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Ziqubu, K., Dludla, P. V., Mabhida, S. E., Jack, B. U., Keipert, S., Jastroch, M. & Mazibuko-Mbeje, S. E. (2024). Brown adipose tissue-derived metabolites and their role in regulating metabolism. Metabolism: Clinical and Experimental, 150, Article ID 155709.
Open this publication in new window or tab >>Brown adipose tissue-derived metabolites and their role in regulating metabolism
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2024 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 150, article id 155709Article, review/survey (Refereed) Published
Abstract [en]

The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as “batokines”, which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.

Keywords
Brown adipose tissue, Batokines, Metabolites, Secretome, Metabolism, Obesity, Metabolic diseases
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-224837 (URN)10.1016/j.metabol.2023.155709 (DOI)001110598400001 ()37866810 (PubMedID)2-s2.0-85175688559 (Scopus ID)
Available from: 2023-12-28 Created: 2023-12-28 Last updated: 2023-12-28Bibliographically approved
Keipert, S., Gaudry, M. J., Kutschke, M., Keuper, M., Dela Rosa, M. A. S., Cheng, Y., . . . Jastroch, M. (2024). Two-stage evolution of mammalian adipose tissue thermogenesis. Science, 384(6700), 1111-1117
Open this publication in new window or tab >>Two-stage evolution of mammalian adipose tissue thermogenesis
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2024 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 384, no 6700, p. 1111-1117Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials. 

National Category
Evolutionary Biology
Identifiers
urn:nbn:se:su:diva-231101 (URN)10.1126/science.adg1947 (DOI)38843333 (PubMedID)2-s2.0-85195438772 (Scopus ID)
Available from: 2024-06-17 Created: 2024-06-17 Last updated: 2024-06-17Bibliographically approved
Klein Hazebroek, M., Laterveer, R., Kutschke, M., Ramsak Marceta, V., Barthem, C. S. & Keipert, S. (2023). Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21. Scientific Reports, 13(1), Article ID 10288.
Open this publication in new window or tab >>Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 10288Article in journal (Refereed) Published
Abstract [en]

Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-221146 (URN)10.1038/s41598-023-37264-0 (DOI)001018464000031 ()37355753 (PubMedID)2-s2.0-85162810710 (Scopus ID)
Available from: 2023-09-15 Created: 2023-09-15 Last updated: 2023-09-15Bibliographically approved
Cavalieri, R., Klein Hazebroek, M., Cotrim, C. A., Lee, Y., Kunji, E. R. S., Jastroch, M., . . . Crichton, P. G. (2022). Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis. Molecular Metabolism, 62, Article ID 101526.
Open this publication in new window or tab >>Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis
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2022 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 62, article id 101526Article in journal (Refereed) Published
Abstract [en]

Objective: Uncoupling protein 1 (UCP1) catalyses mitochondrial proton leak in brown adipose tissue to facilitate nutrient oxidation for heat production, and may combat metabolic disease if activated in humans. During the adrenergic stimulation of brown adipocytes, free fatty acids generated from lipolysis activate UCP1 via an unclear interaction. Here, we set out to characterise activator binding to purified UCP1 to clarify the activation process, discern novel activators and the potential to target UCP1.

Methods: We assessed ligand binding to purified UCP1 by protein thermostability shift analysis, which unlike many conventional approaches can inform on the binding of hydrophobic ligands to membrane proteins. A detailed activator interaction analysis and screening approach was carried out, supported by investigations of UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1 expression-controlled cell lines.

Results: We reveal that fatty acids and other activators influence UCP1 through a specific destabilising interaction, behaving as transport substrates that shift the protein to a less stable conformation of a transport cycle. Through the detection of specific stability shifts in screens, we identify novel activators, including the over-the-counter drug ibuprofen, where ligand analysis indicates that UCP1 has a relatively wide structural specificity for interacting molecules. Ibuprofen successfully induced UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1-expressing HEK293 cells but not in cultured brown adipocytes, suggesting drug delivery differs in each cell type.

Conclusions: These findings clarify the nature of the activator-UCP1 interaction and demonstrate that the targeting of UCP1 in cells by approved drugs is in principle achievable as a therapeutic avenue, but requires variants with more effective delivery in brown adipocytes.

Keywords
Ligand binding, Thermal stability assay, Differential scanning fluorimetry, Brown adipose tissue, Proton transport, Energy expenditure, Mitochondrial carrier
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-210301 (URN)10.1016/j.molmet.2022.101526 (DOI)000861054600004 ()35691529 (PubMedID)2-s2.0-85132531588 (Scopus ID)
Available from: 2022-10-11 Created: 2022-10-11 Last updated: 2022-10-11Bibliographically approved
Klein Hazebroek, M. & Keipert, S. (2022). Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue. Frontiers in Endocrinology, 13, Article ID 909621.
Open this publication in new window or tab >>Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue
2022 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, article id 909621Article in journal (Refereed) Published
Abstract [en]

Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.

Keywords
FGF21 resistance, beige fat, diet induced obesity, beta klotho, browning, FGF21 sensitivity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-209432 (URN)10.3389/fendo.2022.909621 (DOI)000844074800001 ()36034414 (PubMedID)2-s2.0-85136541127 (Scopus ID)
Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2024-01-17Bibliographically approved
Karlina, R., Lutter, D., Miok, V., Fischer, D., Altun, I., Schöttl, T., . . . Ussar, S. (2021). Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice. Life Science Alliance, 4(1), Article ID e202000924.
Open this publication in new window or tab >>Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice
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2021 (English)In: Life Science Alliance, E-ISSN 2575-1077, Vol. 4, no 1, article id e202000924Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights into brown preadipocyte heterogeneity, we use single-cell RNA sequencing of the BAT stromal vascular fraction of C57/BL6 mice and characterize brown preadipocyte and adipocyte clonal cell lines. Statistical analysis of gene expression profiles from brown preadipocyte and adipocyte clones identify markers distinguishing brown adipocyte subtypes. We confirm the presence of distinct brown adipocyte populations in vivo using the markers EIF5, TCF25, and BIN1. We also demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that BIN1 marks dormant brown adipocytes. The existence of multiple brown adipocyte subtypes suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct functions in thermogenesis and the regulation of whole body energy homeostasis.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-191732 (URN)10.26508/lsa.202000924 (DOI)000614606300014 ()33257475 (PubMedID)
Available from: 2021-03-30 Created: 2021-03-30 Last updated: 2022-02-25Bibliographically approved
Keipert, S. & Ost, M. (2021). Stress-induced FGF21 and GDF15 in obesity and obesity resistance. Trends in endocrinology and metabolism, 32(11), 904-915
Open this publication in new window or tab >>Stress-induced FGF21 and GDF15 in obesity and obesity resistance
2021 (English)In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 32, no 11, p. 904-915Article, review/survey (Refereed) Published
Abstract [en]

Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are established as stress-responsive cytokines that can modulate energy balance by increasing energy expenditure or suppressing food intake, respectively. Despite their pharmacologically induced beneficial effects on obesity and comorbidities, circulating levels of both cytokines are elevated during obesity and related metabolic complications. On the other hand, endocrine crosstalk via FGF21 and GDF15 was also reported to play a crucial role in genetically modified mouse models of mitochondrial perturbations leading to diet-induced obesity (DIO) resistance. This review aims to dissect the complexities of endogenous FGF21 and GDF15 action in obesity versus DIO resistance for the regulation of energy balance in metabolic health and disease.

Keywords
energy balance, mitochondrial integrated stress response, obesity resistance, FGF21, GDF15, muscle, adipose tissue
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-198639 (URN)10.1016/j.tem.2021.08.008 (DOI)000707636500007 ()34526227 (PubMedID)
Available from: 2021-11-13 Created: 2021-11-13 Last updated: 2021-11-15Bibliographically approved
Zhang, Q., Delessa, C. T., Augustin, R., Bakhti, M., Colldén, G., Drucker, D. J., . . . Müller, T. D. (2021). The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metabolism, 33(4), 833-844
Open this publication in new window or tab >>The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling
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2021 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 33, no 4, p. 833-844Article in journal (Refereed) Published
Abstract [en]

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-194271 (URN)10.1016/j.cmet.2021.01.015 (DOI)000637370500017 ()33571454 (PubMedID)
Available from: 2021-06-17 Created: 2021-06-17 Last updated: 2022-02-25Bibliographically approved
Klein Hazebroek, M. & Keipert, S. (2020). Adapting to the Cold: A Role for Endogenous Fibroblast Growth Factor 21 in Thermoregulation?. Frontiers in Endocrinology, 11, Article ID 389.
Open this publication in new window or tab >>Adapting to the Cold: A Role for Endogenous Fibroblast Growth Factor 21 in Thermoregulation?
2020 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, article id 389Article, review/survey (Refereed) Published
Abstract [en]

Fibroblast growth factor 21 (FGF21) is in biomedical focus as a treatment option for metabolic diseases, given that administration improves metabolism in mice and humans. The metabolic effects of exogenous FGF21 administration are well-characterized, but the physiological role of endogenous FGF21 has not been fully understood yet. Despite cold-induced FGF21 expression and increased circulating levels in some studies, which co-occur with brown fat thermogenesis, recent studies in cold-acclimated mice demonstrate the dispensability of FGF21 for maintenance of body temperature, thereby questioning FGF21's role for thermogenesis. Here we discuss the evidence either supporting or opposing the role of endogenous FGF21 for thermogenesis based on the current literature. FGF21, secreted by brown fat or liver, is likely not required for energy homeostasis in the cold, but the nutritional conditions could modulate the interaction between FGF21, energy metabolism, and thermoregulation.

Keywords
cold exposure, brown adipose tissue, beige adipose tissue, uncoupling protein 1, endocrine signaling, low protein diet, energy metabolism
National Category
Endocrinology and Diabetes Biological Sciences
Identifiers
urn:nbn:se:su:diva-184528 (URN)10.3389/fendo.2020.00389 (DOI)000553271800001 ()32714278 (PubMedID)
Available from: 2020-09-09 Created: 2020-09-09 Last updated: 2024-01-17Bibliographically approved
Keipert, S., Lutter, D., Schroeder, B. O., Brandt, D., Ståhlman, M., Schwarzmayr, T., . . . Jastroch, M. (2020). Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. Nature Communications, 11(1), Article ID 624.
Open this publication in new window or tab >>Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
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2020 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 624Article in journal (Refereed) Published
Abstract [en]

Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1), however, UCP1 knock-out mice show resistance to diet-induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21-signaling, inducing the browning of white adipose tissue. Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.

National Category
Microbiology in the medical area Biological Sciences
Identifiers
urn:nbn:se:su:diva-179581 (URN)10.1038/s41467-019-14069-2 (DOI)000513245600012 ()32005798 (PubMedID)
Available from: 2020-03-25 Created: 2020-03-25 Last updated: 2023-03-28Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6618-7379

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