11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice

Abstract Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can amplify circulating GC concentrations. Therefore, 11β-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11β-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11β-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 μg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11β-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11β-HSD1 KO mice to model lifetime GC exposure. BAT 11β-HSD1 expression and activity were elevated in response to GC excess and with aging. 11β-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11β-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11β-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.

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KCTD10 regulates brown adipose tissue thermogenesis and metabolic function via Notch Signaling

Journal of Endocrinology ◽

10.1530/joe-21-0016 ◽

2021 ◽

Author(s):

Mingsheng Ye ◽

Liping Luo ◽

Qi Guo ◽

Guanghua Lei ◽

Chao Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Notch Signaling ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Notch Signaling Pathway ◽

Whole Body ◽

Brown Adipocyte ◽

Metabolic Function ◽

Brown Adipose

Brown adipose tissue (BAT) is emerging as a target to beat obesity through the dissipation of chemical energy to heat. However, the molecular mechanisms of brown adipocyte thermogenesis remain to be further elucidated. Here, we show that KCTD10, a member of the polymerase delta-interacting protein 1 (PDIP1) family, was reduced in BAT by cold stress and a β3 adrenoceptor agonist. Moreover, KCTD10 level increased in the BAT of obese mice, and KCTD10 overexpression attenuates uncoupling protein 1 (UCP1) expression in primary brown adipocytes. BAT-specific KCTD10 knockdown mice had increased thermogenesis and cold tolerance protecting from high fat diet (HFD)-induced obesity. Conversely, overexpression of KCTD10 in BAT caused reduced thermogenesis, cold intolerance, and obesity. Mechanistically, inhibiting Notch signaling restored the KCTD10 overexpression suppressed thermogenesis. Our study presents that KCTD10 serves as an upstream regulator of notch signaling pathway to regulate BAT thermogenesis and whole-body metabolic function.

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GPR120 controls neonatal brown adipose tissue thermogenic induction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00081.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. E742-E750 ◽

Cited By ~ 2

Author(s):

Tania Quesada-López ◽

Aleix Gavaldà-Navarro ◽

Samantha Morón-Ros ◽

Laura Campderrós ◽

Roser Iglesias ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Receptor Protein ◽

Brown Adipocyte ◽

Fibroblast Growth Factor 21 ◽

Acid Oxidation ◽

Adaptive Thermogenesis ◽

Brown Adipose ◽

G Protein Coupled

Adaptive induction of thermogenesis in brown adipose tissue (BAT) is essential for the survival of mammals after birth. We show here that G protein-coupled receptor protein 120 (GPR120) expression is dramatically induced after birth in mouse BAT. GPR120 expression in neonatal BAT is the highest among GPR120-expressing tissues in the mouse at any developmental stage tested. The induction of GPR120 in neonatal BAT is caused by postnatal thermal stress rather than by the initiation of suckling. GPR120-null neonates were found to be relatively intolerant to cold: close to one-third did not survive at 21°C, but all such pups survived at 25°C. Heat production in BAT was significantly impaired in GPR120-null pups. Deficiency in GPR120 did not modify brown adipocyte morphology or the anatomical architecture of BAT, as assessed by electron microscopy, but instead impaired the expression of uncoupling protein-1 and the fatty acid oxidation capacity of neonatal BAT. Moreover, GPR120 deficiency impaired fibroblast growth factor 21 (FGF21) gene expression in BAT and reduced plasma FGF21 levels. These results indicate that GPR120 is essential for neonatal adaptive thermogenesis.

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CCAAT/enhancer-binding proteins α and β in brown adipose tissue: evidence for a tissue-specific pattern of expression during development

Biochemical Journal ◽

10.1042/bj3020695 ◽

1994 ◽

Vol 302 (3) ◽

pp. 695-700 ◽

Cited By ~ 27

Author(s):

C Manchado ◽

P Yubero ◽

O Viñas ◽

R Iglesias ◽

F Villarroya ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Brown Fat ◽

Brown Adipocyte ◽

Fetal Life ◽

Inhibitory Protein ◽

Adult Rats ◽

Stage Of Development ◽

Brown Adipose

CCAAT/enhancer-binding protein (C/EBP) alpha mRNA and its protein products C/EBP alpha and 30 kDa C/EBP alpha are expressed in rat brown-adipose tissue. Results also demonstrate the expression of C/EBP beta mRNA and its protein products C/EBP beta and liver inhibitory protein (LIP) in the tissue. The abundance of C/EBP alpha and C/EBP beta proteins in adult brown fat is similar to that found in adult liver. However, the expression of C/EBP alpha and C/EBP beta is specifically regulated in brown fat during development. C/EBP alpha, 30 kDa C/EBP alpha, C/EBP beta and LIP content is several-fold higher in fetal brown fat than in the adult tissue, or liver at any stage of development. Peak values are attained in late fetal life, in concurrence with the onset of transcription of the uncoupling protein (UCP) gene, the molecular marker of terminal brown-adipocyte differentiation. When adult rats are exposed to a cold environment, which is a physiological stimulus of brown-adipose tissue hyperplasia and UCP gene expression, a specific rise in C/EBP beta expression with respect to C/EBP alpha, 30 kDa C/EBP alpha and LIP is observed. Present data suggest that the C/EBP family of transcription factors has an important role in the development and terminal differentiation of brown-adipose tissue.

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Orexin Restores Aging-Related Brown Adipose Tissue Dysfunction in Male Mice

Endocrinology ◽

10.1210/en.2013-1629 ◽

2014 ◽

Vol 155 (2) ◽

pp. 485-501 ◽

Cited By ~ 55

Author(s):

Dyan Sellayah ◽

Devanjan Sikder

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Fat Mass ◽

Core Body Temperature ◽

Brown Adipocyte ◽

Aged Mice ◽

Age Related ◽

Brown Adipose ◽

The Impact

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

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Programming mediated by fatty acids affects uncoupling protein 1 (UCP-1) in brown adipose tissue

British Journal Of Nutrition ◽

10.1017/s0007114518001629 ◽

2018 ◽

Vol 120 (6) ◽

pp. 619-627 ◽

Cited By ~ 5

Author(s):

Perla P. Argentato ◽

Helena de Cássia César ◽

Débora Estadella ◽

Luciana P. Pisani

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Dietary Fatty Acids ◽

Research Trend ◽

Uncoupling Protein 1 ◽

Brown Adipose ◽

Pregnancy And Lactation ◽

The Impact

AbstractBrown adipose tissue (BAT) has recently been given more attention for the part it plays in obesity. BAT can generate great amounts of heat through thermogenesis by the activation of uncoupling protein 1 (UCP-1), which can be regulated by many environmental factors such as diet. Moreover, the build-up of BAT relates to maternal nutritional changes during pregnancy and lactation. However, at present, there is a limited number of studies looking at maternal nutrition and BAT development, and it seems that the research trend in this field has been considerably declining since the 1980s. There is much to discover yet about the role of different fatty acids on the development of BAT and the activation of UCP-1 during the fetal and the postnatal periods of life. A better understanding of the impact of nutritional intervention on the epigenetic regulation of BAT could lead to new preventive care for metabolic diseases such as obesity. It is important to know in which circumstances lipids could programme BAT during pregnancy and lactation. The modification of maternal dietary fatty acids, amount and composition, during pregnancy and lactation might be a promising strategy for the prevention of obesity in the offspring and future generations.

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Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids

Biochemical Journal ◽

10.1042/bj3450091 ◽

1999 ◽

Vol 345 (1) ◽

pp. 91-97 ◽

Cited By ~ 28

Author(s):

Rosa ALVAREZ ◽

MaLuz CHECA ◽

Sonia BRUN ◽

Octavi VI±AS ◽

Teresa MAMPEL ◽

...

Keyword(s):

Adipose Tissue ◽

Retinoic Acid ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Retinoid X Receptor ◽

Expression Vectors ◽

Brown Adipocyte ◽

Signalling Pathways ◽

Uncoupling Protein 1 ◽

Brown Adipose

The intracellular pathways and receptors mediating the effects of retinoic acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA activates transcription of ucp-1 and the RA receptor (RAR) is known to be involved in this effect. However, co-transfection of an expression vector for retinoid-X receptor (RXR) increases the action of 9-cis RA but not the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific {p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid} or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown-adipocyte differentiation RXRα and RXRγ mRNA expression is induced in parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, α, β and γ, decreases. Co-transfection of murine expression vectors for the different RAR and RXR subtypes indicates that RARα and RARβ as well as RXRα are the major retinoid-receptor subtypes capable of mediating the responsiveness of ucp-1 to retinoids. It is concluded that the effects of retinoids on ucp-1 transcription involve both RAR- and RXR-dependent signalling pathways. The responsiveness of brown adipose tissue to retinoids in vivo relies on a complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1 induction and their distinct expression in the differentiated brown adipocyte.

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Immunohistochemical identification of the uncoupling protein in rat brown adipose tissue.

Journal of Histochemistry & Cytochemistry ◽

10.1177/33.2.3881519 ◽

1985 ◽

Vol 33 (2) ◽

pp. 150-154 ◽

Cited By ~ 9

Author(s):

M Cadrin ◽

M Tolszczuk ◽

J Guy ◽

G Pelletier ◽

K B Freeman ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Staining Technique ◽

Cellular Heterogeneity ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Immunohistochemical Technique ◽

Brown Adipose ◽

Pap Method

Brown adipose tissue mitochondria are characterized by the presence of an uncoupling protein that gives them an exceptional capacity for substrate-controlled respiration and thermogenesis. The specific localization of this protein in rat brown adipocytes was demonstrated using an immunohistochemical technique, the peroxidase-antiperoxidase (PAP) method. Light microscopy observations showed that serum antibodies raised against the uncoupling protein selectively reacted with multilocular brown adipocytes. No labeling could be detected in either unilocular adipocytes, capillaries, or muscle fibers (striated and vascular smooth muscle). Staining was more intensive in certain adipocytes than in others, suggesting the presence of cellular heterogeneity. The specificity of the staining technique was demonstrated by showing that treatment of the preparations with antiserum saturated with an excess of uncoupling protein almost entirely inhibited brown adipocyte labeling. The specificity and selectivity of the PAP method allow the clear differentiation of uncoupling protein-containing adipocytes from other cellular types, suggesting that this immunohistochemical technique will represent an extremely useful tool for studying adipocyte function and differentiation.

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Mitochondrial matrix protein Letmd1 maintains thermogenic capacity of brown adipose tissue

10.21203/rs.3.rs-1046884/v1 ◽

2021 ◽

Author(s):

Anna Park ◽

Kwang-eun Kim ◽

Isaac Park ◽

Dae-Soo Kim ◽

Jaehoon Kim ◽

...

Keyword(s):

Adipose Tissue ◽

Cold Stress ◽

Brown Adipose Tissue ◽

Matrix Protein ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Mitochondrial Matrix ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Brown Adipose

Abstract Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (Ucp1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here we identify LETM1 domain-containing protein 1 (Letmd1) is a BAT-enriched, cold-induced protein that is required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that Letmd1 is a mitochondrial matrix protein. Letmd1 knockout mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. Taken together, we identify that the BAT-enriched mitochondrial matrix protein Letmd1 is required for cold-stimulated respiration and thermogenic function of BAT.

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On the potential role of globins in brown adipose tissue: a novel conceptual model and studies in myoglobin knockout mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00662.2020 ◽

2021 ◽

Author(s):

Michael L. Blackburn ◽

Umesh D Wankhade ◽

Kikumi D Ono-Moore ◽

Sree V Chintapalli ◽

Renee Fox ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Conceptual Model ◽

Metabolic Regulation ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Sexually Dimorphic ◽

Brown Adipose ◽

No Signaling

Myoglobin (Mb) regulates O2 bioavailability in muscle and heart as partial pressure of O2 (pO2) drops with increased tissue workload. Globin proteins also modulate cellular NO pools, "scavenging" NO at higher pO2 and converting NO2- to NO as pO2 falls. Myoglobin binding of fatty acids may also signal a role in fat metabolism. Interestingly, Mb is expressed in brown adipose tissue (BAT), but its function is unknown. Herein, we present a new conceptual model that proposes links between BAT thermogenic activation, concurrently reduced pO2, and NO pools regulated by deoxy/oxy-globin toggling and xanthine oxidoreductase (XOR). We describe the effect of Mb knockout (Mb-/-) on BAT phenotype (lipid droplets, mitochondrial markers uncoupling protein 1 [UCP1] and cytochrome C oxidase 4 [Cox4], transcriptomics) in male and female mice fed a high fat diet (HFD, 45% of energy, ~13 wk), and examine Mb expression during brown adipocyte differentiation. Interscapular BAT weights did not differ by genotype, but there was a higher prevalence of mid-large sized droplets in Mb-/-. COX4 protein expression was significantly reduced in Mb-/- BAT, and a suite of metabolic/NO/stress/hypoxia transcripts were lower. All of these Mb-/--associated differences were most apparent in females. The new conceptual model, and results derived from Mb-/- mice, suggest a role for Mb in BAT metabolic regulation, in part through sexually dimorphic systems and NO signaling. This possibility requires further validation in light of significant mouse-to-mouse variability of BAT Mb mRNA and protein abundances in wildtype mice and lower expression relative to muscle and heart.

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