scholarly journals Neuronal Protein Tyrosine Phosphatase 1B Deficiency Results in Inhibition of Hypothalamic AMPK and Isoform-Specific Activation of AMPK in Peripheral Tissues

2009 ◽  
Vol 29 (16) ◽  
pp. 4563-4573 ◽  
Author(s):  
Bingzhong Xue ◽  
Thomas Pulinilkunnil ◽  
Incoronata Murano ◽  
Kendra K. Bence ◽  
Huamei He ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Target Genes ◽  
Fiber Type ◽  
Metabolic Effects ◽  
Whole Body ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Leptin Sensitivity ◽  
Brown Adipose ◽  
Ampk Activity

ABSTRACT PTP1B−/− mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that α1 and α2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B−/− mice. The effects of PTP1B deficiency on α2, but not α1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B−/− mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B−/− mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.

scholarly journals Natural Extracts to Augment Energy Expenditure as a Complementary Approach to Tackle Obesity and Associated Metabolic Alterations

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 412
Author(s):  
Marina Reguero ◽  
Marta Gómez de Cedrón ◽  
Guillermo Reglero ◽  
José Carlos Quintela ◽  
Ana Ramírez de Molina
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Metabolic Stress ◽  
Whole Body ◽  
Acid Oxidation ◽  
Nucleotide Polymorphisms ◽  
Metabolic Alterations ◽  
Natural Extracts ◽  
Brown Adipose ◽  
Critical Components

Obesity is the epidemic of the 21st century. In developing countries, the prevalence of obesity continues to rise, and obesity is occurring at younger ages. Obesity and associated metabolic stress disrupt the whole-body physiology. Adipocytes are critical components of the systemic metabolic control, functioning as an endocrine organ. The enlarged adipocytes during obesity recruit macrophages promoting chronic inflammation and insulin resistance. Together with the genetic susceptibility (single nucleotide polymorphisms, SNP) and metabolic alterations at the molecular level, it has been highlighted that key modifiable risk factors, such as those related to lifestyle, contribute to the development of obesity. In this scenario, urgent therapeutic options are needed, including not only pharmacotherapy but also nutrients, bioactive compounds, and natural extracts to reverse the metabolic alterations associated with obesity. Herein, we first summarize the main targetable processes to tackle obesity, including activation of thermogenesis in brown adipose tissue (BAT) and in white adipose tissue (WAT-browning), and the promotion of energy expenditure and/or fatty acid oxidation (FAO) in muscles. Then, we perform a screening of 20 natural extracts (EFSA approved) to determine their potential in the activation of FAO and/or thermogenesis, as well as the increase in respiratory capacity. By means of innovative technologies, such as the study of their effects on cell bioenergetics (Seahorse bioanalyzer), we end up with the selection of four extracts with potential application to ameliorate the deleterious effects of obesity and the chronic associated inflammation.

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

2009 ◽  
Vol 296 (4) ◽  
pp. E812-E819 ◽  
Author(s):  
Woo Sik Kim ◽  
Yun Sok Lee ◽  
Seung Hun Cha ◽  
Hyun Woo Jeong ◽  
Sung Sik Choe ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Fatty Acid Oxidation ◽  
Energy Homeostasis ◽  
Liver Weight ◽  
Whole Body ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Expression Of Genes ◽  
Ampk Activity

AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.

scholarly journals Assessment of Acute and Chronic Pharmacological Effects on Energy Expenditure and Macronutrient Oxidation in Humans: Responses to Ephedrine

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Antonella Napolitano ◽  
Peter R. Murgatroyd ◽  
Nick Finer ◽  
Elizabeth K. Hussey ◽  
Robert Dobbins ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Small Groups ◽  
Negative Energy ◽  
Metabolic Effects ◽  
Whole Body ◽  
Pharmacological Effects ◽  
Pharmacological Interventions ◽  
Ephedrine Hydrochloride ◽  
Brown Adipose ◽  
Human Adults

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID(n=8)or placebo(n=6)were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds.

scholarly journals p-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation

2021 ◽  
Vol 22 (3) ◽  
pp. 1431
Author(s):  
Linh V. Nguyen ◽  
Khoa D. A. Nguyen ◽  
Chi-Thanh Ma ◽  
Quoc-Thai Nguyen ◽  
Huong T. H. Nguyen ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Blood Glucose Control ◽  
Whole Body ◽  
Ampk Activation ◽  
Coumaric Acid ◽  
Leptin Signaling ◽  
Differential Effects ◽  
Leptin Sensitivity ◽  
Ampk Activity

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p-Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA’s actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.

scholarly journals The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system

2017 ◽  
Vol 235 (2) ◽  
pp. 111-122 ◽  
Author(s):  
Riccardo Dore ◽  
Luka Levata ◽  
Sogol Gachkar ◽  
Olaf Jöhren ◽  
Jens Mittag ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Heat Loss ◽  
Central Administration ◽  
Melanocortin System ◽  
Direct Calorimetry ◽  
Iodothyronine Deiodinase ◽  
Interscapular Brown Adipose Tissue ◽  
Peripheral Tissues ◽  
Dry Heat ◽  
Brown Adipose

Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.

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 AMPK as a mediator of hormonal signalling

2009 ◽  
Vol 44 (2) ◽  
pp. 87-97 ◽  
Author(s):  
Chung Thong Lim ◽  
Blerina Kola ◽  
Márta Korbonits
Keyword(s):  
Protein Synthesis ◽  
Fatty Acid ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Metabolic Effects ◽  
Whole Body ◽  
Acid Oxidation ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Hormonal Signalling

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

scholarly journals Kupffer cells facilitate the acute effects of leptin on hepatic lipid metabolism

2017 ◽  
Vol 312 (1) ◽  
pp. E11-E18 ◽  
Author(s):  
Anantha Metlakunta ◽  
Wan Huang ◽  
Maja Stefanovic-Racic ◽  
Nikolaos Dedousis ◽  
Ian Sipula ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Kupffer Cells ◽  
Liver Lipid ◽  
Myeloid Cell ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Acute Effects ◽  
Peripheral Tissues ◽  
Liver Lipid Metabolism

Leptin has potent effects on lipid metabolism in a number of peripheral tissues. In liver, an acute leptin infusion (~120 min) stimulates hepatic fatty acid oxidation (~30%) and reduces triglycerides (TG, ~40%), effects that are dependent on phosphoinositol-3-kinase (PI3K) activity. In the current study we addressed the hypothesis that leptin actions on liver-resident immune cells are required for these metabolic effects. Myeloid cell-specific deletion of the leptin receptor (ObR) in mice or depletion of liver Kupffer cells (KC) in rats in vivo prevented the acute effects of leptin on liver lipid metabolism, while the metabolic effects of leptin were maintained in mice lacking ObR in hepatocytes. Notably, liver TG were elevated in both lean and obese myeloid cell ObR, but the degree of obesity and insulin resistance induced by a high-fat diet was similar to control mice. In isolated primary hepatocytes (HEP), leptin had no effects on HEP lipid metabolism and only weakly stimulated PI3K. However, the coculture of KC with HEP restored leptin action on HEP fatty acid metabolism and stimulation of HEP PI3K. Notably, leptin stimulated the release from KC of a number of cytokines. However, the exposure of HEP to these cytokines individually [granulocyte macrophage colony-stimulating factor, IL-1α, IL-1β, IL-6, IL-10, and IL-18] or in combination had no effects on HEP lipid metabolism. Together, these data demonstrate a role for liver mononuclear cells in the regulation of liver lipid metabolism by leptin.

Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis

2019 ◽  
Vol 51 (10) ◽  
pp. 678-685 ◽  
Author(s):  
Luka Levata ◽  
Riccardo Dore ◽  
Olaf Jöhren ◽  
Markus Schwaninger ◽  
Carla Schulz ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Body Weight Loss ◽  
Whole Body ◽  
Central Administration ◽  
Adrenergic Stimulation ◽  
Interscapular Brown Adipose Tissue ◽  
Adrenoceptor Antagonist ◽  
Brown Adipose

AbstractNesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce β3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the β3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on β3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.

scholarly journals Energy balance in rats given chronic hormone treatment

1989 ◽  
Vol 61 (3) ◽  
pp. 437-444 ◽  
Author(s):  
Christopher J. H. Woodward ◽  
Peter W. Emery
Keyword(s):  
Energy Balance ◽  
Energy Expenditure ◽  
Insulin Treatment ◽  
Statistical Significance ◽  
Metabolizable Energy ◽  
Fat Free Mass ◽  
Whole Body ◽  
Interscapular Brown Adipose Tissue ◽  
Total Enzyme Activity ◽  
Brown Adipose

1. Sprague–Dawley rats were injected for 16 d with long-acting insulin, and energy balance was calculated using the comparative carcass technique. Two experiments were carried out with females (starting weights 150 and 90 g respectively), and one with males (starting weight 150 g). In a fourth experiment, cytochrome c oxidasc (EC 1.9.3.1) activity was measured as an indicator of the capacity for substrate oxidation.2. Insulin increased weight gain by up to 57% (P < 0.01 for all studies). Metabolizable energy intake (kJ/d) was also consistently higher in the treated groups, by up to 34% (P < 0.01 for all studies). The excess weight gained by the insulin-treated rats was predominantly due to fat deposition.3. Energy expenditure, calculated as the difference between metabolizable intake and carcass energy gain. was expressed on a whole-body basis, or relative to either metabolic body size (kg body-weight0.75) or fat-free mass. Insulin consistently raised energy expenditure, regardless of the method of expression, but this change reached statistical significance in only two of the nine comparisons.4. Cytochrome c oxidase activity was not affected by insulin treatment in either interscapular brown adipose tissue or gastrocnemius muscle. In liver, total enzyme activity (U/tissue) was increased from 2928 (se 162) in the controls to 3940 (se 294) in the treated group (P < 0.02), but specific activity (U/mg protein) was unchanged.5. It is concluded that, despite causing substantial hyperphagia, insulin treatment only slightly increases energy expenditure in rats. The costs of increased tissue deposition may account for this change.

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