Change search
Link to record
Permanent link

Direct link
Luijten, Ineke H. N.
Alternative names
Publications (10 of 11) Show all publications
Boulet, N., Luijten, I. H. N., Cannon, B. & Nedergaard, J. (2021). Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition. American Journal of Physiology. Endocrinology and Metabolism, 320(2), E359-E378
Open this publication in new window or tab >>Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition
2021 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 320, no 2, p. E359-E378Article in journal (Refereed) Published
Abstract [en]

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 β12-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.

Keywords
brown adipose tissue, cold, macrophages, obesity
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-193878 (URN)10.1152/ajpendo.00352.2020 (DOI)000629646200009 ()33284094 (PubMedID)
Available from: 2021-06-09 Created: 2021-06-09 Last updated: 2022-02-25Bibliographically approved
Luijten, I. H. N., Brooks, K., Boulet, N., Shabalina, I. G., Jaiprakash, A., Carlsson, B., . . . Nedergaard, J. (2019). Glucocorticoid-Induced Obesity Develops Independently of UCP1. Cell Reports, 27(6), 1686-1698
Open this publication in new window or tab >>Glucocorticoid-Induced Obesity Develops Independently of UCP1
Show others...
2019 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 27, no 6, p. 1686-1698Article in journal (Refereed) Published
Abstract [en]

An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30 degrees C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21 degrees C and 30 degrees C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30 degrees C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-169257 (URN)10.1016/j.celrep.2019.04.041 (DOI)000467058500006 ()31067456 (PubMedID)
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2024-01-17Bibliographically approved
Luijten, I. H. N., Cannon, B. & Nedergaard, J. (2019). Glucocorticoids and Brown Adipose Tissue: Do glucocorticoids really inhibit thermogenesis?. Molecular Aspects of Medicine, 68, 42-59
Open this publication in new window or tab >>Glucocorticoids and Brown Adipose Tissue: Do glucocorticoids really inhibit thermogenesis?
2019 (English)In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 68, p. 42-59Article, review/survey (Refereed) Published
Abstract [en]

A reduction in the thermogenic activity of brown adipose tissue (BAT) is presently discussed as a possible determinant for the development of obesity in humans. One group of endogenous factors that could potentially affect BAT activity is the glucocorticoids (e.g. cortisol). We analyse here studies examining the effects of alterations in glucocorticoid signaling on BAT recruitment and thermogenic capacity. We find that irrespective of which manipulation of glucocorticoid signaling is examined, a seemingly homogeneous picture of lowered thermogenic capacity due to glucocorticoid stimulation is apparently obtained: e.g. lowered uncoupling protein 1 (UCP1) protein levels per mg protein, and an increased lipid accumulation in BAT. However, further analyses generally indicate that these effects result from a dilution effect rather than a true decrease in total capacity; the tissue may thus be said to be in a state of pseudo-atrophy. However, under conditions of very low physiological stimulation of BAT, glucocorticoids may truly inhibit Ucp1 gene expression and consequently lower total UCP1 protein levels, but the metabolic effects of this reduction are probably minor. It is thus unlikely that glucocorticoids affect organismal metabolism and induce the development of obesity through alterations of BAT activity.

Keywords
Glucocorticoids, Brown adipose tissue, Thermogenesis, Thermoneutrality, Obesity, Cushing's
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-173003 (URN)10.1016/j.mam.2019.07.002 (DOI)000482103700004 ()31323252 (PubMedID)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2022-03-23Bibliographically approved
Luijten, I. H. N., Feldmann, H. M., von Essen, G., Cannon, B. & Nedergaard, J. (2019). In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain. American Journal of Physiology. Endocrinology and Metabolism, 316(5), E729-E740
Open this publication in new window or tab >>In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain
Show others...
2019 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, no 5, p. E729-E740Article in journal (Refereed) Published
Abstract [en]

The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57B1/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 w.k. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly. high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.

Keywords
129S, brown adipose tissue, diet-induced thermogenesis, obesity, UCP1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-169268 (URN)10.1152/ajpendo.00020.2019 (DOI)000467084600005 ()30807213 (PubMedID)
Available from: 2019-06-11 Created: 2019-06-11 Last updated: 2022-03-23Bibliographically approved
Luijten, I. H. N. (2019). Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models. (Doctoral dissertation). Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University
Open this publication in new window or tab >>Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The activation and recruitment of brown adipose tissue (BAT) thermogenesis has been put forward as a promising strategy to reduce the disease burden of obesity and obesity-related diseases. Heat production by BAT can be attributed to the tissue-specific mitochondrial uncoupling protein 1 (UCP1). Upon activation, UCP1 uncouples substrate oxidation from ATP production, thereby dissipating energy solely as heat and thus facilitating the ‘wasting’ of energy. To date, cold exposure is the strongest known BAT activator. However, to harness the energy wasting potential of BAT as a weight-reducing agent, the search for alternative factors that alter the activation or recruitment state of BAT is ongoing. The goal of this thesis is to obtain a better understanding of compounds and processes that modulate UCP1-dependent thermogenesis. 

We investigate glucocorticoids for their potential to alter the UCP1-dependent thermogenic capacity of mice. We provide the novel insight that glucocorticoid supplementation reduces total BAT UCP1 protein levels, but only in mice housed at thermoneutrality. This reduction occurs at the transcriptional level by direct binding of the liganded glucocorticoid receptor to Ucp1regulatory regions. We also demonstrate that the glucocorticoid-induced reduction in BAT thermogenesis does not contribute to the development of glucocorticoid-induced obesity.

Further, we show that high-fat diet- and cafeteria diet-feeding induces the activation and recruitment of BAT UCP1 protein in the obesity-resistant 129S mouse strain. We demonstrate the importance of this diet-induced modulation of BAT thermogenic capacity by reporting an increased metabolic efficiency in UCP1-ablated mice compared to wild-type mice. 

We finally present two novel models that can be used for the identification of novel modulators of BAT thermogenesis, namely a brown adipocyte clonal cell line derived from adult human BAT, and a UCP1-luciferase reporter mouse which facilitates real-time tracking of endogenous Ucp1expression. Using these models, we identify the genes Mtus1and Kcnk3, and the compound WWL113, as novel modulators of UCP1-dependent thermogenesis. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2019
Keywords
brown adipose tissue, UCP1, glucocorticoids, diet-induced thermogenesis, obesity, physiology
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-163376 (URN)978-91-7797-580-9 (ISBN)978-91-7797-581-6 (ISBN)
Public defence
2019-03-01, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius Väg 20, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
The Royal Swedish Academy of Sciences
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 2: Manuscript. Paper 5: Manuscript.

Available from: 2019-02-06 Created: 2019-01-10 Last updated: 2022-02-26Bibliographically approved
Luijten, I. (2016). The effects of glucocorticoids on brown fat: physiological and molecular studies. (Licentiate dissertation). Stockholm: Stockholm University
Open this publication in new window or tab >>The effects of glucocorticoids on brown fat: physiological and molecular studies
2016 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Brown adipose tissue (BAT) is the main site for non-shivering thermogenesis in most mammals. The BAT-specific uncoupling protein-1 (UCP1) uncouples substrate oxidation from ATP production and hereby decreases metabolic efficiency. Currently, the search is on for factors that decrease BAT activity and hereby contribute to the development of obesity and obesity-related diseases. Antagonizing these could thus provide therapeutic benefits.

Glucocorticoids are a class of steroid hormones that signal through the nuclear glucocorticoid receptor (GR) and play a role in glucose homeostasis, lipid metabolism and the immune response. Various studies in lean rodents have reported that exogenously administrated glucocorticoids increase BAT weight, fat content and lipid droplet size, and reduce GDP-binding to BAT, NE turnover in BAT and total BAT UCP1 mRNA and protein. In genetically obese ob/ob mice and fa/fa rats that exhibit hypercortisolism, adrenalectomy improves BAT morphology and increases BAT activity. Human studies on the effects of glucocorticoids on BAT are scarce, but indicate a decrease in BAT activity after prolonged hypercortisolism.

The mechanisms behind the suppressive effects of glucocorticoids on BAT remain unclear. Research in rodents has shown that glucocorticoids may decrease sympathetic output from the central nervous system to BAT in situations of eucortisolism, hereby reducing its thermogenic activity. On the other hand, in vitro experiments show cell autonomous effects of glucocorticoids on the β-adrenergic signalling pathway and a dose-dependent suppression of UCP1 transcription mediated by the GR.

It remains to be determined in which physiological situations either of these two pathways mediate the suppressive effects of glucocorticoids on BAT. Moreover, more research is needed into the intracellular signalling of glucocorticoids in brown adipocytes.

Place, publisher, year, edition, pages
Stockholm: Stockholm University, 2016. p. 64
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-134603 (URN)
Presentation
2016-10-21, E306, Svante Arrhenius Väg 20C, Stockholm, 09:30 (English)
Supervisors
Available from: 2017-04-21 Created: 2016-10-12 Last updated: 2022-02-28Bibliographically approved
Shinoda, K., Luijten, I. H. N., Hasegawa, Y., Hong, H., Sonne, S. B., Kim, M., . . . Kajimura, S. (2015). Genetic and functional characterization of clonally derived adult human brown adipocytes. Nature Medicine, 21(4), 389-394
Open this publication in new window or tab >>Genetic and functional characterization of clonally derived adult human brown adipocytes
Show others...
2015 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 21, no 4, p. 389-394Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated(1-8), its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.

National Category
Biological Sciences
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-116982 (URN)10.1038/nm.3819 (DOI)000352493600021 ()25774848 (PubMedID)
Note

AuthorCount:13;

Available from: 2015-05-15 Created: 2015-05-05 Last updated: 2022-02-23Bibliographically approved
Galmozzi, A., Sonne, S. B., Altshuler-Keylin, S., Hasegawa, Y., Shinoda, K., Luijten, I. H. N., . . . Kajimura, S. (2014). ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue. Cell Reports, 9(5), 1584-1593
Open this publication in new window or tab >>ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue
Show others...
2014 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 9, no 5, p. 1584-1593Article in journal (Refereed) Published
Abstract [en]

Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

Keywords
UCP1, brown adipose tissue, mouse model, screening, Luciferase
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:su:diva-163375 (URN)10.1016/j.celrep.2014.10.066 (DOI)
Funder
Swedish Research Council
Available from: 2018-12-28 Created: 2018-12-28 Last updated: 2024-01-17Bibliographically approved
Luijten, I., Brooks, K., Boulet, N., Shabalina, I., Jaiprakash, A., Carlsson, B., . . . Nedergaard, J.Glucocorticoid-induced obesity develops independently of UCP1.
Open this publication in new window or tab >>Glucocorticoid-induced obesity develops independently of UCP1
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

An excess of glucocorticoids is associated with the development of obesity, as is evident from the accumulation of visceral fat in patients suffering from Cushing’s Syndrome. Activated brown adipose tissue (BAT) reduces metabolic efficiency; correspondingly an inactivation of BAT has been proposed to cause glucocorticoid-induced obesity. Here we determine the extent to which changes in BAT function as a result of glucocorticoid treatment contribute to the simultaneous development of obesity. In mice housed at 21 °C and treated with corticosterone for 2 weeks (CORT), we unexpectedly found no change in total BAT uncoupling protein 1 (UCP1) protein levels or in non-shivering thermogenic capacity. In mice housed at thermoneutrality, a humanized condition, we did observe a reduction in total UCP1 protein levels in BAT in response to CORT, which was reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity developed to the same extent in animals housed at 21 °C and 30 °C, while total BAT UCP1 protein levels differed 100-fold between the two groups. In wild-type and UCP1 knock-out mice housed at 30 °C and treated with CORT, obesity also developed to the same extent. Thus, contrary to what has previously been suggested, our results show that the development of glucocorticoid-induced obesity is unrelated to the presence of UCP1.

Keywords
uncoupling protein 1, corticosterone, obesity, thermogenesis, energy balance, brown adipose tissue, thermoneutrality, cold exposure
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-163421 (URN)
Funder
Swedish Research Council
Available from: 2019-01-02 Created: 2019-01-02 Last updated: 2022-02-26Bibliographically approved
Luijten, I., Feldmann, H., von Essen, G., Cannon, B. & Nedergaard, J.In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain.
Open this publication in new window or tab >>In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and Uncoupling Protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (housed exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. We have therefore examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known tobe obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-KO mice were fed chow, or a high-fat or a cafeteria diet for 4 weeks. The absence of UCP1 augmented obesity (weight gain, body fat mass, % body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain. 

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-163422 (URN)
Funder
The Royal Swedish Academy of Sciences
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2022-02-26Bibliographically approved
Organisations

Search in DiVA

Show all publications