scholarly journals Loss of Imprinting of Cdkn1c Protects against Age and Diet-Induced Obesity

2018 ◽  
Vol 19 (9) ◽  
pp. 2734 ◽  
Author(s):  
Mathew Van de Pette ◽  
Simon J. Tunster ◽  
Rosalind M. John
Keyword(s):  
Adipose Tissue ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Fold Increase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Loss Of Imprinting ◽  
Diet Induced Obesity ◽  
Age Related ◽  
Brown Adipose ◽  
The Stability

Cyclin dependent kinase inhibitor 1c (Cdkn1c) is a maternally expressed imprinted gene with roles in embryonic development, post-natal metabolism and behaviour. Using mouse models with altered dosages of Cdkn1c, we have previously identified a role for the gene in promoting brown adipose tissue formation. Here, we use these transgenic mouse lines to model the loss of imprinting of Cdkn1c in adulthood. We demonstrate that only a two-fold increase in the expression of Cdkn1c during development is sufficient to protect against age-related weight gain in addition to glucose and insulin intolerance. Further to this, we show that the loss of imprinting of Cdkn1c protects against diet-induced obesity. Bisulphite sequencing was performed to test the stability of the two differentially methylated regions that regulate Cdkn1c imprinting, and both were found to be unaltered in aged or diet-challenged adipose tissue, despite drastic reductions in Cdkn1c expression. These data demonstrate a critical role for Cdkn1c in regulating adult adipose tissue, with modest changes in expression capable of protecting against both age and diet-induced obesity and metabolic syndrome, with a natural decline in Cdkn1c expression observed that may contribute to less healthy metabolic aging. Finally, we have observed a post-natal insensitivity of the imprint to environmental factors, in contrast to recent observations of an in utero sensitivity.

scholarly journals The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nabil Rabhi ◽  
Kathleen Desevin ◽  
Briana Noel Cortez ◽  
Ryan Hekman ◽  
Jean Z. Lin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Kinase Inhibitor ◽  
Whole Body ◽  
Mitochondrial Activity ◽  
Pathway Enrichment Analysis ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Brown Adipose ◽  
Metabolic Disruption

AbstractMost strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.

scholarly journals Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Enrique Calvo ◽  
Noelia Keiran ◽  
Catalina Núñez-Roa ◽  
Elsa Maymó-Masip ◽  
Miriam Ejarque ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Therapeutic Option ◽  
Metabolic Activation ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Obesity In Mice ◽  
Treatment Of Obesity ◽  
Visceral Adipose

AbstractAdipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

Abstract 041: mTORC1 is Required for Leptin-induced Sympathetic Activation to the Kidney but Not Brown Adipose Tissue

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Balyssa B Bell ◽  
Donald A Morgan ◽  
Kamal Rahmouni
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Critical Role ◽  
Conditional Knockout ◽  
Sympathetic Activation ◽  
Long Term Effects ◽  
Brown Adipose ◽  
Mtorc1 Signaling

The adipocyte-derived hormone leptin plays a critical role in the regulation of energy homeostasis through its action in the brain to decrease food intake and promote energy expenditure by increasing sympathetic nerve activity (SNA) to the thermogenic brown adipose tissue (BAT). Leptin also increases SNA to cardiovascular organs including the kidney and raises arterial pressure. However, it is unclear whether leptin controls regional SNA via conserved or distinct molecular mechanisms. Multiple intracellular pathways have been associated with leptin signaling including the mechanistic target of rapamycin complex 1 (mTORC1), which has been proposed as a critical determinant of leptin action. Here, we assessed the contribution of mTORC1 signaling to leptin-evoked regional sympathetic activation. Simultaneous multifiber recording of renal and BAT SNA in anesthetized C57BL/6J mice showed that intracerebroventricular (ICV) administration of leptin (2μg, n=5) increased both renal (170±34%) and BAT (208±37%) SNA. Interestingly, ICV pre-treatment with the mTORC1 inhibitor (rapamycin, 5ng, n=6) abolished the leptin-induced increase in renal (10±6%, P<0.05 vs controls) but not BAT (226±31%) SNA. Next, we used conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb)-expressing cells (LRb Cre /Raptor fl/fl ) to determine the long-term effects of disrupting mTORC1 signaling on leptin-evoked increase in regional SNA. We confirmed the inability of leptin to activate mTORC1 signaling in LRb-expressing cells of LRb Cre /Raptor fl/fl mice relative to controls using immunohistochemical staining of phosphorylated ribosomal S6, a downstream target of mTORC1. We observed a significant increase in renal SNA in response to ICV leptin in control mice (127±16%, n=9), but not in LRb Cre /Raptor fl/fl mice (-4±15%, n=9, P<0.05 vs controls). Conversely, ICV leptin-induced increase in BAT SNA was not different in LRb Cre /Raptor fl/fl mice (109±27%, n=5) vs. littermate controls (173±52%, n=4). Our data suggest a critical role for mTORC1 signaling in selectively mediating the cardiovascular sympathetic but not the thermogenic actions of leptin, with important implications for obesity-associated hypertension.

CNS origins of the sympathetic nervous system outflow to brown adipose tissue

1999 ◽  
Vol 276 (6) ◽  
pp. R1569-R1578 ◽  
Author(s):  
Maryam Bamshad ◽  
C. Kay Song ◽  
Timothy J. Bartness
Keyword(s):  
Nervous System ◽  
Adipose Tissue ◽  
Sympathetic Nervous System ◽  
Brown Adipose Tissue ◽  
Pseudorabies Virus ◽  
Critical Role ◽  
Hypothalamic Nucleus ◽  
Brown Adipose ◽  
Sympathetic Nervous ◽  
Diet Induced Thermogenesis

Brown adipose tissue (BAT) plays a critical role in cold- and diet-induced thermogenesis. Although BAT is densely innervated by the sympathetic nervous system (SNS), little is known about the central nervous system (CNS) origins of this innervation. The purpose of the present experiment was to determine the neuroanatomic chain of functionally connected neurons from the CNS to BAT. A transneuronal viral tract tracer, Bartha’s K strain of the pseudorabies virus (PRV), was injected into the interscapular BAT of Siberian hamsters. The animals were killed 4 and 6 days postinjection, and the infected neurons were visualized by immunocytochemistry. PRV-infected neurons were found in the spinal cord, brain stem, midbrain, and forebrain. The intensity of labeled neurons in the forebrain varied from heavy infections in the medial preoptic area and paraventricular hypothalamic nucleus to few infections in the ventromedial hypothalamic nucleus, with moderate infections in the suprachiasmatic and lateral hypothalamic nuclei. These results define the SNS outflow from the brain to BAT for the first time in any species.

scholarly journals Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Danielle Yi ◽  
Hai P Nguyen ◽  
Jennie Dinh ◽  
Jose A Viscarra ◽  
Ying Xie ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Target Genes ◽  
Critical Role ◽  
Direct Interaction ◽  
Fat Cell ◽  
Methyltransferase Activity ◽  
Promoter Regions ◽  
Brown Adipose ◽  
Thermogenic Capacity

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

scholarly journals Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160131 ◽  
Author(s):  
Yuzhong Xiao ◽  
Tingting Xia ◽  
Junjie Yu ◽  
Yalan Deng ◽  
Hao Liu ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Steatosis ◽  
Leptin Resistance ◽  
Hormone Production ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Brown Adipose

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

scholarly journals RalA controls glucose homeostasis by regulating glucose uptake in brown fat

2018 ◽  
Vol 115 (30) ◽  
pp. 7819-7824 ◽  
Author(s):  
Yuliya Skorobogatko ◽  
Morgan Dragan ◽  
Claudia Cordon ◽  
Shannon M. Reilly ◽  
Chao-Wei Hung ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Brown Fat ◽  
Specific Chemical ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Chemical Inhibitors ◽  
Glucose Transporter Glut4

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.

Hormonal regulation of iodothyronine 5'-deiodinase in rat brown adipose tissue

1986 ◽  
Vol 251 (6) ◽  
pp. E639-E643 ◽  
Author(s):  
J. E. Silva ◽  
P. R. Larsen
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Hormonal Regulation ◽  
Fold Increase ◽  
Growth Hormones ◽  
Mrna Synthesis ◽  
Brown Adipose ◽  
Streptozotocin Induced Diabetes ◽  
Complex Regulation ◽  
Intact Rats

Norepinephrine, isoproterenol, insulin, and glucagon increase the type II (low Km) iodothyronine 5'-deiodinase (5'-D) in the brown adipose tissue (BAT) of intact rats. Cycloheximide or actinomycin D blocks the increase after norepinephrine, suggesting new mRNA synthesis is required for this effect. The 3- to 10-fold increase in BAT 5'-D after insulin administration was also blocked by cycloheximide. The effects of all stimulators are blunted by fasting or streptozotocin-induced diabetes. While all these hormones have the potential for stimulating BAT 5'-D, the dose-response relationships suggest that norepinephrine and insulin are the most potent. These and our earlier studies showing additional effects of thyroid and growth hormones on BAT 5'-D point to the complex regulation of this enzyme, suggesting that the triiodothyronine produced from its action has an important role in the thermogenic response of this tissue.

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