Thermogenesis and mitochondrial GDP binding with age in response to the novel agonist CGP-12177A

1992 ◽  
Vol 262 (2) ◽  
pp. E185-E190 ◽  
Author(s):  
P. J. Scarpace ◽  
M. Matheny ◽  
S. E. Borst
Keyword(s):  
Body Temperature ◽  
Binding Sites ◽  
Uncoupling Protein ◽  
The Novel ◽  
O2 Consumption ◽  
Brown Adipose ◽  
Old Rats ◽  
Regulate Body Temperature ◽  
Beta Adrenergic Agonist ◽  
Peak Increase

The ability to regulate body temperature diminishes with age in both humans and rodents. To investigate whether attenuation of sympathetically activated thermogenesis in brown adipose tissue (BAT) may account for the loss of thermoregulation with age, we assessed O2 consumption and body temperature in response to norepinephrine and the specific BAT beta-adrenergic agonist CGP-12177A in 6-, 18-, and 24-mo-old rats. In addition, the effects of this agonist on interscapular BAT mitochondrial GDP binding in young and senescent rats were determined. CGP-12177A rapidly induced an elevation in O2 consumption, which peaked at 25 min, followed by a decline over 4 h. The peak increase in O2 consumption over baseline and the cumulative 4-h response were decreased with age [P less than 0.02, analysis of variance (ANOVA)]. CGP-12177A induced an increase in body temperature that paralleled but appropriately lagged behind the increase in O2 consumption and that was decreased with age (P less than 0.02, ANOVA). The norepinephrine-induced increase in O2 consumption was also reduced with age but was not paralleled by a change in body temperature and was associated with a four- to fivefold increase in physical activity. In young rats CGP-12177A increased the number of available BAT mitochondrial GDP binding sites at 20 and 60 min post-injection, but in senescent rats GCP-12177A was unable to increase GDP binding. These data indicate that CGP-12177A is a novel agonist for BAT thermogenesis. With age there is a reduced capacity for thermogenesis that involves a failure to increase GDP binding, either due to a diminished amount of uncoupling protein with age or a failure to unmask reserve GDP binding sites.

Rapid changes in number of GDP binding sites on brown adipose tissue mitochondria

1986 ◽  
Vol 251 (2) ◽  
pp. E192-E195
Author(s):  
A. G. Swick ◽  
R. W. Swick
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Binding Sites ◽  
Uncoupling Protein ◽  
Membrane Integrity ◽  
Binding Activity ◽  
Bat Mitochondria ◽  
Brown Adipose ◽  
Rapid Changes ◽  
Binding To Mitochondria

GDP binding to brown adipose tissue (BAT) mitochondria increased more than twofold in 20 min when rats were moved from 27 to 4 degrees C. When animals housed at 4 degrees C for 2 h were returned to 27 degrees C, GDP binding decreased sharply in 20 min and returned to control levels in 2 h. These results are consistent with a rapid unmasking and remasking of GDP binding sites. GDP binding to mitochondria from warm and acutely cold treated rats was not modified by prior swelling, by freeze-thawing, nor by sonication of the mitochondria before assay. GDP-inhibitable proton conductance, as measured by passive swelling, was unaffected by this brief exposure to cold but more than doubled in rats kept at 4 degrees C for 10 days. We hypothesize that the rate of GDP-inhibitable swelling may be a reflection of uncoupling protein concentration in the BAT mitochondria, whereas physiological thermogenic activity is more appropriately indicated by GDP binding. The alterations in binding activity appear not to be due to changes in the mitochondrial membrane integrity.

scholarly journals Fatty Acids Rescue the Thermogenic Function of Sympathetically Denervated Brown Fat

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1428
Author(s):  
Qiang Cao ◽  
Shirong Wang ◽  
Huan Wang ◽  
Xin Cui ◽  
Jia Jing ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Body Temperature ◽  
Cold Exposure ◽  
Uncoupling Protein ◽  
Sympathetic Innervation ◽  
Brown Fat ◽  
Key Factors ◽  
Uncoupling Protein 1 ◽  
Physiological Factors ◽  
Brown Adipose

Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here we aimed to uncover the physiological factors compensating for maintaining brown fat thermogenesis in the absence of BAT innervation. After an initial decline of body temperature during cold exposure, mice with SNS surgical denervation in interscapular BAT gradually recovered their temperature comparable to that of sham-operated mice. The surgically denervated BAT also maintained a sizable uncoupling protein 1 (UCP1) protein along with basal norepinephrine (NE) at a similar level to that of sham controls, which were associated with increased circulating NE. Furthermore, the denervated mice exhibited increased free fatty acid levels in circulation. Indeed, surgical denervation of mice with CGI-58 deletion in adipocytes, a model lacking lipolytic capacity to release fatty acids from WAT, dramatically reduced BAT UCP1 protein and rendered the mice susceptible to cold. We conclude that circulating fatty acids and NE may serve as key factors for maintaining BAT thermogenic function and body temperature in the absence of BAT sympathetic innervation.

scholarly journals Leptin Receptor Signaling in Sim1-Expressing Neurons Regulates Body Temperature and Adaptive Thermogenesis

Endocrinology ◽  
2019 ◽  
Vol 160 (4) ◽  
pp. 863-879 ◽  
Author(s):  
Isin Cakir ◽  
Myriam Diaz-Martinez ◽  
Pauline Lining Pan ◽  
E Brian Welch ◽  
Sachin Patel ◽  
...  
Keyword(s):  
Body Temperature ◽  
Energy Expenditure ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Gene Copy ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Core Body

Abstract Leptin signals to regulate food intake and energy expenditure under conditions of normative energy homeostasis. The central expression and function of leptin receptor B (LepRb) have been extensively studied during the past two decades; however, the mechanisms by which LepRb signaling dysregulation contributes to the pathophysiology of obesity remains unclear. The paraventricular nucleus of the hypothalamus (PVN) plays a crucial role in regulating energy balance as well as the neuroendocrine axes. The role of LepRb expression in the PVN in regard to the regulation of physiological function of leptin has been controversial. The single-minded homolog 1 gene (Sim1) is densely expressed in the PVN and in parts of the amygdala, making Sim1-Cre mice a useful model for examining molecular mechanisms regulating PVN function. In this study, we characterized the physiological role of LepRb in Sim1-expressing neurons using LepRb-floxed × Sim1-Cre mice. Sim1-specific LepRb-deficient mice were surprisingly hypophagic on regular chow but gained more weight upon exposure to a high-fat diet than did their control littermates. We show that Sim1-specific deletion of a single LepRb gene copy caused decreased surface and core body temperatures as well as decreased energy expenditure in ambient room temperatures in both female and male mice. Furthermore, cold-induced adaptive (nonshivering) thermogenesis is disrupted in homozygous knockout mice. A defective thermoregulatory response was associated with defective cold-induced upregulation of uncoupling protein 1 in brown adipose tissue and reduced serum T4. Our study provides novel functional evidence supporting LepRb signaling in Sim1 neurons in the regulation of body weight, core body temperature, and cold-induced adaptive thermogenesis.

The concentration of uncoupling protein correlates with Mg2+ activated mitochondrial binding of GDP

1989 ◽  
Vol 67 (2-3) ◽  
pp. 108-112 ◽  
Author(s):  
Mary F. Henningfield ◽  
Robert W. Swick
Keyword(s):  
Binding Sites ◽  
Cold Adaptation ◽  
Chronic Exposure ◽  
Time Course ◽  
Uncoupling Protein ◽  
Time Of Death ◽  
Brown Adipose ◽  
Binding To Mitochondria ◽  
Thermogenic Capacity

Rats were housed at 4 °C for periods of up to 26 days. As little as 2 h of cold exposure caused an increase in the binding of [3H]GDP to mitochondria from brown adipose tissue. Incubation of mitochondria in vitro with 10 mM Mg2+ caused a marked increase in the subsequent binding of GDP to mitochondria from rats housed at 28 °C and a smaller increase in that from rats exposed to 4 °C for 2 h. Chronic exposure to cold led to an even greater increase in the amount of GDP bound to mitochondria incubated with Mg2+. The time course for the increase in the concentration of uncoupling protein was compared with that for GDP binding to mitochondria with and without Mg2+ treatment. The concentration of uncoupling protein appears to be correlated with the GDP-binding values for mitochondria treated with Mg2+ (r = 0.70) but not with the GDP binding to untreated mitochondria (r = 0.36). Therefore, the binding of GDP to untreated mitochondria may represent thermogenic activity at the time of death, whereas that after treatment with Mg2+ may more closely reflect total thermogenic capacity of the mitochondrion.Key words: concentration of uncoupling protein, cold adaptation, unmasking of GDP binding sites.

Increased thermogenic capacity of brown adipose tissue under low temperature and its contribution to arousal from hibernation in Syrian hamsters

2012 ◽  
Vol 302 (1) ◽  
pp. R118-R125 ◽  
Author(s):  
Naoya Kitao ◽  
Masaaki Hashimoto
Keyword(s):  
Adipose Tissue ◽  
Body Temperature ◽  
Brown Adipose Tissue ◽  
Time Course ◽  
Uncoupling Protein ◽  
Physiological Role ◽  
Adrenergic System ◽  
Syrian Hamsters ◽  
Brown Adipose

Brown adipose tissue (BAT) is thought to play a significant physiological role during arousal when body temperature rises from the extremely low body temperature that occurs during hibernation. The dominant pathway of BAT thermogenesis occurs through the β3-adrenergic receptor. In this study, we investigated the role of the β3-adrenergic system in BAT thermogenesis during arousal from hibernation both in vitro and in vivo. Syrian hamsters in the hibernation group contained BAT that was significantly greater in overall mass, total protein, and thermogenic uncoupling protein-1 than BAT from the warm-acclimated group. Although the ability of the β3-agonist CL316,243 to induce BAT thermogenesis at 36°C was no different between the hibernation and warm-acclimated groups, its maximum ratio over the basal value at 12°C in the hibernation group was significantly larger than that in the warm-acclimated group. Forskolin stimulation at 12°C produced equivalent BAT responses in these two groups. In vivo thermogenesis was assessed with the arousal time determined by the time course of BAT temperature or heart rate. Stimulation of BAT by CL316,243 significantly shortened the time of arousal from hibernation compared with that induced by vehicle alone, and it also induced arousal in deep hibernating animals. The β3-antagonist SR59230A inhibited arousal from hibernation either in part or completely. These results suggest that BAT in hibernating animals has potent thermogenic activity with a highly effective β3-receptor mechanism at lower temperatures.

Brown Adipose Tissue and Its Uncoupling Protein in Chronically Hypoxic Rats

1997 ◽  
Vol 93 (4) ◽  
pp. 349-354 ◽  
Author(s):  
Jacopo P. Mortola ◽  
Lina Naso
Keyword(s):  
Adipose Tissue ◽  
Ambient Temperature ◽  
Brown Adipose Tissue ◽  
Body Mass ◽  
Uncoupling Protein ◽  
Total Proteins ◽  
Tissue Mass ◽  
Brown Adipose ◽  
Adipose Tissue Mass ◽  
Old Rats

1. Hypoxia is known to decrease thermogenesis. We set out to determine whether this is accompanied by alterations in the brown adipose tissue, which is a major source of non-shivering thermogenesis. 2. Measurements were performed on 25- and 64-day-old rats, after 4 days of hypoxia (10% inspired O2), and on ∼3.5-month-old rats in hypobaric hypoxia since birth, at an ambient temperature of 25°C. 3. All hypoxic rats had higher haematocrit and lower body mass than corresponding controls. 4. In the 25-day-old rats, hypoxia had minimal and non significant effects on brown adipose tissue mass, proteins and DNA concentration. The content of the mitochondrial uncoupling protein thermogenin, evaluated by immunoblot after electrophoretic separation, relative to the cytoskeleton actin (UCP/Act), was not significantly altered. 5. In 25-day-old rats exposed for 4 days to cold (ambient temperature = 7–9°C), brown adipose tissue was hyperplastic, with increased UCP/Act; hypoxia did not appreciably alter the response to cold. 6. In the 2-month-old rats, after 4 days of hypoxia UCP/Act was reduced to about 40% of control. 7. In the 3.5-month-old rats maintained in hypoxia since birth, brown adipose tissue mass was reduced in proportion to body mass, with little effect on total proteins and DNA; UCP/Act was decreased to about 50% of control. 8. We conclude that chronic hypoxia had a minimal effect on brown adipose tissue total proteins and DNA content. However, the uncoupling protein content can be greatly reduced, depending upon age and duration of hypoxia.

scholarly journals Pyruvate induces torpor in obese mice

2018 ◽  
Vol 115 (4) ◽  
pp. 810-815 ◽  
Author(s):  
Marion Soto ◽  
Lucie Orliaguet ◽  
Michelle L. Reyzer ◽  
M. Lisa Manier ◽  
Richard M. Caprioli ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Body Temperature ◽  
Metabolic Rate ◽  
Brown Adipose Tissue ◽  
Mass Spectroscopy ◽  
Uncoupling Protein ◽  
Obese Mice ◽  
Uncoupling Protein 1 ◽  
Metabolic Intermediate ◽  
Brown Adipose

Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging. Pyruvate does not induce torpor in lean mice but results in the activation of brown adipose tissue (BAT) with an increase in the level of uncoupling protein-1 (UCP1). Denervation of BAT in lean mice blocks this increase in UCP1 and allows the pyruvate-induced torpor phenotype. Thus, pyruvate administration induces torpor in obese mice by pathways involving adenosine and GABA signaling and a failure of normal activation of BAT.

scholarly journals Acute effects of a β-adrenoceptor agonist (BRL 26830A) on rat brown-adipose-tissue mitochondria. Increased GDP binding and GDP-sensitive proton conductance without changes in the concentration of uncoupling protein

1988 ◽  
Vol 249 (3) ◽  
pp. 759-763 ◽  
Author(s):  
R E Milner ◽  
S Wilson ◽  
J R Arch ◽  
P Trayhurn
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Binding Sites ◽  
Uncoupling Protein ◽  
Beta Agonist ◽  
Proton Conductance ◽  
Binding Data ◽  
Adrenoceptor Agonist ◽  
Brown Adipose ◽  
Acute Increase

GDP binding, proton conductance and the specific concentration of uncoupling protein were measured in brown-adipose-tissue mitochondria of rats treated acutely with the novel beta-agonist, BRL 26830A. At 1 h after dosing with BRL 26830A, mitochondrial GDP binding was increased more than 2-fold. The increase in binding resulted from an increase in the number of binding sites. An iterative analysis of Scatchard binding data suggested that there is only one high-affinity GDP-binding site (Kd 0.3 microM) in brown-adipose-tissue mitochondria. The acute increase in GDP binding produced by treatment with BRL 26830A occurred without any alteration in the specific mitochondrial concentration of uncoupling protein, as determined by radioimmunoassay. Treatment with the beta-agonist did, however, lead to a small increase in the GDP-sensitive component of mitochondrial proton conductance. These results indicate that GDP-binding sites on uncoupling protein can be rapidly unmasked after treatment with a brown-fat-specific beta-agonist, and that the increase in binding reflects an increase in the activity of the mitochondrial proton-conductance pathway.

scholarly journals Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

2020 ◽  
Vol 21 (8) ◽  
pp. 3020 ◽  
Author(s):  
Winifred W. Yau ◽  
Paul M. Yen
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Body Temperature ◽  
Uncoupling Protein ◽  
Adrenergic Stimulation ◽  
Adipose Tissues ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Independent Effects

Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues.

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