Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Acute cold exposure leads to norepinephrine release in brown adipose tissue (BAT) and activates uncoupling protein (UCP)1-mediated nonshivering thermogenesis. Chronic sympathetic stimulation is known to initiate mitochondrial biogenesis, UCP1 expression, hyperplasia of BAT, and recruitment of brown adipocytes in white adipose tissue (WAT) depots. Despite distinct functions of BAT and WAT in energy balance, only a few genes are exclusively expressed in either tissue. We identified NUR77 (Nr4a1), an orphan receptor, to be induced transiently in brown adipocytes in response to β-adrenergic stimulation and in BAT of cold-exposed mice. Subsequent reporter gene assays demonstrated an inhibitory action of NUR77 on basal and peroxisome proliferator-activated receptor (PPAR)γ/retinoid X receptor (RXR)α-mediated transactivation of the Ucp1 enhancer in heterologous cotransfection experiments. Despite this function of NUR77 in the control of Ucp1 gene expression, nonshivering thermogenesis was not affected in Nur77 knockout mice. However, we observed a superinduction of Nor1 in BAT of cold-exposed knockout mice. We conclude that NUR77 is a cold-induced negative regulator of Ucp1, but phenotypic consequences in knockout mice are compensated by functional redundancy of Nor1.

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Inducible brown adipocytes in subcutaneous inguinal white fat: the role of continuous sympathetic stimulation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00033.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. E793-E799 ◽

Cited By ~ 45

Author(s):

G. Andres Contreras ◽

Yun-Hee Lee ◽

Emilio P. Mottillo ◽

James G. Granneman

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Sympathetic Innervation ◽

Adrenergic Stimulation ◽

Brown Adipocytes ◽

Main Site ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

White Fat

Brown adipocytes (BA) generate heat in response to sympathetic activation and are the main site of nonshivering thermogenesis in mammals. Although most BA are located in classic brown adipose tissue depots, BA are also abundant in the inguinal white adipose tissue (iWAT) before weaning. The number of BA is correlated with the density of sympathetic innervation in iWAT; however, the role of continuous sympathetic tone in the establishment and maintenance of BA in WAT has not been investigated. BA marker expression in iWAT was abundant in weaning mice but was greatly reduced by 8 wk of age. Nonetheless, BA phenotype could be rapidly reinstated by acute β3-adrenergic stimulation with CL-316,243 (CL). Genetic tagging of adipocytes with adiponectin-CreERT2 demonstrated that CL reinstates uncoupling protein 1 (UCP1) expression in adipocytes that were present before weaning. Chronic surgical denervation dramatically reduced the ability of CL to induce the expression of UCP1 and other BA markers in the tissue as a whole, and this loss of responsiveness was prevented by concurrent treatment with CL. These results indicate that ongoing sympathetic activity is critical to preserve the ability of iWAT fat cells to express a BA phenotype upon adrenergic stimulation.

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Direct detection of brown adipose tissue thermogenesis in UCP1−/− mice by hyperpolarized 129Xe MR thermometry

Scientific Reports ◽

10.1038/s41598-019-51483-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 10

Author(s):

Michael A. Antonacci ◽

Christian McHugh ◽

Michele Kelley ◽

Andrew McCallister ◽

Simone Degan ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Knockout Mice ◽

Direct Detection ◽

Uncoupling Protein ◽

Core Body Temperature ◽

Physiological Effect ◽

Adrenergic Stimulation ◽

Brown Adipose ◽

Shivering Thermogenesis

Abstract Brown adipose tissue (BAT) is a type of fat specialized in non-shivering thermogenesis. While non-shivering thermogenesis is mediated primarily by uncoupling protein 1 (UCP1), the development of the UCP1 knockout mouse has enabled the study of possible UCP1-independent non-shivering thermogenic mechanisms, whose existence has been shown so far only indirectly in white adipose tissue and still continues to be a matter of debate in BAT. In this study, by using magnetic resonance thermometry with hyperpolarized xenon, we produce the first direct evidence of UCP1-independent BAT thermogenesis in knockout mice. We found that, following adrenergic stimulation, the BAT temperature of knockout mice increases more and faster than rectal temperature. While with this study we cannot exclude or separate the physiological effect of norepinephrine on core body temperature, the fast increase of iBAT temperature seems to suggest the existence of a possible UCP1-independent thermogenic mechanism responsible for this temperature increase.

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β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00085.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. E1108-E1118 ◽

Cited By ~ 41

Author(s):

Charlotte L. Mattsson ◽

Robert I. Csikasz ◽

Ekaterina Chernogubova ◽

Daniel L. Yamamoto ◽

Helena T. Hogberg ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Knockout Mice ◽

Adrenergic Receptors ◽

Nonshivering Thermogenesis ◽

Brown Adipocytes ◽

Protein Levels ◽

Brown Adipose ◽

Brown Adipose Tissue Activity ◽

Main Regulator

With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β3-adrenergic receptors. However, vast majorities of β3-adrenergic agonists have so far not been able to stimulate human β3-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β1-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β3-adrenergic receptors. Wild-type and β3-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β3-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β1-adrenergic receptors. Thus, in the absence of β3-adrenergic receptors, β1-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β1-adrenergic receptors or β3-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β1-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.

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UCP1 is essential for adaptive adrenergic nonshivering thermogenesis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00387.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. E350-E357 ◽

Cited By ~ 137

Author(s):

Valeria Golozoubova ◽

Barbara Cannon ◽

Jan Nedergaard

Keyword(s):

Adipose Tissue ◽

Cold Acclimation ◽

Uncoupling Protein ◽

Nonshivering Thermogenesis ◽

Adrenergic Stimulation ◽

Uncoupling Protein 1 ◽

Total Absence ◽

Brown Adipose ◽

Different Temperatures ◽

Enzymatic Pathways

Participation of brown adipose tissue [through the action of the uncoupling protein-1 (UCP1)] in adaptive adrenergic nonshivering thermogenesis is recognized, but the existence of a response to adrenergic stimulation in UCP1-ablated mice implies that a mechanism for an alternative adaptive adrenergic thermogenesis may exist. Here, we have used UCP1-ablated mice to examine the existence of an alternative adaptive adrenergic nonshivering thermogenesis, examined as the oxygen consumption response to systemically injected norepinephrine into anesthetized or conscious mice acclimated to different temperatures. We confirm that UCP1-dependent adrenergic nonshivering thermogenesis is adaptive, but we demonstrate that the adrenergic UCP1-independent thermogenesis is not recruitable by cold acclimation. Thus, at least in the mouse, no other proteins or enzymatic pathways exist that can participate in or with time take over the UCP1 mediation of adaptive adrenergic nonshivering thermogenesis, even in the total absence of UCP1. UCP1 is thus the only protein capable of mediating cold acclimation-recruited adaptive adrenergic nonshivering thermogenesis.

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Interscapular brown adipose tissue recruitment is hindered by a temperature environment of 33°C: Uncoupling protein-1 underexpression is not associated with obesity development in rats

Archives of Biological Sciences ◽

10.2298/abs171215018j ◽

2018 ◽

Vol 70 (3) ◽

pp. 567-579

Author(s):

Gordana Juric-Lekic ◽

Ljiljana Bedrica ◽

Dragutin Loncar

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mrna Expression ◽

Uncoupling Protein ◽

Precursor Cells ◽

Nonshivering Thermogenesis ◽

Uncoupling Protein 1 ◽

Brown Adipocytes ◽

Gold Particles ◽

Brown Adipose

Brown adipose tissue (BAT) generates heat due to unique thermogenic UC-mitochondria, an event known as nonshivering thermogenesis. Cold, adrenergic agents, hormones, etc., activate nonshivering thermogenesis, resulting in lipid mobilization, an increase in the mitochondria and mitochondrial cristae, and increased uncoupling protein-1 (UCP1) expression and its incorporation into mitochondrial cristae. BAT precursor cells mature and contribute to BAT growth in a process known as BAT recruitment. For the first time, we herein report the effect of a thermoneutral environment of 33?C on interscapular BAT (IBAT) in rats delivered and raised at 33?C. The control animals were housed at 20?C. Thermoneutral IBAT was atrophic (73 mg vs. 191 mg) but with more adipocyte precursor cells; euthermia (37.6?C) was maintained without nonshivering thermogenesis. Although IBAT was inactive, the thermoneutral animals did not develop obesity, and on the contrary, the thermoneutral environment of 33?C hindered the rats? growth, weight (65 gm vs. 139 gm), volume (67 gm vs.136 gm) and length (12 cm vs. 16 cm). The thermoneutral brown adipocytes were smaller (7234 ?m3 vs. 9198 ?m3) with more lipids (4919 ?m3 vs. 4507 ?m3) and a smaller mitochondrial cristae area (52504 ?m2 vs. 61288 ?m2/adipocyte). Lipoprotein lipase mRNA expression was 11% (vs. 58% in control) and UCP1 mRNA expression was 34% (vs. 93% control). UCP1 immunoelectron microscopic study detected 160 UCP1-gold particles (vs. 700 in control) per UC-mitochondrion; thermoneutral brown adipocytes had 9-fold fewer UCP1-gold particles (0.34x106 vs. 2.99x106 UCP1-gold particles), and thermoneutral UC-mitochondria developed specific intramitochondrial tubular inclusions.

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Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.1.r183 ◽

1995 ◽

Vol 268 (1) ◽

pp. R183-R191 ◽

Cited By ~ 13

Author(s):

A. M. Strack ◽

M. J. Bradbury ◽

M. F. Dallman

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucocorticoid Receptors ◽

Uncoupling Protein ◽

Lipid Storage ◽

Scatchard Analysis ◽

Nonshivering Thermogenesis ◽

Diurnal Range ◽

Brown Adipose ◽

Intact Rats

Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS)

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v1 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract BackgroundPrescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant sedation, weight gain, and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.MethodsTo investigate the efficacy of interventions of statin aimed at reversing SGA-induced dyslipidemia, young Sprague Dawley (SD) rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks.ResultsOlanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but had no significant effect on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. A down-regulating of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) expression was observed in brown adipose tissue (BAT) in the olanzapine-only group, following a significant decrease in the ratio of phosphorylated PKA (p-PKA)/PKA. Interestingly, these protein changes could be reversed by co-treatment with O+B. Our results demonstrated simvastatin to be effective in ameliorating TC and TG elevated by olanzapine.ConclusionsModulation of BAT activity could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v4 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract Background Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.Methods To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks. Results Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by co-treatment with O+B. Conclusions Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916550117 ◽

2020 ◽

Vol 117 (26) ◽

pp. 15055-15065 ◽

Cited By ~ 1

Author(s):

Mengxi Jiang ◽

Tony E. Chavarria ◽

Bingbing Yuan ◽

Harvey F. Lodish ◽

Nai-Jia Huang

Keyword(s):

Adipose Tissue ◽

Negative Regulator ◽

Brown Adipocytes ◽

Diet Induced Obesity ◽

The Metabolic Syndrome ◽

Brown Adipose ◽

Cold Tolerant ◽

Functional Relevance ◽

Hydrolysis Of

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.

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Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0159 ◽

2017 ◽

Vol 58 (2) ◽

pp. 57-66 ◽

Cited By ~ 11

Author(s):

Rose Kohlie ◽

Nina Perwitz ◽

Julia Resch ◽

Sebastian M Schmid ◽

Hendrik Lehnert ◽

...

Keyword(s):

P38 Mapk ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Peroxisome Proliferator ◽

Cellular Mechanisms ◽

Brown Adipocytes ◽

Peroxisome Proliferator Activated Receptor ◽

Mitochondrial Mass ◽

Brown Adipose

Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential, it may dissipate excessive energy, regulate body weight and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT thermogenesis, but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells. D1-like and D2-like receptors were detectable at the protein level. Stimulation with DA caused an increase in cAMP concentrations. Oxygen consumption rates (OCR), mitochondrial membrane potential (Δψm) and uncoupling protein 1 (UCP1) levels increased after 24 h of treatment with either DA or a D1-like specific receptor agonist. A D1-like receptor antagonist abolished the DA-mediated effect on OCR, Δψm and UCP1. DA induced the release of fatty acids, which did not additionally alter DA-mediated increases of OCR. Mitochondrial mass (as determined by (i) CCCP- and oligomycin-mediated effects on OCR and (ii) immunoblot analysis of mitochondrial proteins) also increased within 24 h. This was accompanied by an increase in peroxisome proliferator-activated receptor gamma co-activator 1 alpha protein levels. Also, DA caused an increase in p38 MAPK phosphorylation and pharmacological inhibition of p38 MAPK abolished the DA-mediated effect on Δψm. In summary, our study is the first to reveal direct D1-like receptor and p38 MAPK-mediated increases of thermogenesis and mitochondrial mass in brown adipocytes. These results expand our understanding of catecholaminergic effects on BAT thermogenesis.

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