| 1. |
- Leebens-Mack, James H., et al.
(författare)
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One thousand plant transcriptomes and the phylogenomics of green plants
- 2019
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 574:7780, s. 679-
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Tidskriftsartikel (refereegranskat)abstract
- Green plants (Viridiplantae) include around 450,000-500,000 species(1,2) of great diversity and have important roles in terrestrial and aquatic ecosystems. Here, as part of the One Thousand Plant Transcriptomes Initiative, we sequenced the vegetative transcriptomes of 1,124 species that span the diversity of plants in a broad sense (Archaeplastida), including green plants (Viridiplantae), glaucophytes (Glaucophyta) and red algae (Rhodophyta). Our analysis provides a robust phylogenomic framework for examining the evolution of green plants. Most inferred species relationships are well supported across multiple species tree and supermatrix analyses, but discordance among plastid and nuclear gene trees at a few important nodes highlights the complexity of plant genome evolution, including polyploidy, periods of rapid speciation, and extinction. Incomplete sorting of ancestral variation, polyploidization and massive expansions of gene families punctuate the evolutionary history of green plants. Notably, we find that large expansions of gene families preceded the origins of green plants, land plants and vascular plants, whereas whole-genome duplications are inferred to have occurred repeatedly throughout the evolution of flowering plants and ferns. The increasing availability of high-quality plant genome sequences and advances in functional genomics are enabling research on genome evolution across the green tree of life.
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| 2. |
- Wikström, Jakob D., et al.
(författare)
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Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure
- 2014
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 33:5, s. 418-436
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Tidskriftsartikel (refereegranskat)abstract
- Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
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| 3. |
- Abreu-Vieira, Gustavo, 1987-, et al.
(författare)
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Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis : Regulation of brown adipose tissue blood flow
- 2015
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:9, s. E822-E829
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.
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| 4. |
- Abreu-Vieira, Gustavo, et al.
(författare)
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Cidea improves the metabolic profile through expansion of adipose tissue
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.
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| 5. |
- Abreu-Vieira, Gustavo, 1987-, et al.
(författare)
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Novel thiazolidinediones distinguish between (UCP1-independent) antidiabetic effects (MSDC-0602) and adipogenic and browning-inducing effects (MSDC-0160) of classical thiazolidinediones (rosiglitazone)
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Thiazolinediones (TZDs), also called glitazones, are a class of drugs traditionally used forimproving glucose tolerance in type II diabetes mellitus. The beneficial effects ofthiazolidinedione are believed to be caused by the drug binding to the nuclear receptor PPARγ,which in turn triggers a general adipogenic program in white adipose tissue, and apparentthermogenic recruitment of brown and brite/beige fat. Here, we present a comparison of thephysiological effects of three thiazolidinediones (rosiglitazone, MSDC-0602, and MSDC-0160)in C57BL/6 mice fed high-fat diet and housed at thermoneutrality. Rosiglitazone and MSDC-0160 caused the classically-described thiazolidinedione effects of increased fat mass,hyperphagia, and increased UCP1 levels in brown adipose tissue. MSDC-0602 and rosiglitazoneimproved glucose tolerance but MSDC-0602 did not induce increased fat mass, hyperphagia, orincreased UCP1 levels in brown fat. The beneficial effects of thiazolidinediones were fullypresent even in UCP1-KO mice, providing evidence for a dissociation between thiazolidinedioneinducedadipose tissue browning and their antidiabetic effects. We conclude that even structurallysimilar thiazolidinediones can act through distinct pathways, and that the glucose-loweringeffects of this class do not seem to rely on PPAR-γ-induced browning of adipose tissues.
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| 6. |
- Alvarez-Crespo, Mayte, et al.
(författare)
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Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance
- 2016
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Ingår i: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 5:4, s. 271-282
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Classically, metabolic effects of thyroid hormones (THs) have been considered to be peripherally mediated, i.e. different tissues in the body respond directly to thyroid hormones with an increased metabolism. An alternative view is that the metabolic effects are centrally regulated. We have examined here the degree to which prolonged, centrally infused triiodothyronine (T3) could in itself induce total body metabolic effects and the degree to which brown adipose tissue (BAT) thermogenesis was essential for such effects, by examining uncoupling protein 1 (UCP1) KO mice. Methods: Wildtype and UPC1 KO mice were centrally-treated with T3 by using minipumps. Metabolic measurements were analyzed by indirect calorimetry and expression analysis by RT-PCR or western blot. BAT morphology and histology were studied by immunohistochemistry. Results: We found that central T3-treatment led to reduced levels of hypothalamic AMP-activated protein kinase (AMPK) and elevated body temperature (0.7 degrees C). UCP1 was essential for the T3-induced increased rate of energy expenditure, which was only observable at thermoneutrality and notably only during the active phase, for the increased body weight loss, for the increased hypothalamic levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and for the increased food intake induced by central T3-treatment. Prolonged central T3-treatment also led to recruitment of BAT and britening/beiging (browning) of inguinal white adipose tissue (iWAT). Conclusions: We conclude that UCP1 is essential for mediation of the central effects of thyroid hormones on energy balance, and we suggest that similar UCP1-dependent effects may underlie central energy balance effects of other agents.
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| 7. |
- Amemiya, Chris T., et al.
(författare)
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The African coelacanth genome provides insights into tetrapod evolution
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 496:7445, s. 311-316
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
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| 8. |
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| 9. |
- Boulet, Nathalie, et al.
(författare)
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Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition
- 2021
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:2, s. E359-E378
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Tidskriftsartikel (refereegranskat)abstract
- Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical proinflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have, therefore, investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and proinflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Furthermore, the anti-inflammatory macrophage accretion was mediated via β1/β2-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.NEW & NOTEWORTHY A regulatory or mediatory role—positive or negative—for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown—or brite/beige—adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.
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| 10. |
- Cannon, Barbara, et al.
(författare)
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A PERKy way to make mitochondrial cristae
- 2021
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier BV. - 1043-2760 .- 1879-3061. ; 32:7, s. 417-419
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Forskningsöversikt (refereegranskat)abstract
- PERK protein, that is canonically associated with the response to endoplasmic reticulum stress, may be acquiring a new role as a regulator of the growth of mitochondrial cristae. This role is pertinent not only to the recruitment of brown adipose tissue thermogenic capacity but probably also to directing cristae formation in highly metabolically active organs such as the heart.
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| 11. |
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| 12. |
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| 13. |
- Cannon, Barbara, et al.
(författare)
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Human brown adipose tissue : Classical brown rather than brite/beige?
- 2020
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Ingår i: Experimental Physiology. - 0958-0670 .- 1469-445X. ; 105:8, s. 1191-1200
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Tidskriftsartikel (refereegranskat)abstract
- New Findings What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice.
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| 14. |
- Cannon, Barbara, et al.
(författare)
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Metabolic and angiogenic consequences of the presence or absence of UCP1
- 2010
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Ingår i: Research and Perspectives in Endocrine Interactions. - Berlin : Springer. ; , s. 111-120
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive adrenergic thermogenesis – both the form that develops subsequent to cold acclimation and the form that develops subsequent to a palatable diet challenge – is entirely dependent on the presence and activity of the brown fat uncoupling protein, UCP1. In a cold environment, the absence of UCP1 can be compensated by alternative means, such as shivering or exercise. Upon a challenge with a palatable diet, similar alternatives are not available, and mice become obese in the absence of UCP1. The recent identification of active brown fat in adult humans raises questions as to its role in protection from obesity and in a potential therapeutic context.
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| 15. |
- Cannon, Barbara, et al.
(författare)
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Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans)
- 2010
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 34:1, s. S7-S16
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Tidskriftsartikel (refereegranskat)abstract
- Only with the development of the uncoupling protein 1 (UCP1)-ablated mouse has it become possible to strictly delineate the physiological significance of the thermogenic capacity of brown adipose tissue. Considering the presence of active brown adipose tissue in adult humans, these insights may have direct human implications. In addition to classical nonshivering thermogenesis, all adaptive adrenergic thermogeneses, including diet-induced thermogenesis, is fully dependent on brown adipocyte activity. Any weight-reducing effect of β(3)-adrenergic agonists is fully dependent on UCP1 activity, as is any weight-reducing effect of leptin (in excess of its effect on reduction of food intake). Consequently, in the absence of the thermogenic activity of brown adipose tissue, obesity develops spontaneously. The ability of brown adipose tissue to contribute to glucose disposal is also mainly related to thermogenic activity. However, basal metabolic rate, cold-induced thermogenesis, acute cold tolerance, fevers, nonadaptive adrenergic thermogenesis and processes such as angiogenesis in brown adipose tissue itself are not dependent on UCP1 activity. Whereas it is likely that these conclusions are also qualitatively valid for adult humans, the quantitative significance of brown adipose tissue for human metabolism--and the metabolic consequences for a single individual possessing more or less brown adipose tissue--awaits clarification.
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| 16. |
- Cannon, Barbara, et al.
(författare)
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Neither brown nor white
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7411, s. 286-287
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Fat cells are usually thought of as being either energy-storing white fat cells or food-burning brown fat cells. The identification of a third type of fat cell in mice and humans might open up new avenues for combating obesity.
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| 17. |
- Cannon, Barbara, et al.
(författare)
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Nonshivering thermogenesis and its adequate measurement in metabolic studies
- 2011
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Ingår i: Journal of Experimental Biology. - : The Company of Biologists. - 0022-0949 .- 1477-9145. ; 214:Pt 2, s. 242-53
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.
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| 18. |
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| 19. |
- Cannon, Barbara, et al.
(författare)
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Thermogenesis challenges the adipostat hypothesis for body-weight control.
- 2009
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Ingår i: Proceedings of the Nutrition Society. - 0029-6651 .- 1475-2719. ; 68:4, s. 401-7
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Tidskriftsartikel (refereegranskat)abstract
- According to the adipostat hypothesis for body-weight control, alterations in body weight should always be compensated by adequate alterations in food intake and thermogenesis. Thus, increased thermogenesis should not be able to counteract obesity because food intake would be increased. However evidence is presented here that thermogenesis in different forms (through artificial uncouplers, exercise, cold exposure) may counteract obesity and is not always fully compensated by increased food intake. Correspondingly, a decreased capacity for metaboloregulatory thermogenesis (i.e. non-functional brown adipose tissue) may in itself lead to obesity. This is evident in mice and may be valid for human subjects, as a substantial proportion of adults possess brown adipose tissue, and those with less or without brown adipose tissue would seem to be more prone to obesity. Thus, increased thermogenesis may counteract obesity, without dietary intervention.
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| 20. |
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| 21. |
- Cannon, Barbara, et al.
(författare)
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What Ignites UCP1?
- 2017
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 26:5, s. 697-698
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue (Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced in brown fat without intracellular lipolysis.
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| 22. |
- Cannon, Barbara, et al.
(författare)
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Yes, even human brown fat is on fire!
- 2012
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 122:2, s. 486-489
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- That adult humans possess brown fat is now accepted - but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity - provided that brown fat becomes activated not only by cold but also through food-related stimuli.
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| 23. |
- Chernogubova, Ekaterina, 1967-
(författare)
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Adrenergic stimulation of glucose uptake in brown adipocytes
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to investigate adrenergically stimulated glucose uptake in brown adipose tissue (BAT) with the focus on receptor subtypes and intracellular signalling pathways. As a model system, we used primary cultured brown adipocytes.Adrenergic stimulation of glucose uptake occurs via β3-AR in wild type cells and β1-/α1-ARs in β3-KO cells, includes activation of adenylyl cyclase and cAMP formation, activation of PKA, PI3K, PKC and AMPK (Paper I, II, III). Interestingly, UCP1 activity is not required for the AMPK function in brown adipocytes (Paper III). Long-term adrenergic stimulation of glucose uptake induces an increase in GLUT1 mRNA and protein levels stimulating GLUT1 translocation to the plasma membrane (Paper IV).
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| 24. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 25. |
- Davies, Victoria S., et al.
(författare)
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Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
- 2023
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Ingår i: Biochimie. - : Elsevier BV. - 0300-9084 .- 1638-6183. ; 210, s. 40-49
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Tidskriftsartikel (refereegranskat)abstract
- Given the presence of brown adipose tissue in adult humans, an important issue is whether human brown adipose tissue is recruitable. Cold exposure is the canonical recruitment treatment; however, in experimental animals (mice), recruitment of brown adipose tissue is normally induced by placing the mice in constant cold, a procedure not feasible in humans. For possible translational applications, we have therefore investigated whether shorter daily excursions from thermoneutrality would suffice to qualitatively and quantitatively induce recruitment in mice. Mice, housed at thermoneutrality (30 °C) to mimic human conditions, were transferred every day for 4 weeks to cool conditions (18 °C), for 0, 15, 30, 120 and 420 min (or placed constantly in 18 °C). On the examination day, the mice were not exposed to cold. Very short daily exposures (≤30 minutes) were sufficient to induce structural changes in the form of higher protein density in brown adipose tissue, changes that may affect the identification of the tissue in e.g. computer tomography and other scan studies. To estimate thermogenic capacity, UCP1 protein levels were followed. No UCP1 protein was detectable in inguinal white adipose tissue. In the interscapular brown adipose tissue, a remarkable two-phase reaction was seen. Very short daily exposures (≤30 minutes) were sufficient to induce a significant increase in total UCP1 levels. For attainment of full cold acclimation, the mice had, however, to remain exposed to the cold. The studies indicate that marked alterations in brown adipose tissue composition can be induced in mammals through relatively modest stimulation events.
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| 26. |
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| 27. |
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| 28. |
- de Jong, Jasper M. A., et al.
(författare)
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A stringent validation of mouse adipose tissue identity markers
- 2015
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:12, s. E1085-E1105
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Tidskriftsartikel (refereegranskat)abstract
- The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.
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| 29. |
- de Jong, Jasper M. A., et al.
(författare)
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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:8, s. 830-843
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Tidskriftsartikel (refereegranskat)abstract
- Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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| 30. |
- de Jong, Jasper M. A., et al.
(författare)
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Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes
- 2018
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-3945 .- 2162-397X. ; 7:3, s. 166-179
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Tidskriftsartikel (refereegranskat)abstract
- Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (fetal bovine versus newborn calf) on responses to differentiation inducers (the PPAR agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion (Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3) was not systematically affected by serum type. However, importantly, acute (2h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.
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| 31. |
- de Jong, Jasper M. A., et al.
(författare)
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The β3-adrenergic receptor is dispensable for browning of adipose tissues
- 2017
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:6, s. E508-E518
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Tidskriftsartikel (refereegranskat)abstract
- Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.
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| 32. |
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| 33. |
- Dima, Danai, et al.
(författare)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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| 34. |
- Dittner, Claudia, et al.
(författare)
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At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1
- 2019
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 25, s. 20-34
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Hyperthyroidism is associated with increased metabolism (thyroid thermogenesis) and elevated body temperature, often referred to as hyperthermia. Uncoupling protein-1 (UCP1) is the protein responsible for nonshivering thermogenesis in brown adipose tissue. We here examine whether UCP1 is essential for thyroid thermogenesis. Methods: We investigated the significance of UCP1 for thyroid thermogenesis by using UCP1-ablated (UCP1 KO) mice. To avoid confounding factors from cold-induced thermogenesis and to approach human conditions, the experiments were conducted at thermoneutrality, and to resemble conditions of endogenous release, thyroid hormone (thyroxine, T4) was injected peripherally. Results: Both short-term and chronic thyroxine treatment led to a marked increase in metabolism that was largely UCP1-independent. Chronic thyroxine treatment led to a 1-2 degrees C increase in body temperature. This increase was also UCP1 -independent and was maintained even at lower ambient temperatures. Thus, it was pyrexia, i.e. a defended increase in body temperature, not hyperthermia. In wildtype mice, chronic thyroxine treatment induced a large relative increase in the total amounts of UCP1 in the brown adipose tissue (practically no UCP1 in brite/beige adipose tissue), corresponding to an enhanced thermogenic response to norepinephrine injection. The increased UCP1 amount had minimal effects on thyroxine-induced thermogenesis and pyrexia. Conclusions: These results establish that thyroid thermogenesis is a UCP1 -independent process. The fact that the increased metabolism coincides with elevated body temperature and thus with accelerated kinetics accentuates the unsolved issue of the molecular background for thyroid thermogenesis.
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| 35. |
- Edgar, Daniel, et al.
(författare)
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Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.
- 2009
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Ingår i: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 10:2, s. 131-8
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Tidskriftsartikel (refereegranskat)abstract
- The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.
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| 36. |
- Feldmann, Helena M., et al.
(författare)
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UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality.
- 2009
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Ingår i: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 9:2, s. 203-9
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Tidskriftsartikel (refereegranskat)abstract
- As original studies of UCP1-ablated mice failed to demonstrate an obesogenic effect, alternative mechanisms for adaptive adrenergic thermogenesis have been sought. However, we demonstrate here that in C57Bl6 mice exempt from thermal stress (i.e., kept at thermoneutrality), UCP1 ablation in itself induced obesity, even in mice fed control diet, and vastly augmented diet-induced obesity (high-fat diet); i.e., the mice exhibited increased metabolic efficiency. In wild-type mice, high-fat diet increased norepinephrine-induced thermogenesis; i.e., diet-induced thermogenesis was observed, but no such effect was observed in UCP1-ablated mice, demonstrating that diet-induced thermogenesis fully emanates from UCP1 activity. We conclude that ambient temperature is qualitatively determinative for the outcome of metabolic studies, that no other protein and no other mechanism can substitute for UCP1 in mediating diet-induced adrenergic thermogenesis, and that UCP1 activity can be determinative for obesity development in mice and possibly in humans.
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| 37. |
- Fischer, Alexander W., et al.
(författare)
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Intact innervation is essential for diet-induced recruitment of brown adipose tissue
- 2019
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 316:3, s. E487-E503
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that recruitment and activation of brown adipose tissue (BAT) thermogenesis could be beneficial for curtailing obesity development in humans prompts a need for a better understanding of the control of these processes [that are often referred to collectively as diet-induced thermogenesis (DIT)]. Dietary conditions are associated with large changes in blood-borne factors that could be responsible for BAT recruitment, but BAT is also innervated by the sympathetic nervous system. To examine the significance of the innervation for DIT recruitment, we surgically denervated the largest BAT depot, i.e., the interscapular BAT depot in mice and exposed the mice at thermoneutrality to a high-fat diet versus a chow diet. Denervation led to an alteration in feeding pattern but did not lead to enhanced obesity, but obesity was achieved with a lower food intake, as denervation increased metabolic efficiency. Conclusively. denervation totally abolished the diet-induced increase in total UCP1 protein levels observed in the intact mice, whereas basal UCP1 expression was not dependent on innervation. The denervation of interscapular BAT did not discernably hyper-recruit other BAT depots, and no UCP1 protein could be detected in the principally browning-competent inguinal white adipose tissue depot under any of the examined conditions. We conclude that intact innervation is essential for diet-induced thermogenesis and that circulating factors cannot by themselves initiate recruitment of brown adipose tissue under obesogenic conditions. Therefore, the processes that link food intake and energy storage to activation of the nervous system are those of significance for the further understanding of diet-induced thermogenesis.
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| 38. |
- Fischer, Alexander W., et al.
(författare)
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Leptin : Is It Thermogenic?
- 2020
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 41:2, s. 232-260
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Forskningsöversikt (refereegranskat)abstract
- Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin- receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred Aston mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.
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| 39. |
- Fischer, Alexander W., et al.
(författare)
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Leptin Raises Defended Body Temperature without Activating Thermogenesis
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:7, s. 1621-1631
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Tidskriftsartikel (refereegranskat)abstract
- Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wildtype or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i. e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i. e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines.
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| 40. |
- Fischer, Alexander W., et al.
(författare)
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No insulating effect of obesity
- 2016
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 311:1, s. e202-e213
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Tidskriftsartikel (refereegranskat)abstract
- The development of obesity may be aggravated if obesity itself insulates against heat loss and thus diminishes the amount of food burnt for body temperature control. This would be particularly important under normal laboratory conditions where mice experience a chronic cold stress (at approximate to 20 degrees C). We used Scholander plots (energy expenditure plotted against ambient temperature) to examine the insulation (thermal conductance) of mice, defined as the inverse of the slope of the Scholander curve at subthermoneutral temperatures. We verified the method by demonstrating that shaved mice possessed only half the insulation of non-shaved mice. We examined a series of obesity models [mice fed high-fat diets and kept at different temperatures, classical diet-induced obese mice, ob/ob mice, and obesity-prone (C57BL/6) vs. obesity-resistant (129S)mice]. We found that neither acclimation temperature nor any kind or degree of obesity affected the thermal insulation of the mice when analyzed at the whole mouse level or as energy expenditure per lean weight. Calculation per body weight erroneously implied increased insulation in obese mice. We conclude that, in contrast to what would be expected, obesity of any kind does not increase thermal insulation in mice, and therefore, it does not in itself aggravate the development of obesity. It may be discussed as to what degree of effect excess adipose tissue has on insulation in humans and especially whether significant metabolic effects are associated with insulation in humans.
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| 41. |
- Fischer, Alexander W., et al.
(författare)
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Optimal housing temperatures for mice to mimic the thermal environment of humans : An experimental study
- 2018
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Ingår i: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 7, s. 161-170
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The laboratory mouse is presently the most common model for examining mechanisms of human physiology and disease. Housing temperatures can have a large impact on the outcome of such experiments and on their translatability to the human situation. Humans usually create for themselves a thermoneutral environment without cold stress, while laboratory mice under standard conditions (approximate to 20 degrees C) are under constant cold stress. In a well-cited, theoretical paper by Speakman and Keijer in Molecular Metabolism, it was argued that housing mice under close to standard conditions is the optimal way of modeling the human metabolic situation. This tenet was mainly based on the observation that humans usually display average metabolic rates of about 1.6 times basal metabolic rate. The extra heat thereby produced would also be expected to lead to a shift in the 'lower critical temperature' towards lower temperatures.Methods: To examine these tenets experimentally, we performed high time-resolution indirect calorimetry at different environmental temperatures on mice acclimated to different housing temperatures.Results: Based on the high time-resolution calorimetry analysis, we found that mice already under thermoneutral conditions display mean diurnal energy expenditure rates 1.8 times higher than basal metabolism, remarkably closely resembling the human situation. At any temperature below thermoneutrality, mice metabolism therefore exceeds the human equivalent: Mice under standard conditions display energy expenditure 3.1 times basal metabolism. The discrepancy to previous conclusions is probably attributable to earlier limitations in establishing true mouse basal metabolic rate, due to low time resolution. We also found that the fact that mean energy expenditure exceeds resting metabolic rate does not move the apparent thermoneutral zone (the lower critical temperature) downwards.Conclusions: We show that housing mice at thermoneutrality is an advantageous step towards aligning mouse energy metabolism to human energy metabolism.
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| 42. |
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| 43. |
- Fischer, Alexander W., et al.
(författare)
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UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment
- 2017
-
Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:1, s. e72-E87
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Tidskriftsartikel (refereegranskat)abstract
- Cidea is a gene highly expressed in thermogenesis- competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue briteness. Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wildtype and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis.
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| 44. |
- Fischer, Katrin, et al.
(författare)
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Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis
- 2017
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:5, s. 623-630
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through beta 3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1(-/-) and interleukin-4 receptor-alpha double-negative (Il4ra(-/-)) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.
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| 45. |
- Frangou, Sophia, et al.
(författare)
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Cortical thickness across the lifespan : Data from 17,075 healthy individuals aged 3-90 years
- 2022
-
Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 431-451
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Tidskriftsartikel (refereegranskat)abstract
- Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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| 46. |
- Gao, Yun, et al.
(författare)
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Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues
- 2022
-
Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1863:4
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that N-acyl amino acids could function as brown or brite/beige adipose tissue-derived lipokines that could induce UCP1-independent thermogenesis by uncoupling mitochondrial respiration in several peripheral tissues is of significant physiological interest. To quantify the potency of N-acyl amino acids versus conventional fatty acids as thermogenic inducers, we have examined the affinity and efficacy of two pairs of such compounds: oleate versus N-oleoyl-leucine and arachidonate versus N-arachidonoyl-glycine in cells and mitochondria from different tissues. We found that in cultures of the muscle-derived L6 cell line, as well as in primary cultures of murine white, brite/beige and brown adipocytes, the N-acyl amino acids were proficient uncouplers but that they did not systematically display higher affinity or potency than the conventional fatty acids, and they were not as efficient uncouplers as classical protonophores (FCCP). Higher concentrations of the N-acyl amino acids (as well as of conventional fatty acids) were associated with signs of deleterious effects on the cells. In liver mitochondria, we found that the N-acyl amino acids uncoupled similarly to conventional fatty acids, thus apparently via activation of the adenine nucleotide transporter-2. In brown adipose tissue mitochondria, the N-acyl amino acids were able to activate UCP1, again similarly to conventional fatty acids. We thus conclude that the formation of the acyl-amino acid derivatives does not confer upon the corresponding fatty acids an enhanced ability to induce thermogenesis in peripheral tissues, and it is therefore unlikely that the N-acyl amino acids are of specific physiological relevance as UCP1-independent thermogenic compounds.
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| 47. |
- García-Carrizo, Francisco, et al.
(författare)
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Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate
- 2020
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 44:3, s. 715-726
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Tidskriftsartikel (refereegranskat)abstract
- Objectives High-esterified pectin (HEP) is a prebiotic able to modulate gut microbiota, associated with health-promoting metabolic effects in glucose and lipid metabolism and adipostatic hormone sensitivity. Possible effects regulating adaptive thermogenesis and energy waste are poorly known. Therefore, we aimed to study how physiological supplementation with HEP is able to affect microbiota, energy metabolism and adaptive thermogenic capacity, and to contribute to the healthier phenotype promoted by HEP supplementation, as previously shown. We also attempted to decipher some of the mechanisms involved in the HEP effects, including in vitro experiments.Subjects and experimental design We used a model of metabolic malprogramming consisting of the progeny of rats with mild calorie restriction during pregnancy, both under control diet and an obesogenic (high-sucrose) diet, supplemented with HEP, combined with in vitro experiments in primary cultured brown and white adipocytes treated with the postbiotic acetate.Results Our main findings suggest that chronic HEP supplementation induces markers of brown and white adipose tissue thermogenic capacity, accompanied by a decrease in energy efficiency, and prevention of weight gain under an obesogenic diet. We also show that HEP promotes an increase in beneficial bacteria in the gut and peripheral levels of acetate. Moreover, in vitro acetate can improve adipokine production, and increase thermogenic capacity and browning in brown and white adipocytes, respectively, which could be part of the protection mechanism against excess weight gain observed in vivo.Conclusion HEP and acetate stand out as prebiotic/postbiotic active compounds able to modulate both brown-adipocyte metabolism and browning and protect against obesity.
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| 48. |
- Gburcik, Valentina, et al.
(författare)
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An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes
- 2012
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 303:8, s. e1053-E1060
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor Tbx15 is expressed predominantly in brown adipose tissue and in those white adipose depots that are capable of giving rise to brown-in-white ("brite"/"beige") adipocytes. Therefore, we have investigated a possible role here of Tbx15 in brown and brite adipocyte differentiation in vitro. Adipocyte precursors were isolated from interscapular and axilliary brown adipose tissues, inguinal white ("brite") adipose tissue, and epididymal white adipose tissue in 129/Sv mouse pups and differentiated in culture. Differentiation was enhanced by chronic treatment with the PPAR gamma agonist rosiglitazone plus the sympathetic neurotransmitter norepinephrine. Using short interfering RNAs (siRNA) directed toward Tbx15 in these primary adipocyte cultures, we decreased Tbx15 expression >90%. This resulted in reduced expression levels of adipogenesis markers (PPAR gamma, aP2). Importantly, Tbx15 knockdown reduced the expression of brown phenotypic marker genes (PRDM16, PGC-1 alpha, Cox8b/Cox4, UCP1) in brown adipocytes and even more markedly in inguinal white adipocytes. In contrast, Tbx15 knockdown had no effect on white adipocytes originating from a depot that is not brite competent in vivo (epididymal). Therefore, Tbx15 may be essential for the development of the adipogenic and thermogenic programs in adipocytes/adipomyocytes capable of developing brown adipocyte features.
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| 49. |
- Hansen, Ida, 1982-, et al.
(författare)
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A partial secretome of brown adipose tissue
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- To identify brown adipocyte secreted proteins a signal-sequence trap method was used. All genes identified were cloned and studied with microarray technique.The aim of this study was to evaluate how these genes were influenced under different physiological conditions, both in vivo and in vitro. Microarray studies were performed comparing primary brown adipocytes stimulated with norepinephrine to non-stimulated, and primary brown adipocytes compared to primary white adipocytes. In vivo studies were performed to evaluate physiological effects on gene expression in brown adipose tissue. Male NMRI mice were placed in cold or at thermoneutrality for 3 weeks and compared. Mice kept at room temperature were exposed to cafeteria diet for three weeks compared to regular diet.Results show that norepinephrine had effects on the expression of these potentially secreted genes. However, gene expression from physiological studies in vivo that could be expected to show similar expression patterns as norepinephrine-treated brown adipocytes did not do so. This indicates that other factors than norepinephrine can regulate gene expression of possible brown adipose tissue-secreted factors.
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| 50. |
- Hansen, Ida, 1982-, et al.
(författare)
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Contrasting effects of cold acclimation versus obesogenic diets onchemerin gene expression in brown and brite adipose tissues
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Based on results from a signal sequence trap, we investigated chemerin gene expression in brown adipose tissue. Male NMRI mice were exposed to 30, 22 or 4 °C for 3 weeks, or were fed control (chow) diet, cafeteria diet or high-fat diet at thermoneutrality for the same time. In brown adipose tissue, cold acclimation strongly diminished chemerin gene expression, whereas obesogenic diets augmented expression. Qualitatively, changes in expression were paralleled in brite/beige adipose tissues (e.g. inguinal), whereas white adipose tissue (epididymal) did not react to these cues. Changes in tissue expression were not paralleled by alterations in plasma levels. The cellular regulation was not congruent with a sympathetic/adrenergic control of expression. The data are discussed in relation to suggested endocrine, paracrine and autocrine effects of this adipokine.
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