Noggin, however, suggested a role in modulating the size and lipid accumulation in fully differentiated adipocytes. The absence of Mgp led to a reduction in body fat and body weight (3-12 animals per group and time point) whereas the absence of Noggin caused an increase in body fat and body weight (4-18 animals per time point and body weight). Tissue culture experiments using white and brown adipocyte progenitor cells showed specific temporal patterns of the BMPs and BMP-inhibitors that were consistent with the mouse findings. In conclusion, BMP inhibitors are essential in distinguishing brown and white adipogenic differentiation. We hypothesize that MGP is critical in the initial separation, whereas Noggin regulates cell size and lipid accumulation.

scholarly journals Resistance to Obesity by Repression of VEGF Gene Expression through Induction of Brown-Like Adipocyte Differentiation

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3123-3132 ◽  
Author(s):  
Xiaodan Lu ◽  
Yan Ji ◽  
Luqing Zhang ◽  
Yuntao Zhang ◽  
Shuzhi Zhang ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Metabolism ◽  
Weight Control ◽  
Specific Gene ◽  
Fatty Acid Transport ◽  
Adipose Tissues ◽  
Genetic Mouse Model ◽  
Brown Adipose ◽  
Body Weight Control

Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances.

Energy balance and brown adipose tissue thermogenesis during chronic endotoxemia in rats

1989 ◽  
Vol 66 (4) ◽  
pp. 1970-1975 ◽  
Author(s):  
J. Arnold ◽  
R. A. Little ◽  
N. J. Rothwell
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Body Weight Gain ◽  
Male Rats ◽  
Brown Adipose ◽  
Brown Adipose Tissue Thermogenesis

The effects of continuously administered endotoxin on 7-day energy balance were investigated in male rats. Three groups of rats were implanted with osmotic pumps; two groups received saline-filled pumps, whereas the third received endotoxin. One of the saline groups was pair fed to match the food intake of the endotoxemic rats. After 7 days, body energy and protein and fat contents of rats were determined together with the energy content of food and feces. Endotoxin infusion not only induced fever, but it also suppressed appetite and significantly decreased body weight gain. Metabolizable energy intake was reduced by approximately 20% in infected rats. Although protein and fat gains were lowest in the endotoxin group, there appeared to be a selective loss of protein when considered as percent of body weight. Percent body fat was unaltered between the groups. Energy expenditure considered in absolute (kJ) or body weight-independent (kJ/kg0.67) terms yielded similar patterns of results; expenditure (kJ) was 10 and 20% (P less than 0.05, P less than 0.01) lower in the endotoxemic and pair-fed rats, respectively, compared with controls. Hence, compared with pair-fed rats, endotoxin-infused animals had a 10% rise in their expenditure. Brown adipose tissue thermogenesis was assessed by mitochondrial binding of guanosine 5′-diphosphate, and results showed that binding was greatest in endotoxemic rats and lowest in the pair-fed animals. The present results suggest that in this endotoxemic model appetite suppression exacerbates changes in energy balance. However, the reduction in body weight gain is also dependent on a decrease in metabolic efficiency and an increase in total energy expenditure.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure

2011 ◽  
Vol 300 (6) ◽  
pp. E1002-E1011 ◽  
Author(s):  
Bart C. De Jonghe ◽  
Matthew R. Hayes ◽  
Ryoichi Banno ◽  
Karolina P. Skibicka ◽  
Derek J. Zimmer ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Food Intake ◽  
Cold Exposure ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Leptin Signaling ◽  
Leptin Sensitivity ◽  
Brown Adipose

The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene ( ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (TC), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b −/− mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in TC. Interestingly, POMC-Ptp1b −/− mice had increased BAT weight and elevated plasma triiodothyronine (T3) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis.

scholarly journals Central angiotensin II has catabolic action at white and brown adipose tissue

2011 ◽  
Vol 301 (6) ◽  
pp. E1081-E1091 ◽  
Author(s):  
Annette D. de Kloet ◽  
Eric G. Krause ◽  
Karen A. Scott ◽  
Michelle T. Foster ◽  
James P. Herman ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Energy Balance ◽  
Food Intake ◽  
Adrenergic Receptor ◽  
Receptor Expression ◽  
Ang Ii ◽  
Sympathetic Activation ◽  
Brown Adipose

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and β3-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.

Characterization of MCH-mediated obesity in mice

2003 ◽  
Vol 284 (5) ◽  
pp. E940-E945 ◽  
Author(s):  
Masahiko Ito ◽  
Akira Gomori ◽  
Akane Ishihara ◽  
Zenjun Oda ◽  
Satoshi Mashiko ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Critical Role ◽  
Acid Oxidation ◽  
Intracerebroventricular Infusion ◽  
Brown Adipose ◽  
Ad Libitum ◽  
Lipogenic Activity

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitum-fed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.

scholarly journals The role of kisspeptin neurons in reproduction and metabolism

2018 ◽  
Vol 238 (3) ◽  
pp. R173-R183 ◽  
Author(s):  
Campbell J L Harter ◽  
Georgia S Kavanagh ◽  
Jeremy T Smith
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Pulse Generator ◽  
Third Ventricle ◽  
Critical Role ◽  
Direct Role ◽  
Hpg Axis ◽  
Area Of Interest ◽  
Brown Adipose

Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic–pituitary–gonadal (HPG) axis. Kisspeptin is produced by two major populations of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC). These neurons project to and activate gonadotrophin-releasing hormone (GnRH) neurons (acting via the kisspeptin receptor, Kiss1r) in the hypothalamus and stimulate the secretion of GnRH. Gonadal sex steroids stimulate kisspeptin neurons in the RP3V, but inhibit kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC kisspeptin neurons act as the GnRH pulse generator. Due to kisspeptin’s profound effect on the HPG axis, a focus of recent research has been on afferent inputs to kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition. Alternatively, evidence is building for a direct role for kisspeptin in regulating energy balance and metabolism. Kiss1r-knockout (KO) mice exhibit increased adiposity and reduced energy expenditure. Although the mechanisms underlying these observations are currently unknown, Kiss1r is expressed in adipose tissue and potentially brown adipose tissue (BAT) and Kiss1rKO mice exhibit reduced energy expenditure. Recent studies are now looking at the effects of kisspeptin signalling on behaviour, with clinical evidence emerging of kisspeptin affecting sexual behaviour, further investigation of potential neuronal pathways are warranted.

Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue

2005 ◽  
Vol 289 (1) ◽  
pp. E68-E74 ◽  
Author(s):  
Michael Koban ◽  
Kevin L. Swinson
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Sleep Deprivation ◽  
Brown Adipose Tissue ◽  
Food Consumption ◽  
Rem Sleep ◽  
Serum Leptin ◽  
Brown Adipose

A cluster of unique pathologies progressively develops during chronic total- or rapid eye movement-sleep deprivation (REM-SD) of rats. Two prominent and readily observed symptoms are hyperphagia and decline in body weight. For body weight to be lost despite a severalfold increase in food consumption suggests that SD elevates metabolism as the subject enters a state of negative energy balance. To test the hypothesis that mediation of this hypermetabolism involves increased gene expression of uncoupling protein-1 (UCP1), which dissipates the thermodynamic energy of the mitochondrial proton-motive force as heat instead of ATP formation in brown adipose tissue (BAT), we 1) established the time course and magnitude of change in metabolism by measuring oxygen consumption, 2) estimated change in UCP1 gene expression in BAT by RT-PCR and Western blot, and 3) assayed serum leptin because of its role in regulating energy balance and food intake. REM-SD of male Sprague-Dawley rats was enforced for 20 days with the platform (flowerpot) method, wherein muscle atonia during REM sleep causes contact with surrounding water and awakens it. By day 20, rats more than doubled food consumption while losing ∼11% of body weight; metabolism rose to 166% of baseline with substantial increases in UCP1 mRNA and immunoreactive UCP1 over controls; serum leptin decreased and remained suppressed. The decline in leptin is consistent with the hyperphagic response, and we conclude that one of the mediators of elevated metabolism during prolonged REM-SD is increased gene expression of UCP1 in BAT.

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