The characterization and energetic potential of brown adipose tissue in man

1. In adult man, brown fat can be detected in perinephric fat depots by visual inspection, electron microscopy and nucleotide binding to the tissue-specific uncoupling protein. 2. The 32 kDa uncoupling protein is functionally active, showing a nucleotide-sensitive conductance to protons and an uncoupling response to fatty acids. 3. The amount of uncoupling protein in human mitochondria is equivalent to that in a partially cold-adapted guinea pig, indicating some potential for thermogenesis. 4. Respiratory capacity measurements indicate that the total perinephric fat in adult man can only account for one-fivehundredth of the whole-body response to infused noradrenaline. Thus, although brown fat has been found to be quantitatively important in animal studies, considerable caution must be exercised in extrapolating its significance to adult man.

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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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Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling

Scientific Reports ◽

10.1038/s41598-019-54036-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Clarissa S. Craft ◽

Hero Robles ◽

Madelyn R. Lorenz ◽

Eric D. Hilker ◽

Kristann L. Magee ◽

...

Keyword(s):

Bone Marrow ◽

Adipose Tissue ◽

Uncoupling Protein ◽

Enrichment Analysis ◽

Whole Body ◽

Mineral Density ◽

Bone Marrow Adipose Tissue ◽

Marrow Adipose Tissue ◽

Reporter Mice ◽

Brown Adipose

AbstractAdipocytes within the skeleton are collectively termed bone marrow adipose tissue (BMAT). BMAT contributes to peripheral and local metabolism, however, its capacity for cell-autonomous expression of uncoupling protein 1 (UCP1), a biomarker of beige and brown adipogenesis, remains unclear. To overcome this, Ucp1-Cre was used to drive diphtheria toxin expression in cells expressing UCP1 (Ucp1Cre+/DTA+). Despite loss of brown adipose tissue, BMAT volume was not reduced in Ucp1Cre+/DTA+ mice. Comparably, in mTmG reporter mice (Ucp1Cre+/mTmG+), Ucp1-Cre expression was absent from BMAT in young (3-weeks) and mature (16-weeks) male and female mice. Further, β3-agonist stimulation failed to induce Ucp1-Cre expression in BMAT. This demonstrates that BMAT adipocytes are not UCP1-expressing beige/brown adipocytes. Thus, to identify novel and emerging roles for BMAT adipocytes in skeletal and whole-body homeostasis, we performed gene enrichment analysis of microarray data from adipose tissues of adult rabbits. Pathway analysis revealed genetic evidence for differences in BMAT including insulin resistance, decreased fatty acid metabolism, and enhanced contributions to local processes including bone mineral density through candidate genes such as osteopontin. In sum, this supports a paradigm by which BMAT adipocytes are a unique subpopulation that is specialized to support cells within the skeletal and hematopoietic niche.

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cAMP metabolism and lipolysis in brown adipocytes of hamsters consuming a cafeteria diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1985.248.2.e224 ◽

1985 ◽

Vol 248 (2) ◽

pp. E224-E229

Author(s):

R. J. Schimmel ◽

L. McCarthy ◽

K. K. McMahon

Keyword(s):

Adenylate Cyclase ◽

Sympathetic Activity ◽

Brown Fat ◽

Adenylate Cyclase System ◽

Brown Adipocytes ◽

Beta Adrenergic ◽

Fat Depots ◽

Brown Adipose ◽

Camp Levels ◽

In Cells

Feeding animals cafeteria diets causes increased sympathetic activity to brown adipose tissue and this is believed to be responsible for the concomitant activation of thermogenesis. Because chronic catecholamine stimulation in other systems leads to a desensitization of beta-adrenergic receptors, we examined lipolysis and cAMP production in brown adipocytes of hamsters eating cafeteria diets for evidence of diminished beta-adrenergic responses. Basal cAMP levels were similar in chow- and cafeteria-fed hamsters. However, adipocytes from overfed animals formed less cAMP in response to isoproterenol than those of control animals. Isoproterenol-stimulated adenylate cyclase activity was similarly decreased in membrane preparations from cafeteria-fed hamsters. However, when the diterpene forskolin was used, equal amounts of cAMP were formed in cells and membrane preparations from control and overfed animals. In contrast to the reduced responses of the cAMP system to isoproterenol stimulation observed in overfed hamsters, isoproterenol-stimulated lipolysis was greater in cells from overfed animals than in cells from control animals. These results are consistent with a desensitization of the adenylate cyclase system in brown adipocytes occurring during chronic hyperphagia. Because eating cafeteria diets has been reported to increase sympathetic activity to brown fat depots, the apparent desensitization of brown adipocytes observed in this study may result from a persistent stimulation of the brown fat with norepinephrine in vivo. Our data also suggest the existence of mechanisms that preserve lipolysis in the face of low cAMP levels.

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β3-Adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.3.e469 ◽

1998 ◽

Vol 274 (3) ◽

pp. E469-E475 ◽

Cited By ~ 5

Author(s):

Toshihide Yoshida ◽

Tsunekazu Umekawa ◽

Kenzo Kumamoto ◽

Naoki Sakane ◽

Akinori Kogure ◽

...

Keyword(s):

Uncoupling Protein ◽

Muscle Fibers ◽

Ectopic Expression ◽

Brown Fat ◽

Obese Mice ◽

Adrenergic Agonist ◽

Brown Adipose ◽

Slow Twitch Muscle ◽

Slow Twitch ◽

White Fat

The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the β3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodiuml-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5′-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the β3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.

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Iodothyronine 5′-deiodinase activity as an early event of prenatal brown-fat differentiation in bovine development

Biochemical Journal ◽

10.1042/bj2590555 ◽

1989 ◽

Vol 259 (2) ◽

pp. 555-559 ◽

Cited By ~ 25

Author(s):

M Giralt ◽

L Casteilla ◽

O Viñas ◽

T Mampel ◽

R Iglesias ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Brown Fat ◽

Early Event ◽

Type I ◽

Fetal Life ◽

Reverse T3 ◽

Deiodinase Activity ◽

Brown Adipose

Iodothyronine 5'-deiodinase activity appears to be a type I enzyme in bovine brown adipose tissue, on the basis of its high Km for 3,3',5'-tri-iodothyronine (‘reverse T3’) (in the micromolar range) and sensitivity to propylthiouracil inhibition. This enzyme activity is already detectable in perirenal adipose tissue of bovine fetuses in the second month of gestation, reaches peak values around the seventh month of fetal life, declines before birth, becomes lower after parturition and finally undetectable in the adult cow. Iodothyronine 5'-deiodinase activity is present in the pericardic, peritoneal and intermuscular adipose depots of the neonatal calf, but it is always undetectable in the subcutaneous adipose tissue. It is concluded that iodothyronine 5'-deiodinase is a specific feature of brown fat in the bovine species that is not shared by white adipose tissue. white adipose tissue. Peak values of 5'-deiodinating activity appear as an early event in the prenatal differentiation programme of bovine brown-fat cells as they occur when uncoupling-protein-gene expression first starts.

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Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00401.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. E1304-E1312 ◽

Cited By ~ 45

Author(s):

Sheila R. Costford ◽

Shehla N. Chaudhry ◽

Mahmoud Salkhordeh ◽

Mary-Ellen Harper

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Uncoupling Protein ◽

Liver Glycogen ◽

Whole Body ◽

Wild Type ◽

Insulin Tolerance ◽

Uncoupling Protein 3 ◽

Brown Adipose ◽

Inner Membrane Protein

Uncoupling protein-3 (UCP3) is a poorly understood mitochondrial inner membrane protein expressed predominantly in skeletal muscle. The aim of this study was to examine the effects of the absence or constitutive physiological overexpression of UCP3 on whole body energy metabolism, glucose tolerance, and muscle triglyceride content. Congenic male UCP3 knockout mice ( Ucp3 −/−), wild-type, and transgenic UCP3 overexpressing (UCP3Tg) mice were fed a 10% fat diet for 4 or 8 mo after they were weaned. UCP3Tg mice had lower body weights and were less metabolically efficient than wild-type or Ucp3 −/− mice, but they were not hyperphagic. UCP3Tg mice had smaller epididymal white adipose tissue and brown adipose tissue (BAT) depots; however, there were no differences in muscle weights. Glucose and insulin tolerance tests revealed that both UCP3Tg and Ucp3 −/− mice were protected from development of impaired glucose tolerance and were more sensitive to insulin. 2-Deoxy-d-[1-3H]glucose tracer studies showed increased uptake of glucose into BAT and increased storage of liver glycogen in Ucp3 −/− mice. Assessments of intramuscular triglyceride (IMTG) revealed decreases in quadriceps of UCP3Tg mice compared with wild-type and Ucp3 −/− mice. When challenged with a 45% fat diet, Ucp3 −/− mice showed increased accumulation of IMTG compared with wild-type mice, which in turn had greater IMTG than UCP3Tg mice. Results are consistent with a role for UCP3 in preventing accumulation of triglyceride in both adipose tissue and muscle.

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The PVH as a Site of CB1-Mediated Stimulation of Thermogenesis by MC4R Agonism in Male Rats

Endocrinology ◽

10.1210/en.2013-2092 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3448-3458 ◽

Cited By ~ 17

Author(s):

Boris Monge-Roffarello ◽

Sebastien M. Labbe ◽

Marie-Claude Roy ◽

Marie-Laurence Lemay ◽

Estelle Coneggo ◽

...

Keyword(s):

Uncoupling Protein ◽

Third Ventricle ◽

Male Rats ◽

Whole Body ◽

Hypothalamic Nucleus ◽

Peroxisome Proliferator ◽

Iodothyronine Deiodinase ◽

Brown Adipose ◽

Series Of Experiments ◽

The Brain

Abstract The present study was designed to investigate the involvement of the cannabinoid receptor 1 (CB1) in the stimulating effects of the melanocortin-4 receptor (MC4R) agonism on whole-body and brown adipose tissue (BAT) thermogenesis. In a first series of experiments, whole-body and BAT thermogenesis were investigated in rats infused in the third ventricle of the brain with the MC4R agonist melanotan II (MTII) and the CB1 agonist δ9-tetrahydrocannabinol (δ9-THC) or the CB1 antagonist AM251. Whole-body thermogenesis was measured by indirect calorimetry and BAT thermogenesis assessed from interscapular BAT (iBAT) temperature. δ9-THC blunted the effects of MTII on energy expenditure and iBAT temperature, whereas AM251 tended to potentiate the MTII effects. δ9-THC also blocked the stimulating effect of MTII on 14C-bromopalmitate and 3H-deoxyglucose uptakes in iBAT. Additionally, δ9-THC attenuated the stimulating effect of MTII on the expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1α), type II iodothyronine deiodinase (Dio2), carnitine palmitoyltransferase 1B (Cpt1b), and uncoupling protein 1 (Ucp1). In a second series of experiments, we addressed the involvement of the paraventricular hypothalamic nucleus (PVH) in the CB1-mediated effects of MTII on iBAT thermogenesis, which were assessed following the infusion of MTII in the PVH and δ9-THC or AM251 in the fourth ventricle of the brain. We demonstrated the ability of δ9-THC to blunt MTII-induced iBAT temperature elevation. δ9-THC also blocked the PVH effect of MTII on 14C-bromopalmitate uptake as well as on Pgc1α and Dio2 expression in iBAT. Altogether the results of this study demonstrate the involvement of the PVH in the CB1-mediated stimulating effects of the MC4R agonist MTII on whole-body and BAT thermogenesis.

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Fatty Acids Rescue the Thermogenic Function of Sympathetically Denervated Brown Fat

Biomolecules ◽

10.3390/biom11101428 ◽

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.

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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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Adaptative decrease in expression of the mRNA for uncoupling protein and subunit II of cytochrome c oxidase in rat brown adipose tissue during pregnancy and lactation

Biochemical Journal ◽

10.1042/bj2630965 ◽

1989 ◽

Vol 263 (3) ◽

pp. 965-968 ◽

Cited By ~ 17

Author(s):

I Martin ◽

M Giralt ◽

O Viñas ◽

R Iglesias ◽

T Mampel ◽

...

Keyword(s):

Cytochrome C ◽

Mrna Expression ◽

Cytochrome C Oxidase ◽

Uncoupling Protein ◽

Late Pregnancy ◽

Brown Fat ◽

Breeding Cycle ◽

Brown Adipose ◽

Pregnancy And Lactation ◽

Brown Fat Mitochondria

Uncoupling-protein (UCP) mRNA expression is decreased to 15% of virgin control levels between days 10 and 15 of pregnancy, and remains at these low values during late pregnancy and lactation. Abrupt weaning of mid-lactating rats causes a slight but significant increase in UCP mRNA. Expression of mRNA for subunit II of cytochrome c oxidase (COII) decreased to half that of virgin control in late pregnancy and during lactation. Whereas COII mRNA expression is in step with the known modifications of brown-fat mitochondria content during the breeding cycle of the rat, UCP mRNA expression appears to be diminished much earlier than the mitochondrial proton-conductance-pathway activity. On the other hand, the reactivity of brown fat to increase expression of UCP and COII mRNAs in response to acute cold or noradrenaline treatment is not impaired during lactation.

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